Januari 13, 2017
>> i get the privilegeof starting today with some basic information. as most of you all know,friedreich's ataxia is a rare genetic progressivedegenerative disease of children, adolescentsand adults. it affects about one out of every 50,000 people but it has affected in someway -- not necessarily directly -- all of us within this room. typically, we think aboutfriedreich's ataxia
as a neurodegenerativedisease. that's what youread in the textbooks. but really, as you allknow, it's a multiple- system disorder. the neurologic dysfunctionis simply the common denominator, perhapsthe most visible sign. rob wilson and massimo pandolfo will be talking a lot about the pathophysiologybut in order to talk about a couple ofthings, which i'm going
to mention in a minute, i have to remind people the genetic abnormality is an expansion of an naturallyoccurring gaa repeat in the intron which leadsto deficiency of frataxin, difficulty with mitochondriaand cellular dysfunction. those things lead toneurologic dysfunction as well as all the otherclinical features of the disorder. so that's the amountof background i'm going
to give in orderto give my talk. so the other thingswhich i'll mention are, since we don't havea cardiologist specifically speaking about the heartand friedreich's ataxia today, though our cardiologist fromthe children's hospital clinic, kim lin, will be here with usfor the question-and-answer session on clinicalmatters just after lunch. i'll remind peoplethe heart is affected in friedreich's ataxiaboth with cardiomyopathy,
what we call degeneratingor abnormal heart essentially, as well as giving riseto funny heart rhythms. the word we usebeing arrhythmia. remember that asphysicians and scientists, we like to make up lots ofwords for the simple purpose of confusing you. it's a talent theyteach us in school. in most individuals,the cardiomyopathy is of a hypertrophic naturewhere the heart grows in size,
the muscle becomesthick, 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 evenstudied recently. people do have ekgabnormalities which don't necessarily mean anythingbut will look like a person's having a heart attackwhen they go to the emergency room eventhough they're not and, but people can have thefunny heart rhythms called
arrhythmias whichcan lead to difficulties. our second speaker stevewilli will talk a lot about insulin resistance indiabetes and the results of studies we've done recently. and then as many peopleknow curvature of the spine, scoliosis, is present andcan affect, require surgery in about 50 percentof people in some studies. so that's our background. that's what i think, mostpeople knew before they
came today fromthe textbooks. i get the task of talkingabout neurological issues. now while we talk aboutcardiac disease as the cause of mortality, the long-termdisability is mainly caused by the neurologicaldysfunction. you can go to any neurologytextbook or wikipedia or whatever, and youcan probably read about the classical form of it. well, we want to rethinkthings a little bit here
because withthe past 10 years, we've entereda different era, an era where we havenew potential treatments and our job is to try and treatthings to make them better. so we have to sort of thinkabout [this]in a very different perspective and think aboutwhat our goals might be. normally we use neurologicfunction to diagnose, but now thisis a different era. we want to thinkabout treating it,
treatment and greaterunderstanding so that we can move forward. so i'm going to reviewa little bit about the neurology and nervoussystem of all of this and then we're going toconsider some new questions. so i'll start atthe beginning. most of you know that wetalk about the brain and your nervous system asa computer and this computer is composed of two typesof processes, let's say:
a cell body, youmight say the chip, and then a longwire called the axon. and these are connectedtogether to give rise to the computerwhich is your brain. and of course i've diagrammedit as two neurons here. your brain has about10 million neurons so it's a bit more complex that i canever draw without making an absolute mess of everything. but this is the prototypeof what we talk about.
so what, if you read atextbook, what do you see? what you see in a textbookis that what happens in friedreich's ataxia isa slowly, progressive loss of the large sensory neurons,particularly the ones which are concerned with whatwe call proprioception, where your limbsand body is in space. that is, the signal is notgetting to your brain where your hands are orwhere your feet are. now that's a crucialcomponent of balance.
in addition, there'sa loss of a long pathway, a wire, which we callthe spinocerebellar tract. now again we like to make upwords but i'm going to make a bet that most peoplefigured out that this is the tract which goesfrom your spinal cord to your cerebellum. and actually where thecerebellum is where it makes that comparison between whatyou want to do and what your limbs tell you you are doingso that's a particularly
important tract, albeit,i'll show you in a minute, it is impressively small. there's also to a moremodest degree, loss of the motor tractswhich start in your brain and go down to your spinalcord to tell you to move, giving the rise to some lossof motor control but less weakness than we seein terms of balance. there's also a very smallarea within the brain called the dentate nucleusof the cerebellum.
dentate, it looks like atooth on sections i think that's why theynamed it that way. so it's lost in fa but tendsto be lost somewhat later and then a fewother sights, you know? it's not like the brainis entirely abnormal. that's important. the cortex of the cerebellumas well as the cerebral cortex, that areawhich we all use to think, to speak, to do thethings which make us us,
for lack of a better phrase,is largely intact. if you were toadd this all up, it's probably maybe twopercent of the neurons in the brain, some smallnumber of like that, and maybe 10 percentof the long wires. now, that's not that much. that's important becausewhen we talk about the therapies we'regoing 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 thereand 90% of the tracts and anything else. so the potential forrecovery is there once we figure out how to slow orstop disease progression. so one step at a time, but weknow that potential is there. so what does this mean? the loss of the largesensory neuron gives rise
to a loss of balance becauseyou don't know where your limbs are. for those people whoare electrical engineers, the cerebellum canbe thought of about as a differential amplifierand where you compare the movement you wantto make with the movement you are making. essentially, if you don't havethe information coming in on what you're doing,you're going to lose
your balance. that same thing is codedin those very small, spinocerebellar tracts. once you get intothe cerebellum, that back portionof the brain itself, which i'll showyou in a minute, there you havesome other issues, speech difficulty, some eyemovement abnormalities and probably some otherfeatures later on.
and then a veryfew other sites. a few people know that visionand hearing could be affected particularly later. those are those few othersites which we mentioned. but remember, people'scognition as you would know from me, is largely spared. you know that because you'reholding your jobs well, you're doing all the thingsyou did 15 years ago but just superimposedwith a motor burden on top.
so this is -- i haveto show a picture -- this is a picture of a spinalcord, obviously at autopsy. the one on the leftis out of a textbook. it's quite normal exceptit's been colored yellow and green, you know? most of our spinal cordsaren't yellow and green. the one on the righthas friedreich's ataxia. this area right here,the blue area, is normal. over here, the blackarea is normal.
this area here the cellbody is, that's normal. what actually happensin friedreich's ataxia is the cells, the cells thatare lost, are these right here which sit rightoutside the spinal cord, called the dorsal rootganglia, where the sensory neurons are, particularlythe large ones which are concernedwith where your limbs are in space. the others tendto be more spared.
they send a branch, a wire,into the spinal cord such that, into thisarea right here. what you see goes away overtime in friedreich's ataxia. the only other thingsthat you see which might be missing here is, there isa little bit of the motor tract loss right therewhich carry the deep, the fibers going downto control muscle and this little "ditzel",as i like to call it, right there which isthe spinocerebellar tract.
it's a very smallpathway but it's crucially important to clinicalmanifestations. so this is what thespinal cord might look like. this gives rise to that lossof sensory information and that sense of balance. so, and we look at theanatomy and what's really going on, the things whichare going on are just these two small things hereat the spinal cord level. not a whole lot.
think about, that'sthe most affected area in the central nervous systemin fa and still it's not everything that'saffected there. the other place -- did i? -- there we are. this is a section througha brain which we've cut down the middle. we call it sagittalfor those who are -- and if you look at it here -- where's my pointer? --
this is the cerebral cortex. it's all the areathat you think with; that you speak with;that you see with, after the eyes;that you hear with, after the ears. that's a fiberpathway there. this is the cerebellum whichis concerned with balance back here. and if you were to go justpast the midline and make
a little dot about the sizeof a half of a small marble, you would find the nucleuscalled the dentate nucleus. that would go away over timein friedreich's ataxia but basically the rest ofthe brain at first glance, and as we look at itclassically, 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 isperhaps the loss of speech and the speech dysarthriaas well as some of the true
cerebellar componentsof the disease. so if you really wantto understand this, we need to look at thesimplified wiring diagram of the cerebellum. here we are. we'll be having a test on thisin just a very few minutes. massimo and i willbe passing it out. we'll see how the peopleat the first table do. so no you don't need toknow it in this much detail.
in fact, do we need toknow it in that much detail? that's an interestingquestion but we can look at this very simply. think about this infriedreich's ataxia as opposed to the otherataxias you may meet people with in support group. you lose the input comingfrom your joint receptors where your limbs are inspace so you have difficulty making thatactual comparison.
you also lose some ofthe dentate nucleus down at the bottom so you losepart of the outflow, particularly later. but, it'sa relatively simple scenario. what does this mean to you? when we see peoplewith friedreich's ataxia, a lot of it is going to bedependent on knowing where your limbs are in spaceand if you don't have those joint receptors, you don'thave that sensation, you're going to useyour eyes to do so.
as you know as well as i do,the balance difficulty will be very dependenton visual input. yes, there are otherfeatures, but that's something that you canremember in everyday life to help you walk better,is simply to use your eyes and use your brain. your brain's intact, it canhelp you out a whole lot. i wish i knew peoplewho remembered that. so the neural anatomyis actually very simple,
you can readthis in a textbook. why do we think about it? well our job now is notsimply to recite this, as we can do quite well, but wewant to try and figure out how to make people betterand really improve them with a new generation ofdrugs which we'll talk about in a few minutes. well i think it's commonsense but often forgotten that if you want tomake someone better,
you have to prove it. and how do you prove it? well you have to beable to measure it. how do we do that? so let me see, probablyabout half the people here have come to see eithermyself or dr. pandolfo or one of the otherneurologists and you'll see us go through anexam with you. and you'll notice that i'llcall out some numbers to
sean or carla or lauren,sometimes i'll even flash them behind my back likea catcher making signals. you know, we, that'sa faster way although i shouldn't bring a baseball infront of such (unintelligible). what are we doing? we're doing a verystandardized neurological exam where we're lookingat very specific things and how far a person shakesin a certain amount. how accurately theytouch the top target.
how long theycan stand for us. where they canbring out reflexes. how long theyfeel a tuning fork. so that we can quantifyour neurological exam. does that seem like a goodway to measure the disease? i don't know. it's what we do, it's whatneurologists do but many people know that neurologistsare basically useless. i'm a neurologist,i can say that.
so is thatreally a good thing? and that'sactually an issue. we call this exam thefriedreich's ataxia rating scale or the fars forshort because it takes a lot, entirely too much timeto say friedreich's ataxia rating scale. we call it the fars for shortand we've done studies that validate that we canmake neurologists pretty similar if we really instructthem, but there are issues
with this. i think as youall well know, not every neurologist, no matterhow much training you do, is going to be the same. that's just whatwe'll call human nature. if susan perlmanand i and massimo rate the same patient, or thesame series of patient, i bet we have the samerank order of it in what the numbers are, but the numbersno matter how much training
we do may not beexactly the same. what does that give rise to? variability. and when you'retrying to rate how someone is doing and make them better,variability is your enemy. you want things asuniform as possible. so if we were to clonemassimo and pass him out to seven different sites, itwould 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 aboutdoing these things, besides the fact that it'ssemi-subjective, will never bequite the same. you can give me anhonest opinion here. when we dothese tests on you, do you think this hasany bearing on your day-to-day life? "no" is a perfectlyacceptable answer. and that's a very good point.
our goal is not to makeneurologic exams better, it's to make people better. and while we may use theneurologic exam as a measure of that, our goal is reallyto make an individual with friedreich's ataxia better. so there's certain aspectswhich may not be relevant. it's important for youto ask us but it's also important for another matter. this is what the fdaasks us.
they'll take these examscales but really they would like us to prove that it meanssomething in people's lives. to a certain extent, that'swhy we ask all those other questions about your lifeand how you're doing all these different thingsso that we can correlate it. but the fda would reallylike us to really prove that people were better ina way which is relevant to their life. and the final thing is,all these things give rise
to what i'll calla lack of sensitivity. ideally, you'd like to beable to do a study with the minimum number ofpatients which you need. why? i think everyone would giveme that's it's a lot more expensive to do a studywith 100 patients than it is with 50 patients in termsof effort, money, time, travel, things like that. if you could have themost reliable measures,
you'd be able to dothe studies with fewer and fewer individuals. or in other ways, as thedrugs get better and better, you'd be able to show add-oneffects of one drug on top of the other withsmaller numbers of people. that's why we keep doingthese things every year when you come back to see usand visit us and that's why we'll be seeing 20 peoplebetween yesterday, thursday and monday,to help evaluate that.
this is how we learn, howwe make better measures. it's important to youbecause when you come for clinical trials and noticei use the word "when". this is what we'll be doingand this is what we'll be doing to measurethese things so that you understand exactlywhy we're doing things. is there another waythat gets around this exam-based problem? well maybe we should justhave people do some tasks
or torture as wesometimes call it. we call theseperformance tests. timed measures where youget rid of the neurologist, always a worthwhilething in most people's mind. no neurologistto be subjective. you just see how fast peopleput things in a pegboard, how fast they walk, whetherthey can read a vision chart, how fast they can speaka certain set of words. some people can speaka little faster than others
and it has nothingto do with disease. these are ways we can timeand no one's going to argue about [results]. we set up the ruleson how we time them, you know, there'sno interpretation, they're objective. they're relativeto lives because, you know, people careabout how fast they walk, people care about whetherthey can do fine finger movements, though, notnecessarily putting pegs
in a pegboard. maybe we should have likea typing test but i'd lose that one so badly. people care about whetherthey can read and whether they can speak. there are very real, in factthe 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 walkisn't useful in people who are having sufficientdifficulty walking where they don't walk well. the pegboards are onlyused with certain points. the vision is a laterstage feature of fa. if we combine thesetogether statistically, we can make a compositewhich works over the disease but this is somewhat a newconcept that is only now
being accepted. so that's oneissue with these nice, highly-quantifiable,timed measures. in addition, supposeyou break your hand. that is going to affecthow you do a pegboard even though i might beable to account for that in a neurologic exam. so there's some confoundersthere and certain random events might be going on.
suppose you trip whileyou're doing the walk and you fall. that's really just somethingthat happens every once in a while but we don't reallyhave a good way to account for that so randomevents can intervene. so which one dowe want to use? the answer is, each studythat you do neurologically is a different experiment. and i want to come back tothe fact that every time we
do a clinical research study,whether it's a natural history study, or a drugstudy, or a blood study, it is an experiment. you want to use the onewhich is best for that particular experiment. wow, they sent me toschool to think about that. oh my gosh, what a wasteof society's money. so, in fact, that's why yousee us doing all these, even within the same eventand you want to be sure
that they at leastall go in parallel, even if within a given studywe 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 wethink about the neurology and we do timed exams andperformance measures which work on, look at thoseneuroanatomical components i said before. so now, i am going to goforward and talk about
the three trials, actually fourtrials we have participated in here for neurologic function. and in the question-and-answer session later you're perfectly welcome tocorner dr. pandolfo and those he's participated in as well. you love me, don't you? you were expecting it. when you read about clinicaltrials, because now this is the information era,you will see the abstracts,
you might seethe full paper. you'll want to understandwhat you're reading, not just trust us. the things you'llwant to notice: what does each stagedo for participants? how effective? was it only ambulatory peopleor did it include everyone? was it only children? these were things whichaffect the results and affect
the interpretation,both good and bad. there will also besomething about, who did they get to comefor the trial, you know? does it say 50 people showedfor trial but 20 of them dropped out. you know? you would wonder about themeaning when that occurs. what happened to the other20 people and why did they drop out? that's an important thing tounderstand because it might
skew the results. how long did the trial go on,the trial duration? this is a particularlyimportant component. let's supposesomething works if we give it to someone fora month and people get better. what happens if you giveit to them for six months? do they keep gettingbetter still? or even better? or do you just get that littlebump you saw at one month? or is the body smart enoughto realize that whenever we
give someone a drug, we'retrying to trick the body. and the body is smart enoughto recover its abilities and go back to the abnormalstate six months later? how do you figurethese 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 uphere and wonder what happens at one month versus sixmonths, and you can never be wrong but,you'll never be right.
so let's talk about thefour trials we have done in the past four years. now remember one thing,as we talk about this, that's four more than we'retalking 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 studiesperformed in recent years, i guess if we addthem all together,
it's probablyeight to ten studies. the ones i'll mentionvery briefly here are the so-called nih phase ii studywhich was done around 2005 and then the american phase iiistudy which we did at chop and ucla. the nih was called nicosiaif you remember that, the phase iii studyhere was called ionia. that's because santheranames all their trials after cities in greece.
you know, someone hasto know those things. in any case,they're very similar. both are six-month studies,similar doses of drug, though notexactly identical. the phase ii had four doses. we only had three doses, oneof which was placebo in each. now, they gavedifferent results. why? well let's take alook at those data. okay, now what i have here,and this slide was given to me
by thomas meier of santherathough it's publicly available data,he did give me the slide. and what i'mlooking at here, if you go up -- because mypointer is burning out a little bit -- up is bad,down is good. and looking at the differencein people's exam scores done with an icarsrather than a fars but that's not importanthere, it's very similar. people get the two doses andthey get better when they do
it at the nih. when they go toucla or philadelphia, the blue is theplacebo group here, the placebo group gets alittle better and the people on drug, get a littlemore better, if that's appropriate english. so what happened? why are they different? well you never know thosethings so you have to think
about this sort of stuff. we don't know exactly whatbut i'll come back to those in a minute. so now let's dosomething else. so that's trial number one. there's actually a secondtrial and what we did, and this is new since wetalked last a year ago. we took the people who gotin that phase iii study and we put them all ondrug for one year.
and i know some people inthe audience participated or their childrenparticipated in this. and then you compare on howpeople would have been expected to do had they just beenliving out in the community, what we'll call a naturalhistory control group. so what happens? this is what happens andi'll take you through this. again, prepared bythomas out of convenience. again, the datais being published.
i think it comes outprobably next month. it's alreadyavailable online. this is the start ofeverything and as you saw people on average,even including the placebo, got better but just a littlebit in that six-month study. and then you keepgiving them idebenone and what happens? well, they get a little bitworse but they're not back to where they were when theystarted the [trial] 18 months earlier.
so that's really goodevidence that idebenone is a great drug, right? no. there's noplacebo group here. how do we know that we justdidn't take some people who were really uncomfortablewith people who talk really fast and bringthem to the office, and by the time they gotto the end of the trial, they were really comfortablewith people like me?
it's possible this is entirelypractice as we had them do their pegboardsand we had them do these complicated exams. you know, you wouldn't wantto 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 havethe quandary of, "does it work one dayand not work the next?" don't know.
and it does giveus to a problem. so how do youactually interpret this? because in the end, we don'tcare as much what happens on those slides as whathappens in real life. and because idebenone isgenerally available over the internet, there actuallyis a question here. do you take it or not? and i'm not going to takea position while i'm up here right now, but it's areally good question.
[are] the side effectsless or better, are the potential sideeffect less or better than the potential benefit? i do have an opinion,particularly based on the fact that it hasvery few side effects, but you can't sit up hereand say that is has been shown to work. you think it might,but you're not sure why. well why might it havebeen different between
the different studies? well the observers change. i mentioned thoseexam-based rating scales. in the second study,it's susan perlman and i rating who have seen probably, withthe exception of dr. pandolfo, more individuals withfriedreich's ataxia than any in the world. our exams arevery practiced in. the individual in thenih study was naive
to friedreich's ataxia. they will rateperfectly fine and perfectly consistent but they willrate different than we do. who's right? neither is right. they're bothinternally consistent, but things will happenas you do these studies. not everything willbe a clean result. the other catch isthe first one is one site.
that person isalmost by definition internally consistent. instead if youtake it to two sites, you're going to seemore variability. i remind you of this forthings which i might show in a later slide. when you go from one sightto more you will see more variability. count on it.
maybe it's differentselection criteria. in the first nih, theytook anyone who was a child. we were required torecruit ambulatory children. so, different group.maybe they're not perfectly comparable on that basis. and you know that peoplediffer in other ways that we don't even know. so as we select people,we may not even be selecting for the group thatwe thought we had.
so we get to this quandary,"does it work or not?" the good news is i don'tthink we'll ever do another study because wehave better things. third clinical trial we'reinvolved in which hasn't been talked aboutmuch is varenicline. i think most peoplehave forgotten about it. you will recall in theliterature there were case reports, of which i was anauthor, of individuals who carry a single-pointmutation and in conjunction
with expanded allele whoresponded dramatically in response to varenicline. as well as some peoplewith some other ataxias, all well documented. but that's only two peopleso let's see what happens when you give it to a biggergroup and the original target enrollmentwas 32 individuals, 16 for drug, 16 for placebo. so it's adouble-blind study.
i don't know whatthe person's on, my co-investigator doesn'tknow what the person's on, the people, the subject,patients don't know what they're on. two sites, here and theuniversity of south florida. our outcome measure wasthat exam-based measure that we're doing everything. we only enrolled atotal of 26 subjects, 17 people actuallycompleted getting the drug.
because when youoversee a study, there's always asafety monitoring board, the dsmb waslooking at the data. they got to know whateveryone was on and they discovered that a largenumber of people were dropping out and getting worsewho were on active agent. so the study was stoppedafter 26 patients due to increased ambulationimbalance in subjects who were on drug and increasednumber of adverse events
in the treated group as well asthe fact that it didn't seem to be working. so the dsmb steppedin and stopped it. good, because we werenot helping people. it was statistically shownthat we were making people worse and that is the time wehave neutral people stop it. so if you actually lookat the adverse events, it's a little small. drug is on thatmiddle column there.
placebo is over here. one particularthing to note: this is the totalnumber of adverse events. we give you aquestionnaire and say, "what's going wrong?" there are 64 adverse eventsin the placebo group, okay. you wouldn't expectthat taking sugar pills, i forget what theactual placebo group was, would cause adverse events,but if we ask you a bunch
of questions, people willfind things which might be adverse events. and the number actually inthe drug-treated group were not that much more. but where itcomes down to is, when you look at therelationship of adverse events to study drug. when you tell us aboutsomething that is going wrong, the investigator orsafety monitor is asked,
"do you think thatcame from drug or not?" and if you do it based on whenit happens, things like that. it was felt that the adverseevents in the drug group were related to study drugwere very few and much less than the placebo group. so this was giving it riseto too many adverse events. and if you lookat the bottom, this one right here,imbalance and really almost loss of the ability towalk in people who were
previously ambulatory, onlyappears on the varenicline side and on the placebo. so this study was stoppedbecause of that reason. but remember we started thisstudy for a very good reason that we saw people gettingbetter 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, weshowed that it didn't work. but this trial didsucceed in accomplishing
the outcome, of figuring outwhether this is a good drug for people onaverage to take. and the answer is clearlyno but sometimes the answer that is right and is correctand that you get is just not the one you wanted. protecting people is equallyimportant to making people better. so i will argue that this isa successful study because it showed how the processcan go through and get us
to the right answer. so now, we have one morestudy, which the results were shown at the ana meetingsin san diego a week ago. a0001. what is a0001? it's a modified form ofidebenone / vitamin e, sort of looks likeyou put them together. it's alpha-tocopheryl quinone. it's actually found inyour bodies all the time
to a very small amount. it's more potentthan idebenone. the slide i've taken hereon the right is the dose response curve. i have to showa little science. this is from rob wilson'sgroup done in collaboration with amale hawi and tomsciascia from penwest. on the right is idebenone,on the left is a0001. they're looking at thenumber of fiber blasts using
a model developed by halamperchio up here at the front table, die in response tochallenge and how much a0001 versusidebenone can protect him. and basically what you seeis that a0001 is about one orderof magnitude, about a factor of 10 better,than idebenone at protecting him from thatoxidative challenge. in addition, a0001is absorbed much, much better. now you do have to do somethings, like eat fat, and when
i was talking to one of theindividuals from the trial the other day, i rememberhim saying how much fat, he asked the question, "howmuch fat are you required to eat to absorb a0001?" and the answer was,"as much as possible." so there are someadverse events, but maybe it doesn't,you know, but it's a trial, you have to do whatwe ask you to do. we get to makethe rules here, guys.
we call this trial frdo2,no named after greek cities. it was done by penwestpharmaceutical with us as a trial. it's double-blind,placebo-controlled, medium and high dosesof a0001, 31 total subjects. we got to replaceone drop out. it is a one-month treatment. the primary outcomemeasures those people who participated knows we dothis glucose tolerance test
on you where we shoot youfull of a lot of glucose and we shoot you upwith a lot of insulin. we measure of thesediabetic measures. now that's the primaryoutcome but then we measure the neurologicalthings as well. it's a reasonably toughprotocol and i'll note we're measuring the neurologicaloutcome measures after we have put these peoplethrough these various iv treatments.
remember that when wecome to generalizability. so what does itactually show? well, the glucose outcomemeasure just didn't sort of work. they were very noisy and wecouldn't establish anything. however, the individualson a0001 had a significant improvementin their fars score. people on placebo gotabout two units better. people on low dose gotabout five points better.
people on high dosegot 6.1 units better. these are statisticallysignificant very high levels. it worked across all aspectsof that neurologic exam. in addition and thisgoes to the bottom point, it actually happened injust about every subject. so it was very uniform. this change wasn't driven bya couple people getting a huge amount better. it's actually everyindividual, except for maybe
one or two, gettingbetter out of the 10. the improvement, this amountof improvement, yes. well how does that mean? it's about the, six pointsis about what people change in one to two years. so this would meetthe definition of clinically significant. so great outcome. what are theproblems 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 outand that's do the experiment. yes, these were not thethings we meant to measure as our primarymeasure to begin with, we just found thatthey were better. you always have to becautious in interpreting
such things. maybe it only happens afterwe give people an iv glucose tolerance test and challengeand fatigue them with that. if that's true, it'snot so generalizable. that said, this isa very nice result. it's a reason to keep movingforward with this drug without doubt. and the question is whathappens if we give it to people for sixmonths or a year?
we'll see. so this is, i've stolen frommy good friends at santhera the pipeline slide again. i think i copied this awhile back but i've added something over hereto emphasize a new announcement, righthere at the corner, this thing called ox1,this is a new drug for which safety data is available inadults, which is now been licensed to viropharma fortrials in friedreich's ataxia.
now the one good thing aboutthis is jen and i might fly all around the country tovisit various drug companies. they're local, we don'thave to fly anywhere. so we can save some of ourtime which is always a nice thing and we can getback to more work for you. works for me. notice though,in particular, the real emphasis hereis not so much, is on ox1, but all thethings on this list.
that i mentioned a0001 butthere's lots of other shots coming as well and that'swhy i want you to know about all the details aboutthese clinical trials so that you could be activeparticipants. and there's some thingsthat we ask you to realize in clinical trials. clinical trialsare experiments. there are rules. oh my gosh, dave hasto enforce a rule.
we call them, in some cases,inclusion/exclusion criteria that we write the study sothat we can do the best, most generalizable experiment atthe safest scenario for people. sometimes we'll want to lookat the individuals who are likely to be at themost responsive window so that we can get themost reliable result. sometimes we will excludepeople in whom we are worried that they are morelikely to have a safety event. that would be drug dependent,as sometimes well as not
drug dependent. we do this because weneed to do it right. that said, they arelargely inflexible. a few of them haveinterpretational components and usually it's the principalinvestigator 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 theright thing as you're there. there are also personalpracticality issues. we set the visit scheduleso that we can do the experiment right. for example, massimoemphasizes this from the phase ii, the deferipronetrial which we were almost involved in many years ago. the first, because theadverse events potential with that drug, the first fourweeks involve six visits
to the children's hospitalof philadelphia. now, i don't even like togo to children's hospital of philadelphia sixvisits in a month. i'd prefer to stayat home and work, but in any case,it's a rugged schedule for particularly people comingout of town but it was necessary for safety reasonsand it was non-negotiable. and the otherthing was cost. it does cost money to getto the children's hospital
of philadelphia,or to ucla, or to iowa, or chicago or minnesotaor emory or the other places i'm forgetting, torontoor melbourne or brisbane. and i know i forgotsome, what did i forget? university of south florida,university of florida. so it costsmoney to get there. i will compliment my friendsat santhera for in their trial because they had suchtight recruitment criteria. they actually covered thecost of everyone coming
to chop for nine visits overthe course of a year and a half, which if you calculated out,is about $700,000. it's not a trivialamount of money. companies are notrequired to do that. it may affecttheir recruitment, their ability to moveforward in a trial, but it's not a requirement. so as we move forward,the varenicline study covered only a minimaltravel expense,
a0001 had travelexpense covered after the first screening visit. these are all things thatyou will have to consider as these announcements come up. so if you want to participate,what do you do? you sign up on the registryfor the friedreich's ataxia research alliance so whenthat trial is announced, you will get an e-mail. so i started this as a talkabout neurologic dysfunction
and the things which weare going to measure. so what's the upshot withclinical trials at this moment with that veryencouraging result? there's reason to beoptimistic, you know? we've done some trials. we have one, somethat is neutral. one we have shownthat the drug didn't work and one which at first glance,emphasis first glance, showed that the drugmay well be efficacious.
let's see whathappens long term. but i think the other thingwhich i wish to emphasize is the only way to truly moveforward with a systematic approach and gettingthe answers. i think we've gotten theright answers and the right answers are the onesin which actually protect people as well as helppeople out long term. so at this point, i get tostop and we'll go from there. thanks.
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