Questions & Answers Session, Friedreich's Ataxia - The Children's Hospital of Philadelphia (4 of 5)

Author: The Children's Hospital of Philadelphia

This afternoon, we're going to start out by doing a clinical, question-and-answer session so that you can, any questions that you have from this morning's clinical presentations or anything else that you'd like to know about the clinical aspects of friedreich's ataxia. Up here with me and i get to be moderator, of course, massimo as well as our genetic counselor karlla brigatti, who was the prime coordinator in the a0001 study which we collected. And in a minute we'll be joined by kim lin our cardiologist from the children's hospital program. So we have microphones at either side. I'll ask you to step up to them and ask away. If not, i'll create some questions for massimo.

Which, he really doesn't want me to do. Questions? we have a wealth of clinical information up here. A few, so let's take an example of what might be asked because people came up to me at the break and asked this question. They mentioned that their child has been taking amantadine for about 20 years as well as rilutek, both those off label. So the question is, "is that a good idea? what's the evidence behind it?" so massimo, in europe do you have anyone taking either of those agents? no. that is, that is a very, so you don't have anyone on it? not my patients. No one that i'm following has been on those. That is, amantadine in particular has been popular, was popular in canada before i went back to europe.

But over there, no, that's really not used now. okay. and on top of that it has also disappeared from commerce in belgium. I was using it for dyskinesias in parkinson's disease which is a different subject for which it was useful but cannot even find it in the pharmacy anymore. oh, that's interesting. Well in the united states, amantadine is a molecule which was really developed i think in the 1960s to keep you from getting the flu, something like that.

It was discovered later it has mild anti-parkinson's activity through an action of a particular glutamate receptor called the n-methyl-d-aspartate receptor. I have to get a commercial in there for myself. In any case, it has been shown in multiple sclerosis to improve fatigue in a double-blind manner.

Questions & Answers Session, Friedreich's Ataxia - The Children's Hospital of Philadelphia (4 of 5)

How it improves fatigue is entirely unknown. Thus in the late 80s, it was actually subjected to a couple of randomized trials on friedreich's ataxia. The first of which suggested a mild benefit, the second of which suggested no benefit. As an available medication, some people elected to take it and some people didn't. It has some very mild side effects. It's not an expensive medicine because it's well-off patent years ago. Does it help people? that's a very good question.

I think some people probably are helped by it based on what i've heard from reports. Individuals studied either by myself or other individuals but certainly not everyone. Probably a minority of individuals, probably very specific symptomatology, either increased muscle tone or fatigue. Should one take it? it's relatively side-effect free so if, but again, it's not particularly efficacious overall. So it's really very much a situation, the potential benefits against the potential side effects, and it's an individual decision. If it's worked, it's good.

If it hasn't worked, it isn't good. It is also thought of in some concepts as a neuroprotective agent and one question which does come up, and that's what it's actually been used for in several of the disorders, in parkinson's disease, it's been suggested that it might be. Being on amantadine for a long time, has been neuroprotective in friedreich's ataxia compared to where a person would have gone.

who knows? once you start down that road, you don't know what the answer is going to be in that individual person. You can only tell it from a large, a relatively large blinded study essentially. So we won't know. We know, i think, that the potential gain is not enough that we, if we have $500,000 to spend on a double-blind clinical trial we're going to use to spend on an amantadine trial since it's a relatively benign agent.

So the answer is one's choice. I have some people on it and i have a lot of people who aren't on it. The second was on rilutek.

Do you have anyone on rilutek? you don't. no, again, i don't have anyone on rilutek but of course, i get a lot of questions from patients with all kinds of ataxia because rilutek, actually riluzole is another drug that also should act on glutamate receptors and that's been used for a disease called amyotrophic lateral sclerosis which is a dreadful disease. This drug used to be, now there are some other things that are coming out, but for a long time it has been the only drug that has given any detectable affect on this disease in double-blind, placebo-controlled trials. A minor affect, unfortunately, because that's a lethal disorder but, some detectable affect. So it's approved for the treatment of als and it's available.

It's, at least in europe, it's kind of expensive. It's not a cheap drug and there has been reports that it gives a symptomatic relief of ataxia in patients with a number of different causes for ataxia. And in particular, there's been a paper published in a very widely read journal of neurology which is called "neurology," by a group in rome and they actually studied i think, for a relatively short time, i think six months if i remember correctly, patients with ataxia that were due to cerebellar diseases.

But you know, including heredity ataxias, there was some fa patients in there. But there were also patients with degenerative ataxia of unknown cause. There were even a few ms patients, multiple sclerosis patients who have ataxia because multiple sclerosis can attack the cerebellum. So and in general their idea was that this drug could have relieved the symptom of attacks.

And if you think about it, that would be a really good thing if it was true because we don't have any really effective drug for ataxia. You know, we are, what you heard today is the treatment of the underlying disease which of course, is the most important thing. But it would be very nice if we had a symptomatic drug.

You know like we have for parkinson's disease. You know in parkinson's disease, we cannot cure the disease. It's uncertain if any of the existing medication can actually slow it down and act on the underlying process, but at least we have very effective treatment to relieve the symptoms for a number of years at least. We don't have that for ataxia so that was the concept. And it was this paper in which they reported that there was some improvement that, in an ataxia rating scale, with this eye cursor that you may have heard about, which is one of those standardized neurological examinations that you have heard about this morning, that was better in those who had taken this drug compared to the control. So the problem is that the group was extremely heterogeneous. Some diseases were only represented among placebo patients and some diseases were even only represented among treated patients in there.

For instance, if i remember correctly, the few ms patients were all in the placebo group, as an example. And the diseases that progressed at quite different speed that, you know, give different types of ataxia in which you have different parts of the nervous system that are affected. So to me, this was very preliminary and needing to be further studied if you think it's worth studying. In europe we tried to contact the company that makes rilutek, you know, they're at least to have the drug for free because it's kind of expensive, in order to do a controlled study on patients with, on a more homogeneous group of patients which actually were focusing first on the dominantly inherited ataxia, spinal cerebellar ataxias like probably type i, ii, and iii, and see whether we could see, at least in this group of patients, any effect, but the thing has been, i mean, in the end, we still haven't been able to organize such a study. And now what i hear is that based on direct observation, there is a lot of skepticism about the possible effect of this drug, but i am not aware of any other published placebo-controlled study after this first one that would go in the opposite sense of just of, you know, small case reports or small series that have been followed without, out of the controlled study. yeah, and i'd agree with that. Again, the difference between amantadine and rilutek in the anecdotal sense is that amantadine is very cheap, you can get insurance to pay for it, you can buy it for almost nothing. Rilutek in the united states, i believe, costs about $10,000 per year is my recollection.

So that if your insurance isn't paying for it, it's a very steep amount of money for something which has very little proven benefit in fa. That said, in that same article, i was least impressed by the friedreich's ataxia patients as compared to everyone else. And as you'll recall from this morning, the anatomy of friedreich's ataxia in the brain is substantially different. So that was the question i had gotten earlier. I'll welcome up here kim lin, our cardiologist from the pediatric cardiology department at chop. So next question from the audience anyone? don't be shy. Andy, down front.

can you say anything about the a0001 follow-up? (inaudible). andy has asked the question, "can you say anything about the a0001 follow-up study?" and since, i'd like to direct that one to karlla. No, i think that's probably not one on karlla's plate. And being sure that, remember that i cannot talk about things which are of a confidential nature, i think we could use some logic that i think most people would suspect that i might have talked to the individuals who own the indication for this that'd be edison pharmaceuticals of mountain view, california. And come to some thoughts about the moving forward and stuff like that. Now the paperwork to go from, to get a trial done is significant. At this point one would have to apply to the fda, one would then have to take, once the fda approves, and sometimes they approve by not saying anything, it is the federal government after all.

So you wait for them to not say anything. Then that protocol would have to go through the institutional review boards of whatever sites are there, each one taking somewhere between three weeks and three months to approve. Once you've done that and every place agrees, you can start the study. That said, i think it would be a fair statement to say that if we have not announced the initiation of a follow-up study in a0001 six months from now so let's say, april 1, 2012.

I've made this offer to several patients. They should take a baseball bat and track down whoever is responsible for this and be sure that you make it aware that we're not doing our job. Our job is to make this move as fast as possible. There's no getting around it. There will be obstacles that we haven't foreseen yet. You'll get to the obstacles you haven't foreseen faster if you just keep working and find them. Your only responsibility is to remind us of what our responsibility is.

You all know my e-mail address. You all know, most of you know karlla's e-mail address. Can i give you massimo's? no. i think a lot of people know it anyway because i receive e-mails all the time. and i'll just hit the forward, correct? so. and i'll forward to you.

it'll bounce back and forth. So i would hope that it is going well before april 1, 2012, but if it is not going then, remind me in detail. that april 1st is no-- no joke. no joke. it looks like linda, his wife, might have a follow-up question. i'm not sure it's been found with words so maybe you can help it but the f, you know the fancy graph they show all the drugs there, the pipeline. yes.

is that just the supply in america or is that international? the question is, "the fara pipeline, okay, which is derived, is that just the united states?" and this is easy because i can ask the people at fara. I think it more or less includes certain things that are in europe, everything that is known about. we try and be international, everything we know about. and the follow on to that is, is it easier, some of the others like in europe, is it easier to get drug trials through or started? no, it's not easier. the question was, "is it easier in europe?" and massimo anticipated the answer.

Being a mind reader. I would agree from my limited interaction on trials which they have attempted to go forward in both the united states and europe and australia, it's not necessarily easier. It's different in some ways. Different regulatory agencies, they have different things they might look for, and some cases will be easier in foreign countries and some people, cases might be easier in the united states. Usually, it's about the same. yes, with the, maybe the slightly added difficulty in europe is that you have to go through two steps. The first you need to have the approval of the european medicine agency, ema, which it's a regulatory agency, a europe-wide regulatory agency that particularly is directly involved in certain categories of drugs including drugs for rare diseases, so-called orphan drugs, and drugs for neurodegenerative conditions. So friedrich's, a drug for friedreich's falls in both categories, and that's why you have to go through ema.

Ema has a number of programs to makes things a little easier, a little to those who apply, particularly for orphan drugs status. But i think, fda has a similar procedure. And ema and fda have even a common application procedure so that you can apply to both sides at the same time which means that in the end the path of least resistance can be by chance here or there. But the problem is that then when you want to move to actually run a trial, you also need approval from the national health authorities. That's another step even if ema has already, and then you have the ethics committees that do that, the equivalent of the irbs so, you know, the step is long and difficult to there as well.

a question over-- yes, kathleen? can we anticipate a clinical trial under epo, the procrit, over here in north america or was it just in europe? the question is, "clinical trials of epo in the united states?" as opposed to the one which is, the two really which have been published from the austrian group in europe. There are no ongoing recruiting trials for epo in the unites states at this time. As you see from the fara pipeline, there are various epo mimetics being developed which might come to trials in the united states. Lundbeck recently was working with a second, a different epo mimetic, carbamylated epo, and they stopped development of that. The reasons are not entirely clear.

We haven't, i haven't talked to them or heard anything more about it. I don't know whether it's on the basis of data or on the basis of other practical aspects to drug development. At lunch we were talking about some practical aspects that had come up in some of the other drugs so we don't really know why. Right now there is no recruiting epo trial in the united states and i don't believe there's really one recruiting in europe right now. Is that correct, massimo? to my knowledge, so epo is actually, is an austrian idea, the fact of using epo in fa.

And so this, the group particularly of sylvia boesch in innsbruck has done some also preliminary clinical work on epo and then another group in naples, in italy has also done some work on epo. The problem is that we have no idea of how to translate this findings in culture cells. Basically the observation was that they made frataxin levels increase in some culture cells in terms of patients. How much we have to give, how often we have to give, what kind of doses needed to be used? and so the first studies that have been going on and published are just about this concept of dose findings, see what happens, and the, now the current notion is that probably low doses of epo may be of interest and that increases in frataxin levels are sort of delayed. And when i say delayed, a delay of several weeks after a single injection of epo. There is a paper from the naples group. In that sense, we don't know yet whether there is any clinical impact and we don't know how that can be translated into a potential treatment.

So there are studies that i think, are still in the planning stage but not yet going on. But there are essentially these groups and i think also in milan, in milan, italy they are planning to go ahead with some epo studies. next question back there, mary lisa.

yeah, my son has both very violent like spasms like, you know, hit the bottom of the table, and stiffness in his legs where, you know, you go to put him in the car and you almost can't get his knees bent to get him in. With diazepam to stop that sort of spasm, he's got to take so much he's practically knocked out. He's now got a prescription for medical marijuana and that has done wonders both for his mood and his spasms. In fact, i'm ready to put it in his food.

remembering this is all being taped for the internet. [laughter] it is legal in arizona. But i just wanted to know had any studies been done on it because i mean, i've seen a huge difference. massimo is pointing at me. The answer is to my knowledge, there's no systematic study of marijuana or its derivatives in spasticity, dystonia or any other increased-tone scenario. That said, i mean typically, for example, i don't use a lot of valium for that situation it's usually baclofen and tinzanidine, amantadine and then valium after that, diazepam is valium. So that i wouldn't have necessarily have gone that order anyway. In other disorders, i am familiar with anecdotal reports of patients who might say that they have identified the same phenomenology.

I don't know whether that's, and i, and one thing that you will know about any form of excess tone in the nervous system is that your emotional state will contribute to that positive, to break that positive feedback which gives rise to the dystonic spasm or spasticity. So it is even possible that effective noted, and i did not say it was or wasn't, might be an effect primarily on mood and breaking it. So it's open to possibilities as such novel therapies are advanced, not only here but in belgium as well.

So i'm going to ask kim lin a question here. We see a lot of people from around the country come to see us and that's really easy. We see people once a year. You can find us by phone. There are very few neurologic emergencies and i stressed this morning how worthless neurologists are. So it's easy for us to follow people. As a cardiologist, you see some of the people who come to see us.

How comfortable do you see given the cardiac urgencies, may arise, with people only coming to see you versus having a local cardiologist 500 miles away from the children's hospital of philadelphia? thanks for having me here. I would say at this point, there's so much that's not known about the hypertrophic cardiomyopathy in friedreich's ataxia so my gestalt of the cardiomyopathy in children is really based upon very little actual experience and then reading what little is out there. At this point, i would be most comfortable with someone say, seeing me if possible on a once a year basis and having a local person in between. So every six months to me seems to make the most sense and that's an evolving process. Does that answer your question? i think that answers my question. I think it's a good perspective because urgencies can arise in the heart which do not normally arise in friedreich's ataxia from the nervous system thus having somewhere where you can be seen right away is quite an important phenomenon. and i guess the second part to that is, what's the local person's job and what would be the cardiomyopathy specialist person's job? i mean, it would be my job to pass along as much as we know or don't know about hypertrophic cardiomyopathy in friedreich's ataxia in general and in particular with respect to each individual person.

Passing along that information so that the local cardiologist can sort of integrate that into, "okay, so this means fluid may be better tolerated, less well tolerated." being dehydrated may be less well tolerated in particular to that patient so that they can translate that into, "how do i handle an urgent sort of situation?" and how's that handled in belgium, massimo? do you have local cardiologists or do you have centralized individuals? i prefer to send my, you know belgium is a small country and people don't like to travel very long distances. So and also in belgium we have this kind of an integrated centers for neuromuscular diseases that usually include a, that must include a cardiologist actually to be funded. So i have sort of educated some and motivated some of our cardiologists to follow friedreich's patients and they got interested in it in fact, and i refer my patient to them. okay. Next question from the audience? okay, yes, pam. yeah, i wanted to follow-up with the a0001.

Will it be at multiple sites and will the criteria be the same as before because the end point shouldn't be the same because of diabetes, right? right. The question is, in the phase ii study, the end point was diabetes, an insulin-resistant measure slash diabetes measure. It was not successful and was found to be noisy. Until we act, i'll be honest, until we find ways to refine the noise, it shouldn't be used end point in any study much less the next follow-up a0001. It is also a labor-intensive protocol so i would think it a safe bet, that one would not be seeing that again without disclosing everything confidential. So a couple things on the follow-up study, there are no inclusion/exclusion criteria decided. It's being thought about obviously because it's probably going through my brain at this very moment, and it's probably even being refined and maybe, you know, it's being refined a little bit more. As drugs move farther forward and you get more data, you're able to refine your target population and your end points better and better.

Thus it is not necessarily typical, notice the double negative essentially. It is not necessarily typical that a pivotal or phase iii trial will use the same end points or exactly the same population. You hope that you've learned from your experience rather than just regurgitating your experience. That's a pretty good analogy, i like it. So i have said absolutely nothing other than to say, we'll see the way things turn out.

The things which can be said for sure, the safety data on a0001 is in adults. Thus the next step will be to increment lower. One might expect that one might try to go a couple years younger than age 18.

It would be logical because there is no safety data at this moment in five-year-olds that we would be including five-year-olds. Somewhere between the age of 18 and 5, that would be a reasonable scenario on that particular study, but also you have to think on the top end. Remember, as i age my blood pressure goes up and up and i become more and more susceptible to all sorts of medical complications.

You would not really want me taking in a0001 and having something bad happen because my heart's going in general and have it be attributed to drug. So you have to understand if your risk adverse, you have to think about the coincidental disorders i get as i age. The rest of you don't get them, but just me. So think about those possibilities. So it is an important question. All we can do is go into the rooms and decide what is fair. Karlla, i'll let you amplify on that answer.

i just wanted to say that when those inclusion and exclusion criteria are identified and we've gotten the trial rolling where we're open, we're thinking about how we're going to recruit our subjects, we put together a sort of a basic this is what we're looking for, if you have these criteria, then contact us and we can discuss your participation in the trial, sort of a general patient instructions. Those go out on the fara registry as a mass e-mail and we send one as well. I mean, we get contacted all the time from individuals with friedreich's ataxia and their families interested in participating. With the phase ii study when we opened, when we made that announcement that we were enrolling patients, we received our first phone call within the first minute and of a mother with children who are, or adult children interested in this study and just want to say, we love that enthusiasm that within a couple days we had like 50 people who were on the list and very interested in participating.

If it is an adult study or if it's a study limited to adults, then it is that adult who needs to call and not, you know, mom or dad or an interested friend or something like that. yeah. Yeah. Mom and dad can't call. It has to be the person.

Other questions from the audience here? yes. You had had your hand up for a while. my question is,on the fara trial, only because i can actually buy it here in the u. S., i am wondering if, well i have a cluster of questions, i'm wondering if it's actually got some profound information? if it's actually helping patients in australia, what information do you know about it?" because i was researching and i did take it for a while and nothing happened, a while would be six weeks. And perhaps i didn't take enough or i just didn't know what i'm taking. so the question is, on resveratrol, which is right now in a double-blind study in melbourne. It's open label.

Is it placebo-controlled or not? i forget. it's open label. it's open label. I do know that there's a ds and b and they are recruiting patients i know because i have to go to a phone call about some time. So they are recruiting patients? they don't know the data.

they're in the process. they're in the process of accumulating it right now. So they'll go forward. They'll judge it at the end. I don't know the exact dose they're giving. That's one of the reasons why we frequently, what reassures us that an effect is real is a dose response.

And as you go up, the effect you see gets more and more until you reach a maximum. Obviously you can't do 15 different doses. there are two different doses. okay. 1,000 milligrams and 5,000 milligrams.

okay. So in thinking about that, relating your own experience, the questions would be several. "did you take the same doses?" so when this paper eventually comes out, you would compare the amount of time that you took it for as compared to the amount of time they were taking it for, by how they measured what they were judging improvement basis, compared to the way you might have judged improvement. You also have to look at the preparation because from what i understand about resveratrol, different preparations are very different. Now i know there's some in fine french wine.

I'm told that you have to take a lot of it actually, to get enough to reach what they're giving in the trial, like many, many bottles. So as you eventually read their trial and interpret what you did and whether you just didn't take enough or take it long enough, those are the things you'll think about. I don't think there's any systematic data right now, but eventually, every trial which is done in an appropriate manner should be submitted for publication and a scientific review would come out. It is very important to publish negative data as well so that you can understand the limitations of the experiment.

yeah, maybe just to add a couple of things. Resveratrol is, so when we think about any possible new treatment, of course, you know, there are different ways of thinking about a possible new treatments in the past that was just empirical. One stumbled into something and you know, there was no rational between, behind testing the treatment, tradition, serendipity, whatever.

If we wanted to use a rationality in proposing a treatment, of course that has to be based on some biological data that we know. As we discussed this morning, we know something about, you know, disease process and we identify possible targets. This doesn't mean that something has, will be effective, of course. So the fact that resveratrol, one may imagine, may be, have anti-oxidant and may be promoted at, you know, increased mitochondrial biogenesis. We were talking about that this morning, those may be beneficial effects but we don't know. But this kind of reasoning is just at the basis for doing the experiment of testing.

And the experiment of testing requires that we have an intellectual position and that we call it equipoise, which means we really don't know what the results is going to be. We consider that a good result or a better result can be both expected and we just want to do the experiment and see what the results are going to be. So we have the rational to do it, but we don't know the answer.

We will see, we will see. If it's well-conducted, we can get some important information. In terms of the number of bottles of wine, i'm afraid it's around 800 which even i, on a good day, cannot make. i'd actually heard a thousand so you, where do you get your resveratrol wine? you got 10 percent more in your stuff. I would have to amplify one other thing as we think about things, not everyone will respond the same. That is part of the biological variability among all of us. So that's why individual responses are good for developing hypotheses on things which might be useful, but you have to look at a larger population to know that they are more generally useful.

Question back there. i had a follow up from the diabetes presentation. Is there anything that the rf part, fa patients can be doing now to help delay the onset and is there, what challenges does the diabetes present to the friedreich's patient that a person dealing only with diabetes doesn't face? a question about diabetes and friedreich's ataxia. You can start first and then i'll amplify if you want.

what was exactly the-- the question was first, is there anything one can do to delay the onset if it does occur? so we have actually carried out a rather detailed study on diabetes and friedreich's ataxia in brussels that was mainly the work of myriam crump. And one of the things that we noticed is that the same factors that can trigger or accelerate the type ii diabetes, the adult type of diabetes, can do the same for diabetes in friedreich's ataxia. It was, individuals with friedreich's ataxia tended to be a little lighter than controlled individuals but unfortunately, their body composition is, but they have a little more fat in their body composition and that is clearly a risk factor for developing type ii diabetes. So i think that what someone with fa should do in terms of reduce the risk of developing diabetes is what everyone should do, try not to get fat, and i shouldn't say that because i'm not a good example. Try to do-- it's the 800 bottles of wine a night. i think we shouldn't say that because we aren't good examples.

But anyway. The ladies are okay. [laughter] but and so reduce the intake not much of sugars but of fatty foods, and be as physically active as possible. I think that these are things that can be done and can actually have an impact on diabetes in fa. and the second part of your question, john? does it present any different challenges in the fa patient than in a normal diabetes patient? does it present any different challenges? well i think it does for a couple reasons. A person that i know of that theresa zesiewicz has been following, actually developed much worse cardiomyopathy when they presented with diabetes.

That's the example of any metabolic disorder, be it thyroid disease, diabetes, will make your other disorders worse. With treatment of the diabetes, their cardiac condition returned to where it was but there's some, in reviewing that individual, very tough moments. So it is important that you control what your diabetes so that simply your cardiomyopathy or even your neurologic's function doesn't get worse. You can develop a neuropathy from diabetes which simply go on top of the features of fa so that you really have two different neurologic diseases. In addition, if you follow sue beromen's studies on cardiac mri from ohio state, one of the risk factors for having a more abnormal cardiac mri based on profusion scanning was actually your, whether you had metabolic syndrome, in particular your insulin resistance. So those people who have elevated insulin resistance in her studies, are more likely to have more abnormal cardiac mris. So it is a multi-system disorder as we mentioned this morning, where it is all interacting all the time.

hello, my one question was about resveratrol so we did have that answered. And then my second question was about ginkgo, which you will probably end up telling us the same thing you told us about resveratrol, maybe not. And then i wanted to know if you had any thoughts about coq10 versus ubiquinol, which is supposed to be the souped-up version of coq10, the better version of coq10. okay. So the questions are about ginkgo, which i don?t know of any specific evidence in fa either way. I don't know of anyone who's done their own individual trial of it. And then the question about ubiquinol versus generic, i'll call it generic coenzyme q10. Your thoughts, massimo? well the concept that coq10 is, the nature of product but has some limitations in terms, both in terms of functioning as a drug in terms of being effectively absorbed, and getting to the brain, and then getting into the cells and then to mitochondria which is a little more difficult, but there are other properties of this molecules that are related at their side chains, the way that they, to their structure.

I don't, i think one can work on this properties, but the newer molecules seems to be from this point of view, behaving better than the natural product so their immediate derivatives in terms of absorption and distribution, penetration into the cells and possibly even mechanism of action. So i don't know exactly the difference between, if, i don't know, i'm not aware of anyone that has looked at the difference on a clinical level between these drugs. But i'm afraid that the newer molecules are going to be more, i'm afraid, i hope that the newer molecules are going to be more satisfactory and probably take the place of this, of the natural products.

That's all i can say thus far. Yeah, i mean the major reason the ubiquinol has been proposed to be better is that it's a different form which might be absorbed better. Both of them pale in comparison to a0001 or epi-743 on absorption. It's as simple as that. Because you're talking about things in which single-digit percents eventually enter your body as what you want them to be versus roughly 100 percent.

So that's the big difference. Question in back from, it looks like jean. yeah.

I guess this is a practical question for me, do you guys have any suggestions for how to be your own advocate with their local physician to talk to you guys without stepping on their, like, don't get in the way where they still like you, basically? so massimo and i have been doing all the talking. We?ll let karlla and kim handle this one. How do you interact with your local, suggest they interact with their local physician? karlla can go first on this. i think it all varies.

Obviously it's really important to have a good relationship with your primary care physician for all the other non-fa related things that crop up in life. And speaking for the fa group at chop, we're certainly very encouraging of any communication with any of us, including Dr. Lynch regularly gives out his e-mail address and phone numbers and is always speaking with them, with those providers. I think in some senses, there may be some hesitance on their part that they don?t want to seem like that maybe they don't know enough about the disease, or they can't handle their patient.

And i think we're really just here to support or to help them with any of those questions that they might have specific to fa or fa management. correct me if i'm wrong, but what i'm hearing from you is that there may be, the hesitation or the resistance on the side of the primary care physician. I mean, from a, at least from a pediatric practitioner standpoint, they love it when we reach out to them. And so i think us communicating to them our openness and willingness to talk and our open admission of the fact that there's a lot we still don't know, but this is what we do know.

I mean, in our program we have, you know, a staff of nurse practitioners, and an administrative coordinator who's available very easily. We have a direct line to her. And she can get in touch with any of us who see the fa patients, but you know, i actually lay that back a little bit.

In one sense, the practitioners to make that know to your primary doctors to make sure that our letters are getting out to them and maybe a phone call once in a while, "hey, you know, whenever you have a chance, we'd be happy to talk about x, y and z with you. And if not, here's the, you know, you'll see a letter in a week." so from my perspective, sometimes we need to reach out more to them. But i don't know how much i can help you when they're not wanting to hear it.

But it may just be us starting that conversation and saying, "hey there are a lot of things that aren't known about this, but these things are and let me make sure that we convey that to you and give you the tools you need 500 miles away to help take care of this patient." i would make one comment which is, it's a lot easier to reach out to them if they're willing to use e-mail as a mode of communication because the phone tag which occurs when you try and call them and they try and call you back becomes burdensome on both ends. Where i've heard primary care practitioners, if you don't reach them the first time not want to call back. You get one shot. Other questions? yes, over here. is there like anywhere where we can like, i mean say if it's the middle of the night or something like that, when it's an emergency and (unintelligible) but, where you want to have your doctor, you know, go to a website or somewhere, get more information? because i know i've talked to some parents and they've actually had instance where they've gone to a hospital and you know, the nurses themselves are googling because they don't even know what it is. We've even experienced some of our doctors where our son is the first person they've ever seen or met with fa. So is there anywhere that we can even guide them, that, you know, "if you don't know or you have more questions or you need more information, can you please look at this website or go to this location or number or something like that?" and i think you're giving a great suggestion and i don't personally have that resource in place yet.

I mean, our resource is always, we have an on-call person 24/7. And so they just call in, you know, it's a patient of ours at chop, the children's hospital of philadelphia, they call into the operator and ask for the cardiomyopathy specialist on call, but that type of a set up, also is, i don't know. Does fara have anything like that set up yet? we do have some resources on the website specific for cardiac issues and Dr.

Payne. like chop. We do have some resources on the website that mary-lisa and Dr. Mark payne have gathered, like for cardiac issues. And some of the cardiologists and some of the physicians do make themselves available basically 24/7 as much as you can be 24/7. I know Dr.

Payne will if we can get in touch with him, is basically available and has made himself available for that kind of an instance. So we try and work through fara and through the fa parent's group and when there's an emergency that comes up, there is actually a phone chain. And so if a parent posts something on fapg for example that says, "my child's in the er and we're having these problems." there is a phone chain between paul konanz and mary-lisa and a few other people that get people put in contact and they will contact the local er to help provide information. yeah. The one other thing i would emphasize, have your copy of your most recent ekg whenever you go to the doctor. And i would also add, have a, if you know us and have had a troponin level checked. Because we are finding that many fa patients are on elevated troponins all the time which, if i break over here right now, a troponin is an index that i'm having a heart attack. It's not in fa patients, it's just an artifact essentially, but people run them high.

We have seen people sent to cath labs based on the abnormal ekg and the troponin level. So have those checked, carry them with you so that you can show the er physician that that ekg is unchanged, and that the troponin level which they're finding is high, was high last time. It was checked in an asymptomatic state.

you can even, if you carry a smartphone, which more and more people are doing, you can even take a picture of the ekg and then not have to actually carry it with you. yeah, and there's an, jim is saying there's an app for this as well. I have trouble with any of the touch phones, you know. I can't do any of this so.

Question over here. i have a question about hypertrophic cardiomyopathy. We're new to the fa community and we just found out that my son has this condition as well as hypertension and tachycardia. And i'm wondering which tests should be done that would be, that would constitute a thorough work-up of this condition, and how it's generally treated, and what, and what and if there is any medications to slow the hypertrophy of the heart? sue, there's a fair amount known about hypertrophic cardiomyopathy in general, but as it relates to friedreich's ataxia and how a friedreich's ataxia patient may be the same or different from the rest of those with hypertrophic cardiomyopathy, we're just only starting to understand better.

In general with anybody who has hypertrophic cardiomyopathy, the two main important points of intervention would be one for treatment of, or prevention of heart failure. So if the hypertrophy is getting to be the point where it's obstructing flow out of the heart, and, or the heart is getting, for lack of a better term, getting tired of pushing against that obstruction and starts to dilate and starts to function less well, then medications need to be considered, or interventions even need to be considered for prevention or slowing the progression of that. The other main area of treatment or intervention would be to assess for the risk of arrhythmia and sudden death from arrhythmia. So heart rhythm abnormalities, which may or may not be related at all to how thick the heart is. And in terms of an intervention for that, the really--once somebody meets a certain threshold, meaning they've shown that they're at a significantly increased risk of having a heart rhythm problem, then we generally would look to whether placement of an internal defibrillator to shock a patient's heart if they go into a bad rhythm is indicated. Now the degree of risk of those rhythm abnormalities in a friedreich's ataxia hypertrophic cardiomyopathy as compared to the at least tenfold higher number of patients with run-of-the-mill hypertrophic cardiomyopathy, we don't know.

And i would say at least in children, i can't speak yet to the adult population, we're not running to put in internal defibrillators and go to that extreme because we, at least anecdotally, at our center haven't seen those life-threatening heart rhythm problems crop up early. and that's correct. Kim makes a very good point.

Most of what we know about the heart is based on analogies slash extrapolations from autosomal dominant hypertrophic cardiomyopathy which is a disease where the heart gets much thicker. So you might have far less same type of substrate but in the end, the risk of those arrhythmias and certainly the risk of outflow tract obstruction is substantially lower. The risk instead which may occur will be long term and more equivalent to diastolic dysfunction and tight maintenance of fluid balance which come up in urgencies. That's something which we talked earlier, you're new to the community. I think we should talk in a few minutes and let you get introduced to some of the resources we have for parents which could be used under those sorts of situations. And we're going to take one last question over here. there's been talk this last week about xo, a new drug or ?" ox1, okay.

yeah, ox1. yes, one new drug, new from the past week, ox1. It's an indole-based chemical compound which was originally being developed for alzheimer's disease by intellect neurosciences. It's a potent antioxidant.

It works in a variety of models including animal models of oxidant damage, mainly based on ischemia. Instead the target became friedreich's ataxia perhaps because of the relative, i'd like to think because we've done so much to make it easy for people to bring drugs to our community, and the model of fa is a prototypic mitochondrial disease. After several months of talking to experts in the area, viropharma is now licensing the agent from intellect neurosciences and i think, they have no specific timetable but i think they'd like to move forward expeditiously. And i think it's one we can be optimistic about. As rob said, the more shots on goal, the more likely one will go in, or more likely two will go in, or four.

So with that joke, i will thank our panel up here today.

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