Confirmation Number:334285
Event Started: 3/16/2005
Please take your seats. We will begin what promises to be an interesting and busy day . I want to welcome everyone to the 99th RAC session. And we'll begin by the conflict of interest guidance from Dr. Amy Patterson .
Good morning. I would like to read into the record and also to refresh your memory, although we went over this yesterday, it's important to begin with it. There was a conduct and conflict of interest. Being a member of this committee makes you a special government employee, and thereby, subject to the rules of conduct. The rules and regulation are in the report called standards of conduct and you each received a copy when you were appointed to the committee. At every meeting, in addition to reminding you about the importance of following ethics rules, we like to review the steps that we take and that we ask to you take to ensure that any conflicts of interest are addressed. As you know, before every meeting, you provide us with information about your personal, your professional, and your financial interests. We use this information as the basis for assessing whether you have any real potential or apparent conflicts of interest that could compromise your ability to be objective and getting a device -- advice during committee meetings. While we weigh conflicts of interests for general matters because we believe your ability could be objective will not be affected by your interest in such matters and we rely to a great degree on you to be attentive in our meetings to the possibility that an issue will come up during a discussion that could affect or appear to affect your interest in a specific way. If this happens, we ask to you recuse yourself from the discussion and this means for us that you actually physically leave the room. You're also required to recuse yourself from the review process when you have a real or apparent conflict of interest regarding a specific protocol. And as always, if you have any questions during the meeting, please address them to me and if you have questions in the -- of rules of conduct or conflicks of interest, our committee management officers will be happy to address them as will lori LouEllen, the program assistant for the program. Thank you.
The minutes of the December 16th, 2004 RAC meeting will be reviewed by Dr. s Thomas Gelehrter and Emmett Barkley.
Once again, a wonderful review of the minutes. Dr. Barkley and I reviewed them, they're completely accurate and nicely presented and I think we have very minor type-Os we have communicated already. I would like to move.
I will second it. Thank you.
Let me move that we approve the minutes.
And we will take our first vote of the day. Dr. NEMERAL.
I.
BOHN.
I.
[ Indiscernible ]
I.
miss KWAN.
I.
[vote taken] Thank you.
Our first presentation for the day is an update on protocol 322 entitled phase I study of NGF ex vivo gene therapy for Alzheimer's disease and Dr. Mark Tuszynski from UCSD will present.
Good morning. We are ready. Thank you. No problem. We started promptly on time.
Just so you know, was up at 8:20. I should add for those of you who, in the audience and may not be Aware of this, the two updates that we're doing first this morning are presented and framed as background for our first review .
Good morning. I was decide return to the RAC to give you the results, the clinical results of our phase I ex vivo factor for Alzheimer's disease. The results of our cognizant testing and test scan studies in this nerve growth factor and clinical trial, the findings are in nature medicine and this trial was using an MLV-based vector system to transduce primary ontologist fiber glass of Alzheimer's patients and they were planted into a region of the brain to constitute an ex vivo cell source fortrophic support of degenerating neurons in Alzheimer's disease. Again, I talked about this previously so, again, right to the results after a small bit of background and, of course, I would like to acknowledge the many people who contributed to this study. So to establish the foundation of why we did this study, just to remind you that growth, the premise of growth factor therfy -- therapy for neurological disease is that these natural proteins of the brain promote the death of the responsive cells and potently augments the function of the responsive cell populations. Hence in the sense they have unprecedented potential for the treatment of progressive disorders of the nervous system, and this is the only slide I will show you as further background, but this illustrates this affect of preventing cell death. This is the adult monkey brain and these dots are the individual coloneurojij neurons which degenerate and die in Alzheimer's disease. We can -- showing here on the right side of the brain, we transject to the hippo campus. Following the ex vivo nerve growth factor delivering, there is a quite striking protection of the cells from death and potential for progressive neurological disorders. So in this clinical assessment group we're here to update you on, there were six subjects who constituted the group who all safely completed the cell injection procedure. The main age was 67 years and they all had a diagnosis of early probable Alzheimer's disease, and that were reroute -- recruited at early stages of disease to allow for informed consent, and because the earlier one intervenes in an ongoing degenerative process, the better potential for this mechanism of protect. This was the dose of escalation study. The first two zudy -- studies received on one part of the brain and the next four bilateral on escalating doses. Here are the results in the realm of cognizant function, we used two of the most none comonly used in Alzheimer's disease, a mini mental status examination, this is a 30-point scale in the mean point of our subject growth in the time of growth vector treatment was 21. Another commonly used scale in Alzheimer's strils is the scale, the cognizant subcom51ent, a 70-point scale, and I will show you now the outcome data but I will remind you we have to interpret this cautious lis -- cautiously. This was an open phase I trial with no controls or blinding. So that said, here are the actual date. -- data. These are the mean mini mental status examination scores and on this particular scale, we have preoperative data at a baseline one year before undergoing therapy. So this is the mean score in the scale of lower score indicates progression. Can you see a decline in the time before going to gene transfer and this was the rate of decline afterward. These are the mean scores for these patients and the standard areas of the mean. And another way of looking at these data are to show the, the decline rates in the one-year EPOX. This is the mean score in the column centered areas and the individual six patient data that constitutes this mean. And as can you see here, they have the mean rate of decline in the first year was six points and in the firstior after undergoing Gene delivery, one season apparent reduction and the next six to 18 months this is the overall rate of decline and then in the one- to two-year period, this is the overall rate of decline, and this different -- difference on a test of post operate testify preoperatef of this Epox happens to be significant. Again, a small cohort. Overall for the mean 2.2-year period of followup now in the study, there was a 49% reduction in the rate of decline, compared to preoperative rate and just to give you context to what this could mean if this magnitude of effect held up in subsequent trials, the currently-approved drugs for Alzheimer's disease, including the inhibitors are on the same scale of 5% persisting for three to six months. Were this to hold up, this would be a substantial difference over therapies. This is the other cognizant testing scale, the ADS COG. We don't have a declined rate on this scale, this is the data at preoperative date line and the Epox after treatment, again means and standard errors and these are the rates of decline from the time of treatment and the subsequent Epox afterward. Again, you see some suggestion, perhaps, of reduction rate of decline. Given the smaller data set and some variability, I will show you the median scores and, once again, one has a suggestion there is consistenty with the findings on the MMSC, some reduction over rate of decline over time. Now, I'll show you the imaging results of the deoxyglue close eptake as a result of the corti keys metabolic activity and the pet activity diminishes over time, as you might expect. We did pet scans in the four subjects that underwent bilateral injections and those show an increased meaning of cort key pet activity in the period following NC -- NGF activity and this is significant. This that is shown here. Hopefully the colors can be appreciated. But these are the mean pet scans of the four sents superimposed to one another. The average, the first scan and the second scan performed six to eight months lrght later. Blue is left activity, the ved the hotspots, the increased areas of activity, so, again, relative to the pre, to the first baseline, six to eight months later, you see general increases in CORTICO activity and the trophyics effect if this holds up. This is a reversal of the expected pattern of decline over time in Alzheimer's disease. So, to wrap it up, there were no adverse events related to the growth factor or to the gene delivery system in the human brain using a non-regulated vector and follow up now is four years in the first treated subject. There was a significant increase in CORTICO activity by pet scanning and cogative analysis, again, cautioning all of us this is a small unblinded non-control cohort showing the rate of decline in the extent substantially exceeding the effects. This combines the rationale for the followup drug you heard about here a year ago, using now AAV, the growth factory delivery sponsored by serogene and Dr. Raymond Bartus will give you an update on that trial. Any questions regarding this? Yes.
could you go back to your pet scan map and show us exactly where you injected the finer -- fiber glass and how that fets with the pattern you're seeing.
Sure. A level of detail that would require the -- [ Indiscernible ] Let me see ifky make this clear in a briefer answer. The cells targeted with the growth factor on a 1-centimeter region of the brain. They're deeper in the brain and send their projects throughout the cortex. They're the SOLE source for the cortex and the normal local is to modulate the excitability of systems in the cortex. They can target a small practical area and, thereby, affect their defused cortical projects. That's what we did. We targeted the growth factor in the cell bodies, these are the affects in the modulating of the cort cool -- activity. They're deep in the brain -- cortical activity. They're deep in the brain. You can't resolve them with pet scan here. They would be roughly in this area here. Okay, thank you very much.
Wait just a minute. Are there any other questions for Dr. Mark Tuszynski?
Be happy to weight as long as you want me to.
.
No, thank you very much for sharing your data with us.
You bet.
The second update, if you will Son human gene transfer protocol 623, phase I/II dose-esicate -- escalating randomized and controlled study to assess the safety and tolerability and efficacy of CERE-1110 and AAV vector-mediated delivery beta-nerve growth factor in subjects with mild to moderate Alzheimer's disease and Dr. Raymond Bartus will be here for us. Again, thank you for being here so early in the morning . --
Morning.
Morning.
Happy to present an update on CERE-110 for Alzheimer's disease. Are we ready? Okay, thank you. Sorry. Happy to present an update of CERE-110, products for Alzheimer's disease, this is a phase I dose-escalating trial conducted at Hospital. It's using AAV to delivery NGF to nucleus BACILLUS, the same thing Dr. Mark Tuszynski talked about. CERE-110 is an engine eared form of virus 2, expressing NGF protein. An open-label trial with two doses, 8 timen -- times 10 to the ninth and four times 10 to the ninth. Three subjects each. The primary purpose, of course, is to assess the safety and tolerability and a number of secondary measures exist to evaluate the efficacy activities of daily living, distribution of CERE-110 in and look at immunogenis etto human growth factor and AAV II. We have enrolled three subjects to date range of age is 64 to 73. Exposure is nearly eight months and the longest subject and nine weeks in the shorter subject. To date there have been no adverse events relate and the trial has been remarkably unevent envelope that regard. Human, HUMONOimmune response to growth factor is not detected. There was one transient, a single point detection, a low level of antibodies to AAB II, that went Away quickly at three and six months, no evidence of it and a distribution data in serum and eastern are negative. So the dose one cohort was completed, the three subjects in January started in January 11th and completed in March. We had a cumulative review of the data by the DSMB. The unanimously recommended going forward with the dose escalation. We have scheduled a second subject for April 2005. We anticipate enrollment being completed somewhere near the end of the first quarter, we're very early second quarter this year. Thank you. Any questions?
Were your subjects prescreened for antibody, were they negative at entry or not?
They were not prescreened.
So when you said the three had no AV -- AAV antibodies, in retrospect, they were CERE negative?
That's correct.
Just in terms of compareson, were the subjects about the same point clinically as the previous study was presented or how do they compare in.
The intention was to have very similar level of disease. Mild to moderate. Dr. Mark Tuszynski's trial, of course, the study requires identifying the patients enrolling them, Harvesting fiberglass and then, of course, manufacturing them to reinject so there was a delay as Dr. Mark Tuszynski showed you Dr. During the sufficienteral months to a year delay, there was a decline in the patients, or subjects, so in ours, probably less in period in the time of the -- impaired at the time of the treatment and similarly impaired at the time of the treatment and diagnosis of enrollment.
Thank you.
Dr. .
How were the results of the pet scan data from the last presenter, do you also have pet scan data or do you plan to do that?
We intend to do that when we obtain -- obdane -- obtain a longer and more meaningful time period, treatment period with the subjects. Thank you.
Other questions? Thank you very much, Dr. Raymond Bartus.
Thank you.
Going to take us one minute to organize for the beginnings of the first protocol. I want to remind everyone before you leave the room that there are a number of people in conflict with this next protocol. We will all step out. There is then a break after the first protocol at 10:20 and we're scheduled to resume at 10:35. I would like everyone who is leaving to be back by 10:30 so that we can be certain to start on time. Thank you.
The -- among those that needs to be recused for this particular protocol, ands that asked Dr. DOLUCA to chair this portion of the meeting. The people that are recused are Diane Wara, Dr. lo , employees at USCF. Dr. ZARE, Dr. ZENSKA, and -- I'll wait until they're settled here. At this point, I would like to ask for the people on the telephone line to identify yourselves.
Good morning, this is Dr. William Marks from UCSF.
Thank you.
Thank you.
Dr. Jill -- [ Indiscernible ]
Okay great.
[ Indiscernible ]
Thank you, Dr. Gage. Anyone else on the line? And one of our ad hoc reviewers, Dr. Howard Federoff will be calling in momentarily . We're going to wait about two more minutes. We're returning a little ahead of schedule, so we can get the proper people on the line. -- we're running a little ahead of schedule, so we can get the proper people on the line All right, and we would also ask Dr. Philip Johnson and Dr. Martha Bohn to read into the record before they do their reviews. Not right at this moment, but when they do their reviews, a statement of desclosure of their activities in in this arena. We'll just wait a couple more minutes. We understand that Dr. Howard Federoff, one of the ad hoc reviewers will be dialing in. I appreciate your patience. Yes, good morning.
Morning, Howard Federoff here.
Super. Thanks, Dr. Howard Federoff. Dr. DoLucca, are we ready in.
Yes. Let's begin the presentation with Dr. OSTRO.
Thank you very much, I'm Jeff OSTRO, the chief operating officer of -- chief executive officer of Ceregene and we're the sponsor of this protocol. I appreciate the RAC and the office of biotechnology activities for the logistics of this meeting, as well as the very comprehensive review of this important protocol. SeroJean -- serogene is a company involved in the the genetic therapy using growth factors for the treatment of neurodegenerative diseases that you heard about in the CERE-110 product briefly thats that in human clinical trials. We'll be hearing about CERE-120, an AAV NEURTURIN that has the ability to affect open dopamine neurons and it's used for the treatment of parkinson's disease. In terms of the order of events, we do have a number of people that will be on the telephone or on the telephone as you know from the West Coast, so it's been difficult to get everybody here logistically, but the principle investigator is Dr. William Marks who is on the telephone as we heard earlier, as well as Jill OSTRO, both neurologists at UCSF, where the trial will be held. Dr. Phil Scar, I don't know if Phil is on the phone or not at this point in time will be the primary surgeon, and Paul Larson. He's in the audience today. We appreciate that, also involved in this study. In additions that another neurosurgeon, Dr. ANDRE LAOZANO also in the odd here today and might be able to answer any questions related to this. I'm going to give this brief intrckz and then the clinical protocol will be discussed by Dr. OMANO, who is on our scientific advisory board. Warren and Bill Marks will be involved in this, and then Dr. Raymond Bartus will come up and present some extensive preclinical non-clinical data summary, specifically trying to address the points that were brought by the RAC reviewers. In additions that a number of scientific advisory board members either here in the audience as shown in the maroon or on the telephone in black who can also answer potential leany of these questions that might Arise from the committee. So, CERE-120 is an AAV type II based vector system delivering the human nurturing -- Neurturin gene, a member of the family of growth factors. The construct that we're using is similar to the construct that we used in setting up our CERE-110 program. This is a human Neurturin gene with a CAG promoter with a hune bait globin side and flanked by the AAV ITR's. So there are no AAV genes in this construct and only the ITR's are present. This is the transcript and we sequenced the NOS -- sequence of the Neurturin protein as it's secreted from cells and shown it to be an effective Neurturin protein. At serogene, we developed CPMG manufacturing procedures to produce the product. It's the same procedures that we presented last year at the RAC actually a year ago at the meeting which, involve a triple transsection method using 293 cell qualified cell bank. This is all done under GMP conditions. Produced, actually quite a large number of doses of the product. The AAV undergoes multiple calm chromotography purification steps to end up with a highly purified, highly-concentrated, formulated final vials that then go through extensive testing according to the USDA points to consider guidelines. It's a pharmaceutical-grade product that we're using and injecting into man. With this being said at any point later if we want to discuss CMC questions, we're happy to address any of those. At this point because of the time, I would like to ask Dr. Warren OLANO, the chief -- and a member of the scientific advisory board to present the protocol. Warren.
Dr. OSTRO. I will now -- thank you . Thank you very much and good morning, Ladies and gentlemen. As you have heard, my name is Warren ALANO, the head of the department of neuro neurology at mount Sinai school of medicine and head on the parkinson's disease center. My primary activities are dealing with clinical and research interests related to Parkinson's Disease, and I wanted to start by telling you a few words about this condition. There have been so many famous people that have developed parkinson's disease lately that I suspect bee watching television, you have some familiarity, but I did want to remind you it's the second commonest neurodegenrative disease in the United States, approximately 1 million people have this disease. It affects men and women, it affects people of all occupations. It's seen with an average age of onset of approximately 60 years, but it can affect young individuals as well. Classically, it's seen with the four cardinal features, which are tremor, rigidity or stiffness, slowness and trouble walking or trouble maintaining posture. And pathologically, while it has wide areas of distribution, it's characterized by a loss of DOMPAMINURGEC cells as a consequence of NIGRAL neurons which object to the STRIATUM, it's largely an attempt to restore and induce refunction in these cells the current protocol is designed. I want you all to appreciate we have good treatments for the early stages of parkinson's disease. LEVADOPA and other therapies that perhaps you're familiar with. What I want you to realize is the patients eventually reach more advanced stages of this disease, and when that happens, they begin to suffer disabilities which can't be adequately controlled with medication. Firstly, about 80% of patients develop what are called motor complications, which means that, which means that their function cycles between periods in which they respond to the drug but they have these wildest KINESIA that perhaps you have seen similar to what Michael J. Fox has shown on television and then they cycle down to periods where they can hardly respond at all and they become almost frozen look you sometimes see the Pope looking on television. For some spashts, that becomes disastrous because they never have a period of time or they men 3458 periods of time about they can function at a relatively good level. In addition, they develop features which our current treatment caents help. They develop problems with walking Wfreezing, with falling and even di -- with freezing and falling and dementia. Finally, none of the drugses that available today can slow the progression of the disease or restore function, and, that of course, is why we're so excited about this current protocol, and I would say so far that it would be virtually unanimously agreed among parkinson's disease specialist that a therapy that can restore function to parkinson's patients or prevent and slow down the rate of progression is clearly the single most unmet medical need in this disorder. Now in our current study, we will look at CER- -- CERE-120, AAV II delivery of Neurturin to assess its safety anditollerability. The study will be done as an open-label study. It will be done in a dose escalation manner, looking at two different dose levels, with six to nine patients in each dose regimen. There are two major objectives. The first is to test the safety and tolerability of these dose levels of CERE-120 or AAV Neurturin. The second is to look at the effects of this delivery on the parkinson syndrome itself, primarily using the UPDRS but also using a variety of other testing parameters and secondly, to image the NIAGRAL striatal system by looking at the pet, a standard method of looking at this system. Our primary inclusion criteria include males and females of any race, age 35 to 75 years. Patients who have advanced Parkinson's disease of at least five years duration and who can't be satisfactorily controlled with existing medication. So I want to emphasize to you the patients who will be entering this trial are patients who have been treated with medication, have enjoyed a good response to medication, but couldn't be adequately controlled despite manipulations of medication, and so they are bad when the medicine is not working. But at the same time still show a medication response so that's the type of patient that we're looking for. Not someone where there is no response to medicine, but someone where the response is good but because of complications couldn't be adequately controlled. And all patients will be on stable doses of medication for at least 30 days prior to entry into the study. The primary exclusion crier toia include not being able to give an informed consent and Atypical or secondary parkinsonism. In other words, they have to have true parkinson's disease using the united kingdom criteria. They can't have other clinically significant medical or psychiatric problems and they can't have had other serious intercraneual surgery or gene therapy. The target of our procedure will be the PUTANUM. This is the major portion of the striatum. What I want you to appreciate here is we will be using four tracts. We will make two deposits of gene vector into each of these deposits, and these have been carefully calculated so that the deposits will permit full and complete homogenous coverage of the PUTANUM. The reason we chose the PUTANUM as the major target, this is the area that is primarily depleted of dopamine in the parkinson condition. This is the region where the substangz of NIAGRAL nerve cells that in parkinson's project and this is the area primarily connected to the motor systems. In other words, this gives us the best chance of being able to restore motor function. At the same time, the PUTANUM is distant from the vent kills and, therefore, men -- the VENTRICLES and risks the contamination and vector and gene product into the CSF. The PUTANUM is relatively easy to target, ands that substantial experience with targeting this structure in in other interventional procedures such as transplantation experiments. This is a sense of how we will enroll patients in the study. Patient number one will be enrolled and followed for a nothing. After a month, the DSMB will review the safety on that patient and it's then intended that the next patient would be inrolled. After the first two patients have been enrolled, patients three and four will be enrolled coupleatively, and after another month -- couplelatively, and after another month, patients five and six. Notice that each cohort of patients is entered into the study, safety will be performed looking couplelatively at all patients before the next -- CUMATIVELY before the next patient is inrolled. There will be a pause of four to five weeks and we will begin the second cohort using a similar pattern but using the higher dose this time. The assessment times will be at screening at baseline, weekly for the first month, monthly the first three months and every three months thereafter. We will continue to follow the parts on an ongoing basis to be sure that these patients do well and if they develop side affects we're there to see them. It's our plan to evaluate side affects at every single vision using an open approach where all side affects are gathered in an open and free fashion. These will be reviewed periodically by the DSMB after each patient cohort as I have shown you, as well as by Ceregene that will continuely monitor the patients. The assessments will be performed include the safety assessments that will be a search for antibodies in each of these visits and when&we will look at parkinson's motor efficacy bee looking at motor efficacy in the standard UPMS scale, looking at the motor complications, this wearing off and diskinesia using home diaries, a world dated technique. We will evaluate cognitative function, sitting with the quality of life and seeing with measures of clinical global impression of both the patient and the physician and then finally at baseline, and at time points throughout the study, we will measure striatal fluid uptake on pet as a measure of the integrity of the NIAGRAL striatal system and an opportunity to see restoration of the system. I conclude in summary by telling you that we on the clinical side are extremely excited about this protocol, and we are extremely excited about the opportunity of gene therapy delivery of trophic factors to our patients. I want to leave with you a message that parkinson's disease patients, despite the fact that we do so well early on, suffer unacceptable disability as time goes on. They need a treatment and they need it now. The animal data that you will see I hope will convince you that this is an extremely inciting promising Avenue. I read the trials for fetal migeral transplantation for the NIH and I was the senior investigator for deep stimulation procedures which, have been approved by the FDA, and I can tell you that in my personal opinion, this is one of the most exciting opportunities for our patients and a study that I personally would be happy to recruit my own personal patients into. Thank you very much.
Thank you, Dr. ALANO. Now we'll go to Dr. Bartus .
Thank you, I'm happy to provide the non-clinical overview of the program. We believe that AAV Neurturin provides an opportunity for truly innovative therapy for this terrible, debilitating and dehumanizing disease. The reason we believe that is we're targeting the dopamine striatal neurons and they have been implicated as a key pathogenic event in the disease. We intend to provide a supply of neurotrophic vector to the neurons, which should enhance the condition and function, as well as strengthen their ability to withstand further degeneration. In principle, targeting neurotrophic factors should offer two benefits to parkinson's patients. First, it should improve the disease symptoms. Secondly, it should be -- [ Indiscernible ] The disease progress. Most experts in the field say these goals could be, it would revolutionize the treatment of parkinson's disease. That's what we hope to do at this program. We worked very hard the last few wires coming to this point and will be -- few years coming to this point and we'll be happy to review the comprehensive program that put us in place. We realize the responsibility it has and I think we'll be taking that responsibility very seriously. At first, I would like to start though by showing you some of the affects that can occur with the AAV Neurturin or CERE-120 as we call it in the company, and this is a model of parkinson's disease using MPTP, the neurotoxin that can cause parkinson's disease in humans, the gold standard for animal models of parkinson's disease, and it shows performance on a motor task that captures the essence of the deaf -- seen in human subjects. Higher scores are worse, lower scores better. Two groups of animals are ploted. One got MPTP and are treated with controlled substances in the brain rather than active CERE-120. In this formulation buffer or controlled gene. This group of animals, excuse me, got AAV Neurturin. From which can you see over time, they were balanced at beginning as a progressive, steady, substantial and persistent recovery of the performance on this parkinson's task. Now while these animals are still Alive and we haven't had the opportunity to look at their brans. One could presume the trophic responses indeed is nourishing the stra -- striatal nurons helping restore function and helping them overcome from further degeneration. We at Ceregene cam to the conclusion the company's inception the only effectef way to deliver growth factors to the central nervous system is by way of gene transfer, which we don't think there is another effect of way. You have seen some of the materials that we provided. So we have taken this challenge very seriously. We realized gene transfer has a field, has had some desappointments and taken some lumps and we recognize the responsibility to help the field go forward responsibly as well. The first thing we did was try to control the risks the subjects as, picturively as we could. So we used AAV in our turin as a gene transfer for parkinson's disease because AAV is a vector currently used in other CS trials, including AAV orange -- [ Indiscernible ] As I talked with you earlier, a parallel or negative fort of approach. Secondly, we're administering small quantities of the a vector in the transgene directly to the target. Different from a lot of the jeep transfer trials you're familiar, and fineally, we're avoiding significant systemic exposure. We don't have detection to the exposure to the transgene at all and little to the vector. On top of that, we would like to control the risks even further by stepping back and looking at the field and incorporating what we know about the field into our program. So we're leveraging much of the prior experience that exists with neurotrophic factors into the brains of animals and especially humans. We're delivering Neurturin gene, which is functionally similar to GGNF. GGNF has been well-characterized and administered to human brains for years. And finally, we put together and launched a comprehensive safety toxicology program with very high dose multiples. Looking for any problem we might see, hoping if we identified the problem it would help put us in position and we can address it in the clinic. As you see, 19 total subjects, studies. I'm sorry, 19 total subjects, studies are responsible for this program involving seven monkey studies and 12 rat studies. So, over 45 monkeys and almost 400 rats involved in three different types of studies, specifically pharmacology, efficacy, and safety toxicology. Now, I'll briefly describe what they are and the results. Pharmacology, we basically established the expression kinetics, the volume of distribution and the dosing of CERE-120. [ Indiscernible ] Of Neurturin expressed in the brain. We established that we can control the expression of the protein. It's related, define the volume of decrease and use that for future -- future studies. You will see some of the data says as we go forward. The efficacy, we established that bioactivity and efficacy and a dose response of Neurturin as administered by or delivered by CER- -- CERE-120, several rats and 1 monkey. For safety toxicology, you will see a wide safety marriage know established with this product. Several different rat studies, almost 200 rats, including 25 agent rats we put in there to ensure we were looking for potential safety problems in a more FBIel model system and four different monkey studies. The results are un, ventful in one regard. Quite promising the other. First I would like to remind you of a large dose of multiples we have tested. The efficacious dose in rats is 125 times lower than the highest toxicology dose that we test in rats. That's safe. A huge dose range and in monkeys, the safe dose is 100 and 400 times higher than the proposed human doses. We literally gave as much vector to rats and monkeys as is physical really -- physically possible, looking for side affects, toxicology, toxicity. We didn't see any. We will go more into that later. So, no one -- no adverse effects seen in body weight appearance, anything like that. They look normal. Up to 12 months in rats and eight months in monkeys at this point. No adverse effects on neurological or behavioral assessments, no functional affairments in the striatal system, looking carefully at motor-related activities, no historio pathological changes in the striatum, with the cerebrum, cerebellum, spinal cord or any prolific organ. No effects on blood chemistry or hematology. The bottom lope, there was no seen of any toxicity of any kind and a very large dose multiples over many months in rats and monkeys, involving multiple studies. So that's a brief overview of the program. I thought rather than going into more detail at this time, we received very interesting and inciteful questions from members of this committee. We have pulled seven out that we think are the most important, clearly deserve a public discussion. We're happy to have the opportunity to discuss these with you. Listed here, we'll go through them sequentially for the rest of the presentation. The first one involves questions regarding the efficacy of CERE-120. This came up in any number of ways from what were the methods, what kind of results do you get, what about Alpha 1 versus Alpha II reent isors, would it have been worthwhile to extend the pet scan imaging, a number of things like that. In the end, what is really being asked, it's a question of how certain are you this product is really doing what you hope it to do. We believe it is and we hope you agree when you see all the data. You saw this data already in the gold standard for parkinson's disease, a very effective response for the product. Agent monkeys provide another model for early parkinson's disease. This study is still inon p going. s that the three Asian monkeys we recruited in the study and they will give FLEURADOPA, using pet one, two measure, the activity in the NIAGRAL stre atum system. They're treated on the left side as you face the screen. The right side is normal and a highly statistically significant increase in fluorodeepa show we're energizing, act vite -- activating the system in the monkeys. This study is ongoing, looking forward to another scan in the future N.reality, it's the comprehensive program giving us the confidence we have an active product. We have corroborating evident for bioefficacy N.monkeys, we enhanced the striatal TH standing. We show enhanced activation of signaling, an important signaling event for trophic responses to Neurturin. In the six hydroxymodel of Parkinson's disease in a rat, we show protection and cell up to seven months of treatment, a long time in a rat's life span. Protection of a range of doses, including a fraction of doses as I said. 1, 125th of the doses efcaecious is efficacious compared to what we were shown to be save. So we have 1 -- went 125 times higher in the dose to be safe over what is necessary for efficacy. A huge dose range. Functional behavioral effects we've seen are positive. MPT monkey, antiaging monkey we talked about and the data of rats recently cam in. It's not in appendix M. We apologize for that. The hypertrophy of neurostriatal nurons, we're happy to show you the data if you're interested. So, this is CERE-120 provides clear and consistent support for the in ourons in the monkey studies, including the best models of parkinson's disease. Another question of all the kinnetsics and Neurturin, how quick is it coming on, is this a problem. We looked at this carefully. This is the so-called pharmacology studies. Several studies in rats and monkeys. I will summarize it quickly. As early as two days, the earliest time point we looked at. The approach is four weeks. As it spreads within the targeted area, it reaches the maximum of four weeks. Shows no significant increase there up to seven months. We than we can control that volume of distribution by changing the dose of CERE-120 and that no further accumulation occurs after a range of dose after a month. This product of CERE-120, Neurturin, stays in the targeted area nicely. These are the data showing the rapid onset of expression, two days after inject 120 in the rat's striatum, you show evidence of Neurturin and the staining with a rapid increase on the volume of distribution within the target. And here, after four weeks, which is when we reached absent, can you so a month, three, six, seven months, studies state levels in terms of volume and distribution. This is not spreading within the outside target or increasing in volume at all. It's reached a steady state. So the conclusions of this kinetics and human relation, the onset of nur tur sin rapid, the volume expression reaches a steady state of four weeks and shows a significant increase. No accumulation over many months over a range of doses. Legitimate concerns of possible multigrain ingredients being targeted and non-grain brain regions, something we have been Aware of since the inception of all the programs. First of all, there might be a point of confusion, grabs simmant tech. While we're giving multiple target passes, as Warren pointed out, multiple injections to target the striatum, we consider it a single site. We focus on the targ oat PUTANUM and hope to get protein to the next -- [ Indiscernible ] I would like to clarify that point regarding the multiple brain regions, a single system we're targeting with multiple needle passes, and the issue about non-targeted brain regions is an important one, one that we looked at carefully. We need to control. We have an obligation to control. I hope you see the data that convinces you as well. This is data from a monkey. This is done in Jeff's lab. Neurturin staining, chemical staining, formulation buffer, internal capsule. As we increase the dose of CERE-120, we get an increase in the volume of expression of Neurturin protein. You see how nicely it stays in the targeted area. Indeed, if we give a dose of 1.75 times 10 to 12th vector genes per hemisphere, which is, again, the most can you give physically to monkey. Took us hours to give each monkey, pushing the doses as high as we physically could could, this is what happens. You see the PUTANUM, few elsewhere. You see the MIAGRA. We want to get protein there. You see the light fuzzy signal, the globe uulous PELLETUS -- [ Indiscernible ] From the front striatum, it's not surprising that there is a signal there. Not cell bodies. It's FIBRALS and -- [ Indiscernible ] Nowhere else appreciationiaibly, so if you look at all the brain regions we carefully looked at, striatum and Niagara have the targeted protein as we would hope, shows it in the neuropils and fibers only. This area of the brain doesn't express any of the receptors necessary for transduction of Neurturin. VTA thalamus, cortex, areas that we're particularly sensitive to showed nothing, nor did the serible um, by the way, and the re -- the CEREBELLUM and the remainder of the brain and nothing at all. Better than I thought it would be. These are the data. The targeting of CERE-120 is limited to the niing aeral system and limited to the system as well. This is an issue of use of regulatable and non-regulatable vectors. We realize this is an extremely interesting active area 92 in gene transfer. Many people, and both associated with directly and indirectly associated with surgery enactive in this field, taking leading positions many people in RAC are as well. We appreciate that. We appreciate that is a lot of passion for this work in this feel. We as surge run work hard to make a decision to use a regulatable vector or not. We decided not to. I want to show you the reasons why. I hope you agree this is a responsible approach to this question. I would like to offer -- to deliver neurotrophic factors to the brain. The first important point is several human trials delivered neurotrophic factors into the central nervous system and some up to several years. The risk appeared well-characterized and related to non-target delivery, a point this sery gene intends to -- directly with sery gene transfer. I think you see it does that nicely. This is perfect for gene transfer enthusiasm is how gene transfer should be used this year. Ceregene trials proved by the rat the heart and for indications, delivered growth factors by way of non-regulatable vectors. We're doing nothing different in that regard than what has been done before. The growth factors have been delivered to the brain and heart without regulatable vectors. We're doing the same thing. Regulatable vectors have their own risks. Unnatural transscrpgz of proteins expressed without regulation and can genrate immune reaction. In fact, some people published on this in notable journals. The regulator is unrel -- unregulated. Finally, -- unknown risks are associated with the small molecule regulator. They need something else to turn the Gene on and off it's a regulator. That's a non-protein. The commercial entities we're looking closly with in terms of interactions in the future are developing new molecules can do this, and they have not been shown to be safe yet themselves. The regulator itself has its own inherent risks. Noinally, the point I have allowed to, no regulatable vector has been tested in humans and the full vector is still several years Away. That's one perspective. More specifically, with regard to AAV nur tir -- Neurturin for parkinson's disease, CERE-120 shows no toxicity or effects of poorly targeted factors in the brain. We have give know doses hundreds of times higher than those in human trial and demonstrated the expression of proteins is restricted on the stre atum as you see and no significant increase in volumeous,s -- occurs after four weeks as you have seen. No adverse effects in the CNS or systemically as you have seen. This is a very safe product and very high doses, much higher than we need to go into in humans. Again, the rat does multiple, the rat efficacious dose is shown to be safe. 250 times. I have been in drug development, research and development for 30 years and I don't know any that has, that I am personally familiar with with a dose multiple that large. s that a side affect with 250 times the efficacious dose. When you deliver it to the target, that's what is key, what we do. The rat-to-human dose multiple by waif brain wave is 50 to 200 times. It shows to be safe in a rat and it's 50 and 200 times higher than a dose we proposed in the humans by brain wave. In the monkey, that decease shown to be safe, versus the proposed human dose is 100 and 400 times higher than we need to do in humans. In conclusion,s that a wide safety margin for CERE-120 without regulation. The express of protein is controlled up to one to seven months and safe in large dose multiples. The arguments against a regulatable vepghtor -- vector in our opinion they have been established. The regular victor could increase the risk due to the more complicated first in human construct that would have to be used. Finally, no prior studies required for the reg latable vector and the CERE-120 has no reason for greater concern. Soy in conclusion, while concerns of unregulated exprgz Neurturin might seem understandable, they're not supported by the data and safety directionor the nature of the proposed protocol for the advanced patients. There was a question of rescue strategy and I think this involves confusion. We haven't seen side affects of the program. We were not sure how to address this Apend sexix perhaps it was an oversight. Of course, we fought hard about the adverse affects. Any time you do's first in human study. You have to look for the unexpected and we. Have I'm show you that in a second. We have a rescue strategy for everything that we think could potentially or hypothetically be a problem. So we took an approach to it with three different levels of analysis. The first thing in terms of addressing is possible adverse events, we carefully considered them based on the collectef past experience of growth factors, the nuances of park knowson's disease, working close with the world's authorities and a comprehensive review of the literature. We tried to imagine what sorts of things could go wrong with putting Neurturin into the brain of Parkinson's subjects. Having done that, we're providing clear information regarding all of these potential hypothetical risks of each subject by way of informed consent. Each subject is aware of all these hypothetical risk. Final, we'll monitor the subjects at ease and manage it with available therapy. I put this up briefly to show you these are some of the sources of hypotheticals. We have shown no evidence that any of these are tolikely to occur in any of our subjects, CERE 110 or 120, I'm soar. Some have been seen in other growth factors. We believe that most if not all are in the nan targeted protein and the Mannimal study -- studies show this nicely. Warren will be happy to talk with you about this in more detail. If any of these were to come up, we feel they're all pharmacologically manageable. So rescue strategies exist to deal with hypoet thatical risks of CERE-120. We have not ignored the issue, we Val -- apologize for not making that clear. There was a question of the toxicity reported with the GGNF monkey study. We have been supporting directly andp directly. Recently there has been a buzz in the scientific community and the press release involving possible toxicity&in some of the monkeys and given that Neurturin is indeed, structurally and functionally related to DDNF, it's a fair question of toask of us what. Do you think -- impacts your program. I would love the opportunity to show that. It shows what we're trying to do and what all of us here have an interest in doing with jeep transfer. The toxicity report is a focal cell lost in the serible umand a handful, -- sery bellum, three out of six, and out of 70 monkeys total, six-month high-dose treated monkeys. s that six months of the highest dose in the safety stud and in the three month recovery. They were go ofen a pump enfusing GGDF into the brain constantly and the pump was turned off. For three months after they had six months of treatment, they got nothing and then they were sacrificed. Now, information about this trial is still to prove the scientific community. We all know something about it. Some of us more than others, perhaps, but all of us, none of us have all the information because it hasn't been reviewed. We know nothing of the history of the monkeys. I haven't seen. We don't know about the surgery reports, the post operative recovery there. Is a possibility this has been raised by others, not us, that this may not be regulated to GGNF. This is post operative recovery anesthesia, the toxicity is Rems inent -- reminiscent of the iskeepec focal facts. We don't know that. This is a potential issue for the discussion today. More importantly, let's assume the link between GGNF and toxicity is proven. You look at the data, it suggests it was caused by deficiencies in the system, leakage from the system. It's stuck in the brain Permanently and you're pumping protein through the cannule and it's bound to leak through the sides, a fact. This position goes far beyond the statement. If you look at the monkeys and the mid-- and high-keys monk -- dose monkeys, reported over a year ago. If you look at them, they see clear classic changes of a more trophic factor to the meninges. Each of the monkeys, not just these monkeys here, every monkey in the mid- and high dose, had hyperplasia and sympathetic end growth. These monkeys have a system that links protein in a non-controlled fashion. There's no question about that. Confirmation on this was provided independently by don GASHOP in Kentucky, where the GGnext 23,, he showed -- GGNF, he showed in the supercortex and the CERle, -- CEREBELLUM at post-OP. The evidence and leakage and the possible toxest that might be associated with that re-enforces the improved delivery method, indeed, in the Seminole medicine nature paper a couple of years ago suggested gene therapy as an example of approved delivery method. Indeed, our data coroar -- coraabe rate that. We see no evidence of leakage or sery bellum toxicity. Following high dose. No evidence in this problem . -- an initial autopsy said from one study revealed no cerebellum toxes et. So,or -- toxicity. Our position on this most likely reflects on targeted delivery in the monkeys and other inherent limitation of the protein. This argues for not against the use of gene transfer in this application. There's a question about the rationale for our human dosing schedule. We're happy to address that as well. Warren went through this nicely. I don't need to repeat it again. I will point out two things, though. This is a cumulative review. As each patient accrues, we get more data as we go deeper into the trial, and secondly, this is a dosing schedule that is -- common to use. Similar to what we use for CERE-110. But used by many other people. This is not really novel. We believe it's appropriate for our program, though, more to the point. First of all, the purpose of the study, remember, is to look at the safety in the subjects. The volume expressed in Neurturin early has reached a steady state bee four weeks. The non-clinical package reveals a safety toxic program in high doses. We push them intentionally. We want to know what could go wrong to prepare for it. We were unable to get toxicity and doses higher than imagined we could go. That's after many months of treatment in rats and monkeys. You give these high doses, months later you don't see anything. No animal -- evidence of toxicity or evidence of greater risk over time. Also important to remember the protocol leverage decades of experience with growth factors. In the animals and humans. Some of the humans have been dosed for several years each, including with the close cousin GGNF. The close cusin to nur turen. No studies show the greatest risk for toxic effects in animals and humans including on target delivery. As we're talking about. These are within days to less than four weeks. Now, the hypoet thatical risk of Jon transfer does exist and it's uncontrolled spread. But I hopes that convinced you with the data we have given, the studies we have run, the large-dose multiples we have given there is no evidence for that and in our studies and it's unlikely to occur in the proposed human trials. So, while the dosing protoing -- protocol that we provide using one month -- I'm sorry. That's, sorry, it's bothering me. Thank you. So, the proposed dosing schedule --
Excuse me --
Generating data with 120 --
Dr. , Let me interrupt for a second. People on the telephone, somebody's listening to the webcast and it's coming through here. Now, I'll also remind you the webcast is delayed. So we're hearing the same thing over and over again. If can you turn down the volume of your, on your computer, we would appreciate it.
I apologize for that. It was really distracting me. Thank you. Synopsis of the dosing rationale is a proposed dosing schedule supported by the data generated by CERE-120 and neurotrophic factors generally. They need to find more affective treatments for advanced disease as Warren talked about and the careful safety monitoring we're to do for this protocol. These are the issues we thought were the most profound. We hope we have addressed those effect elf with the data. We would be happy to talk with you further about them. We would like to focus on the datas that generated and the issues that may still remain. There mean other questions that the RAC committee members have thats that not chose to put up on the board. We'll be happy to talk with you about those as well and we look forward to an active and object objective review in general. [ Indiscernible ]
I would like to take the opportunity to introduce Joan Samuelson. She was asked to come before you. s that donated some of our time so she can speak to you.
Thank you, Dr. Bartus. That was very clear. Thanks.
Thank you .
Hello, my Jame is Joan Samuelson. I'm a lawyer by training. -- my name is Joan Samuelson. I'm a lawyer by training. Quite a long time ago, my parkinson's disabled me from that. Fortunately, I wasable to apply my training to my current work as a patient advocate. I'm President of the parkinson's advocate network, a national voice for the parkinson's community and working in Washington in the state for research funding and changes in research policy to speed the earliest possible cure. What I wanted to do today is just be sure that you have in mind the appropriate context in making the decision that you're going to make about the, the safety of this proposed therapy. I'm not a scientist and I don't enstepped at all to try to weigh in -- intend to weigh in on the safety of this, this therapy, and I would appreciate that you need to give this serious serious consideration. But I think it's enormously important in doing that that you're thinking about the actual real life circumstances in which the patients who would be candidates for this trial are living. And so that's what I wanted to make sure I can describe to you so that you have that clearly. I have been diagnosed with parkinson's for 18 years, and so I know it intimately and I have also worked with lots of other folks in the parkinson's community, and I see what parkinson's is like when one is advanced. I am not advanced, greatful -- greatfully. Many people, most people, I think, who have had Parkinson's for 18 years post diagnosis are. I'm very lucky. My, here is a little vignette of my well. I week up this morning, essentially frozen stiff. If I were to load up on enough L-deep to prevent this the night before, I wouldn't be able to sleep. It has that side affect. So, I live with the fact that I wake up knowing that at that point I can barely move and yet takes great difficulty to reach over to get a pill, get some water and get it into my system. And then I wait. I can't really move. I can't hold a book. I can't write. I attempted this morning at the minimal, a scribble. It took this morning 65 minutes for the drug to go down through my gut up into my blood stream into the brain and what we call kick in to the point where I could get out of bed and get functioning. And that's about average. If there is still food in my system, if I'm stressed, i've I'm -- if I'm tired and other things will delay the kicking in of the drug and delay my ability to function. I am L-deepin responsive, obviously. It does work when it works. I typically have other periods during the day when it doesn't, so I struggle through those as well. I am one of the lucky ones and I am tremendously grateful For those that are not so lucky and also to patients who would be in this trial, they not only have the difficulty when the drugs report working at all, but if, even when they are working most activities of daily living aren't working very well. Patients, I don't know anyone in an advanced stage who hasn't long before lost their employment, lost their ability to drive, lost their ability to keep themselves from drooling. Lost their ability to control bladder function. Lost their ability to stick clearly enough to be under -- speak clearly enough to be understood in all situations. Independent living for someone who is advance side almost always impossible. They need help eating, dressing, getting around. People in that state are really very much prisoners of their homes in most situations. I think there is often a missed impression about Parkinson's. Because you see us, the public sees us when we're on. We can't get out of our houses or we don't want to because life is so difficult when the drugs aren't working. And for the advanced patient that is usually the case. Those who just have direct effects added on top of the affects of chronic L-dopea use and the combination of drugs that need to try to ramp up the efficacy of L-dopplera when it's not working. Those are, I described, sleep disruptions. I don't know anyone who is advanced and most people aren't advanced yet. Who doesn't suffer chronic problems with sleep, unable to sleep at night and unable to stay Awake and think clearly during the day. Chronic L-dopea causes hallucinations, mood and cognitive problems, and then we add on top of that, when you add a combination of other medications to increase the efficacy of L-dopea, or to address the complications, that it's really a pretty chaotic combination of side effects. So in the late stages, prisoners, parkinson's patients at that point, are really prisoners of their bodies, unable to move and often upably to speak. So I would just like for to you keep this in mind. There is an urgent need and the words found me when I tried to really convey how urgent the need is. There is an incredibly urgent need to quickly, as soon as is possible, tomorrow, to get an effective therapy for parkinson's. Please don't assume that the patients who would be candidates for this trial are doing well in almost any respect. Please don't make a decision about risks and benefits in a vacuum. This is not a risk mutual environment that those patients are looking at, and please don't protect us from this risk inappropriately. There are many risks that patients who would enroll, would happily accept in exchange for the possible benefits on the outside. Please think about all of this as you make your decision. Thank you.
Thank you very much. Luckily we started early, so we have enough time for a very thoughtful and very rigorous review. What I would like to do now is begin the review, have the individual RAC reviewers summarize their concerns for the record. If and how the participants in this protocol have addressed their concerns and then also summarize any remaining or additional concerns they may have. So, what we'll do is we'll start with Dr. Martha Bohn and before Dr. Martha Bohn starts, she has a statement to read into the record .
So before I, is this on? Before I begone my review, I would like to make a desclose ear. Academically, one of my research interests relates to the development of regulated vectors for parkinson's disease, and I am participating in the large multicenter, multidisciplinary program funded by NIH's national institute of neurological disorders and stroke. That is working on a coordinated program of basic research, preclinical evaluation and ultimately clinical testing in gene therapy for parkinson's disease. Dr. Howard Federoff is the principle investigator of this cooperative agreement . So, first I would like to thank the members of the Ceregene financial a -- family for their very interesting and informative presentations, as well as Joan Samuelson for her cogent remarks about this disease and all her hard work in advocating parkinson's disease research. I certainly, and I am sure everyone in this room would like to see a neuroprotective strategy for this devastating disease. It's an exciting protocol and I have long worked in, I've long been an advocate for neurotrophic factor gene therapy. The investigators provided abundant data. The reviews were quite long. The responses to the reviews, I believe, was 56 pages. Many of the points were addressed in the presentations this morning so I would like to just focus on some of the points of my review that I feel strongly about. There is no doubt we need a good therapy for late stage, mid- to late-stage parkinson's, and this protocol is the first trial using a secreted growth factor for parkinson's disease. This is still a major departure from all previous jeep therapy trials in the CNS; there are two gene therapy protocols, both using AAV vectors for parkinson's disease, one is using GLUTAMIC acid decar box Ellisa, the other amino acid DEBARCOACYLASE, they use strategies or ways to remove the gene expression in both protocols. The data on the Alzheimer's trial is very interesting. I believe the course of that disease is different from packinson's, although they're both devastating and the nerve growth factor gene is the into one small brain area with supporting data on the, from the ex vivo trials. I believe it adds also different. I find this presents an ethical issue of whether putting a gene into the brain that is likely to be there for man years for a secreted factor, I believe it can be done as long as all of the safety and efficacy studies are in place. It should be noted that all the scientific community also had very secure abundant data showing efficacy and safety for field transplantation in parkinson's disease. The human trials were ceased due to unexpected diskinesia's that developed in some patients, which had not been protected by the animal studies. The response, as you heard this morning, that Ceregene has presented Abundant efficacy and safety data for the Neurturin gene therapy approach in rats and monkeys and if side affects develop, they're ready to use medical means to treat these affects. They suggest a number of hypoet thatical side affects that meet occur based on previous trials with the related protein GGNF, however, one can't fully press secretary these possible side affects. Therefore, in the absence of a rescue strategy, one has to be fully confident about the safety and efficacy data in the clinical designs. So let's examine those data. I believe the toxicology safety data are really admerable. Compared to other protocols we have reviewed, I think you have provided a tremendous amount of toxicology data that looked very encourages. The efficacy data I have more of a problem. It should be noted I did not receive all the details on the experimental paradigms until yesterday evening. I didn't know I had requested those details. This made yet somewhat difficult to fully evaluate the efficacy data but what I find is not totally convincing to me if we look at the rat, the two rot rat models, one is the rat protective model where the AAV Neurturin vector was put into rat striateum two weeks before six hydroxyadults lesion. There is clearly significant protection, and I don't think any of us doubt that nur tursen a dopea MINERGIC trophic factor. On the other hand, I'm not sure how well -- that relates to the crinical protocol because this is not a damaged system. And the question would be if you put the Neurturin gene in the rat model after the hydroxy dopea mean lesion, would putting it in the striatum be effective and I suspect it wouldn't be, but that experiment's not been done. I think you would probably have to put it in the Niagara to protect the neurons if you put it in after the six hydroxy dopeamine. Then there is the agent rat model, which interestingly, the surgeon investigators used for toxicology studies and they reported there was, so they put the GGNF vector in unilaterally into the agent rat striatum. It reported there was no affect on dopeamine neurons or on behavior in these rats and that, therefore, the vector was safe. On the other hand, I believe they should have seen a unilateral affect of the vector on the -- on the dopeamine system. If putting the gene into a degenerating dopea mean system in the center atum is effective, when Dr. Bartus presented, he mentioned some data that was not in the protocol showing hypertrophy of dopeamine neurons in the agent rat, and it would be nice to see those data because I think they're very important . Then the very efficacious data shown in the MPTP monkey model, as I understand it, the vector was put into the PUTANUM CAUDATE and importantly substantium -- and they saw a radiance course in these monkeys. I have a problem with that protocol also and how it relates to the clinical protocol because the vector was put into neingra. It won't be put into neingra in the humans and no one knows whether in this MPTP model it would work. Just putting it in the sights to be used clinically. Therefore, I don't think that model reflects the clinical protocol and I would like to see data in an MPTP monkey model that parallel the clinical approach. So for the efficacy studies in my mind, this leaves the aging monkey model which, is really a very good model. You have degeneration of the adult dopplera mean system. The -- dopamine system. The doctor showed the GDNF delivery can reduce that system in the aging monkey model. And in their study, they put the vector into the PUTANUM and caughtate, which, let me -- CAUDATE. Let me ask you a question. In the clinical protocol and the abstract of this protocol, it's stated that the four sites to be injected are three in, two in the posterior PUTAnext, M, one in the anterior and one in the CAUDAT,. In the response to the reviewers and also we heard this morning, all the sites will be in PUTANUM. I would like to know if that's a change in the protocol or if that, what is going on there. But any case, similar to what is proposed in the clinical protocol, the Viktor and the agent monkeys was put into the CAUDATE and PUTANUM and pet data show it three months, an increase in the range of about 20%. The investigators say that is significant to be less than 0.001. I think they should look at those numbers again. I don't think they're significant. But I am willing to be convinced but I don't think they're significant. The reviewers requested longer-term data in the monkeys. I think it's an important model there. Is only three monkeys. The investigators stated it would be too stressful for the monkeys to travel Across state lines for more pet image. I think it's probably -- it might be more important for long-term data in non-human primates than to undertake a trial in humans prematurely. In summary, as this section, the efficacy data leaves some questions in my mind about proceeding with the clinical trials, especially in the absence of any way to remove the gene. The next thing that I would like to discuss is the eight sites to be targetetted. Again, this is a question in my mind of what the sites are really going to be. And I think, I was concerned about the distribution of Neurturin and inappropriate targeting, I think, the data has shown support that this might be minimal. It was not clear to me how many sites were injected with the vector in the monkeys where this distribution study was done. I also think it might be aggressive surgically to do eight needle tracks in, in this trial and suggest this might be designed more as a phase I/II, than a phase I safety study. I had questions, as well as I know Dr. Howard Federoff had questions on the rationale for Neurturin and what receptors it would be acting through. The response is it's probably acting through the preferred GGNF respet -- resupportor, GGRF Alpha I. That's probably the case. I asked for levels of Neurturin protein and whether it accumulates over time. I believe the response to on that was adjat -- adequate. And then I had questions on the, using the pro-NGF sequence before Neurturin and whether there is any pro-Neurturin detectable and whether it might have a separate biological affect. I think the investigators misunderstood that I was suggesting this meet work through the soil and P-75 receptor system. I don't think that would be the case since nur tur sin not known to bend to P-75. On the other hand, there mean some unknown actions biological affect of this promolecule, for example, made it through some interaction of the receptor with GFR Alpha's. I think at the very least, they need to look at levels of different forms of Neurturin following the injection of the vector into the CNF. The other points in my review, which I believe were adequately addressed were the criteria for adding additional subjects to cohorts. Description of what will be done with autopsy material. Relationship of pre, human antibodies to AAV and vector activity and appearance of vector DNA and cerebellum and lymph nodes in the actions of expression which seemed a bit strange. In summary, the clinical design is aggressive. The efficacy data leave open some questions and relevance to the actual clinical protocol or, and the disease stage that will be targeted in the subjects. My recommendations would be to consider fewer injection sites, to consider longer intervals between cohorts and since 28 days might be minimal, I understand that's where you you get steady state levels of the trophic vector, but if one gets untoured, unexpected side acts of this G gene expression, yet may take longer to detect those, see those in subjects. To provide long-term compelling data in monkey, an agent monkey or the MPT monkey model for which vector epjection sites directly parallel those to be used in the clinical trial to determine the different levels of species in the vector and CNS, to clarify the sites that will be used in the clinical trial and to submit data, hivet logical data supporting the -- histological data supporting the contension that the vector does induce a rejuvenation of the dopamine system in the agent rat model.
Thank you, Dr. Martha Bohn. Would someone from the team like to address some of the remaining questions, and I will summarize the major ones and, Dr. Martha Bohn, can you add to that if you like. The major question was that regarding efficacy, it was noted in the MPP model, it was injected into the Niagara, may be you want to discuss the relevance of that with respect to the trial. And if you intend to do studies that more closely parallel the clinical approach. There were questions regarding the significance of the 20% effect in the pet data. It was noted that, there was a question about where will the sites of, the sites of Enooklation in the clinical trial be -- of inoculation in the clinical trial be. The need to do longer-term studies in non-human primates, the questions regarding the distribution of Neurturin. Discuss the risks of eight needle tracks and consider longer-term intervals between cohorts. If I left any of them out, bring them up as they go along.
just the agent rat data.
the agent rat data.
Whether, whether in the agent rat the dopamine system wasoff 98d unilaterally.
Okay. -- was -- was rejuvenated.
We need to address the questions. Do so. [ Indiscernible ]
We're does Going to discuss it and at the end, formulate recommendations. These may not end up in the recommendations.
Help me go through them. First of all, we apologize for two things. One, lack of information. We were not clear on what detail the reviewer is looking for in terms of the methods, of the six hydroxydopamine MPT study. There was a lot of travel going. We got that late. I hope we got it in time. We have to give you more details about that if we wish. We would also like to, this needs to be inlocked. Thank you. We have will be happy to show you the more reTrent -- recent data by the agent rat. Let me start wheel you're setting up the computer. You raised an important point of the use of animal models for the product of human use. This is something we could talk about for a long time. I have been involved in this in my career for 30 years. I think it's important, first of all, to have a respect -- perspective on what we're trying to do. We're trying to treat parkinson's subjects to develop a product for parkinson's patients. These patients, of course Va disease in microstriatal systems involving different positions from neurons that are dead and can't be rejuvenated there. Is nothing we can do to save those, to neurons on the way to death, and growth factors, of course, can, by the way of animal studies and human studies, reoff 98 some of the nurons rejuvenate history neuron -- nearons. Neurons that are impaired and some that can't be affected by the disease at all. We believe three out of four of the neurons just describe are appropriate targets for Neurturin that can be regenerated. It's important. Hope the audience holds on to that. With regard to animal models, it's true to say it, but it runs to the core of what we're talking about at this point. It's impossible to mimic every aspect of a human disease with any animal model. Dr. Martha Bohn has asked for an example we have in a paradeem with the six hydroxy dopamine model, a sledgehammer to the to treat after the effect. If we got a positive act, that would be wonderful. If we didn't, did does that mean this drug wouldn't work in of course not. That model is nowhere mimicking the pathology that occurs in parkinson's patients. It occurs in a matter of hours to days as opposed to months and years. It destroys neurons very quickly. Almost uniformally intoday is of progress elf and hit and miss. So mimicking that at all. When you talk about a growth factor intended to rejuvenate nurons, that's a key point. I could go on about MPTP, monkey agents, I won't. I will say the following: What we do with animal model when is we're zep developing drugs to put into mines when they're approved is activity the principle will this in fact work. Is there sufficient specific evidence to suggest that this, in fact, could be useful N.this case, could be revolutionary for the treatment of parkinson's patients. Martha Bohn made a key point and she was reading from her notes. I hope this is agreeing with what you're saying. None of us doubt nur tur sin appropriate factor for Niagara striatal nurons. That says it all. If you believe that the degeneration of neingra tree is atal neurons is a key pathogenic for parkinson's disease and if you believe nur tur sin a key for these neurons, that is scientific evidence to justify the potential efficacy of the treatment in mines. We have done more than that. I hope you acknowledge that. We could talk back and forth about the -- [ Indiscernible ] And models epTerpitation on data. It really doesn't matter. The data collectively overwhelmingly shows a bioactivity of the AAV Neurturin in a number of rat and monkey model systems. There is no question on that. I hope that's the case and I would love to talk about that point specifically if, in fact, it's a question. The point is you have sufficient specific evidence. The question now is: Is it appropriate going forward? Are we putting parts or subjects in this case, at updo risk to treat this? So, we have this, I would like to show the agent data. I am going to need help to -- exactly where this is. The point is from is not a single system we looked at, rats or monkeys, the way we set up the system that we didn't have positive affects. We set up the system in the most conventional ways . -- the point is that no matter what system we use, we have positive acts. We didn't condrive the system. The MPTP model was used exactly as it was published for lengthy GGNF. We mimicked that system. That was the validated model. We have the deep discussions with the agents of the FDA about what model should be used. They said validate a model. Don't get a new model if you're trying to prove the principle that your product could work on parkinson's parts. We used the model as it was published. We're using the model as is typically used. We're not trying to recover dead neurons and a frank Acute degenerative condition. We're trying to show we can provide trophyim -- trophic support for the neurons to generate . This is one of the slides I wanted to show you. This has to do with the differences --
excuse me, you have to speak into the microphone.
Sorry. This has to do with theative reps of the protocol and what has gone on with the past. Martha Bohn raises valid destensions. One of them is there is a rescue therapy for all the other protocols. That's something, frankly, we don't think that is practical and I would like perhaps neurosurgeons in the audience to address that specific issue is how well prior trials could have, in fact, removed the transduced cells. The second distinction Dr. Martha Bohn makes with CERE-110, the RAC approved last year, the similar dose protocol, this time, it was far, far less safety and efficacy data. The A-was that whole this is a small new low -- the argument was that while this was a small newly -- nucleus in the brain, this is a small victor. We have shown the exprelgz -- expression of nurin very actively with this product. We don't get targeted factor. Three decades of data show that if you keep the targeted area, you don't hit problems. We looked at point 0, ground 0. There is no degeneration in the neurons where we put the vector. We have no levels what's idea what the levels of protein are. They have to be sky-high. No problem there. Untargeted delivery is the problem. Yes, we're given more vector. It's a larger target and we're controlling the protein to stay in the target. More importantly is the data on the slide. The top half is CERE-110. The program that RAC approved last year and I share with you data from thend of our uneventful first quarter. This shows the high of the safety monkey dose we test side four too times 10 to the 10th vector of the genes hemisphere. The vect on -- we complete side four times 10 to the 10th. Using brain weight as a multiple for comparison, the monkey-to-human dose multiples is 53 and two and 63 times. What that mopes is we gave to the monkey and to be safe, doses that were 53 and two and 63 times higher than the two doses that were approved for CERE-110.
Dr. Bartus.
Yes.
When you say high, monkey high safe dose, that means that's the highest you have gone. That doesn't mean if you use more it's toxic, is that correct in yo That's exactly correct. Thank you for clarifying it that. We have seen the toxicity in another of our products, this is high end tested. The high safe dose of monkeys is as high as can you go. It's impossible to safely administer more volume, more vector genomes given the concentration than we did in more sites. We load -- we loaded the brain up. To answer Martha Bohn's question, you saw with the deliver, this is Viktor was with multiple injection in the PUTANUM. That was a safety TOX study. An added, high-dose, again, looking for safety problems that might occur and didn't occur. This dose in monkeys compares to the proposed doses in humans by one to 400 times. So, yes, you're right. It's largering -- larger target. We control the protein. We're getting hier-vector genomes. We accounted for that and went up higher, almost twice as high as what we did for CERE-110. We think that adequately accounts for the problem. We are as responsible about this as we, the RAC is, and we believe that we have done everything that can be done to address the issue. [ Indiscernible ]
Dr. Bartus.
Yes.
One, let me sort of refocus, I guess, the initial question. Maybe in a different way. Where, in this trial, where will the clinical inoculation be and what regions of the brain.
Thank you, that's an excellent point. We had considered the CAUDATE PUTANUM. One in the CAUDATE, three in the PU, -- PUTANUM. We had stated a vector genome dose. We set the parameters based on our comprehensive safety TOX program believing that we could justify that. In fact, we feel we have. As we refined the protocol further, we elected to focus on the PUTAnext, M, the antearior post Cu -- PUTANUM and not CAUDATE the targ.
The. Okay, therefore, have you done the MPTP monkey studies and the agent monkey studies by inject into this PUTAnext mu, in.
We have. Several rein reasons for that. That monkey model we use is a standard parameters used for testing drugs and for parkinson's disease. They were simply used in the Val dated model. Secondly, MPTP destroys both components and it would not be a fair test or developed test of the product in that regard. Again, we're not using that monkey model to determine whether or not our drug is going to work in parkinson's subjects. The only way we're going to know if our drug works is to dose parkinson's subjects. We're using that model to test the principle. Can we demonstrate the Neurturin delivered a AAV II into the monkey brain can do what we want it to do to degenerating neingra striatal nurons. That's the key point. Have we demonstrated the principle that Neurturin can do what we wanted to do when delivered eye AAV II. We saw it with agent monkeys and rats, with MPTP monkeys and young monkeyses.
can I make a couple of comments.
Sure.
I think the Princible is whether delivering the gene to the terminals remaining in the parkinson's patients is going to be effect of. And, therefore, and you talked about a gold standard model. Yet, MPTP and one of the reasons I ask kept requesting data on how the MPTP was administered is there is a variety of MPTP models in montho. And it's possible to model the monkey with MPTP so that you have a stable chronic lesion with fibers remaining in PUTANUM that would mimic the clinical state of the patient group that you plan to target.
Let me just address it. That is a key point. I agree with that 100%. If we don't have -- didn't have trophic support in the nur opposite, I'm not sure the specific basis of the program would be sufficient to go forward. We showed the following N.yong monkeys given our product, we showed not only enhanced TH in the Niagara, but Pradio in the Niagara. We showed the cells in the Sdopamine model. We have shown agent monkeys with an uptake.
shown, in fact, we get protein there. The protein is there. You have seen the signals itself. You said yourself that nur tur sin a trophic factor for the neurons. You're right. We set that for ourselves. We needed to see evident we are getting proteins and seeing the biolongic response. We satsified the important criteria. Trying to refine the models that mimic the nuances of parkinson's disease is something that is potential -- potentially interesting, useful on the road, it's possible to do to everyone's satisfaction. We believe we can approach the appropriate way.
Let me, one second, Warren. These are the data, Dr. Martha Bohn. It was not fair to talk about them without showing you. We had no way to show that. These are recent data. This is just looking at blinded analysis of Niagara neurons looking at the TH and the uninjected side and injected side of agent rats. Can you see a 15 to 20% increase in the size of the neurons, the neurotrophic factor. You typically get them in the studies and the highly reliable phenomenon.
Is the report in your response to the reviews stated there was no change in the TH or V-met staining of fibers in the striatum. Does that still hold up in.
Yes, that still holds. Yes. Yes. No change in numbers as well. One other point in that before I provide more crenically-related points. There was one think this I believe was misspoken. We didn't mean to say there were no acts on dopamine neurons in agent rats. We didn't look into them recently. What we said was there was no effects on motor performance. We, frankly, didn't expect an effect. We used it as the toxic models. We were interested in patient safety. The concern, of course, was GDNF was reported doing a number of things in the Niagara stri atal system. We believed they were compensitory, not toxic. We believed if they were toxic, they would be worse and they were not. If we had shown the agent rats with L-dope AI believe we would have gotten behavior because the effect on one side. The fact that we didn't get it to behave spoon tappeously, as I think you know, doesn't demonstrate a lack of trophic response. It was not a good test of it. That was not a purpose of the study, this was part of a pre-laid plan associated with the FDA. Nothing we're doing post-HOC. This wasp tended to be an agent.
yes.
Dr. Bartus.
Yes.
we have three other reviewers. Perhaps the issues will commune with other reviewers. There are a couple of remaining things from Dr. Martha Bohn. One is the risk of eight needle tracks and the consideration of longer-tomorrow intervals between cohorts.
So, I'll briefly make a couple of clinical comments. First of all with respect to the CAUDATE, the anterior PUTANUM is embryo logically and functionally similar to the CAUDATE by using the anterior PUTAUM and not go to CAUDAte,. We can get higher dose into the region and risk getting into the vent kills and we're capturing the same system in the same degrees. We're capturing here And the transplant data that can you still see effects into the CAUDATE. To me it's a judgment call and I didn't know there was a right or wrong answer. I think we went through the same discussion with our fetal transplant studies and ended up with the same kinds of conclusions. The second thing I wanted to mention and Andre can say the same sort of thing is we routinely implanted eight needle tracks per side, per side in our fetal neingeral transplant studies without a single side affect or complication using the similar kind of protocol to a similar sort of target. And for deep stimulation, we routinely use five needle tracks per side and rarely have a complication and Andre can confirm that from his point of view. I just wanted to mention a word about the diskinesia we saw in our transplant patients. As we have gone back and looked at those and gathered more information in the hist tearia of that -- the hysteria has passed, what it looks like, we're now publishing is that these are turning up to be DYPHASIC, occurs with the low level the dopea men everyone,ic agent. We didn't anticipate that because we didn't anticipate we would deliver a low lovely of dopea men everyone,ic agent. We should have anticipated that. That's been seen with infusion. I think there is a good chance we request with get around that. An important problem is had we not done this in parkin sewn's patients, we never would have known about this. had there is no way to effect elf model this in animals. I don't think they get that type of diskinesia. I want to make the point that there is only a limit to how much safety can you do in an animal model that ultimately you have to take it to the disease if you're ever going to really know what to expect in the disease.
I'm going to address that. A professor of neurosurgery in Toronto and President of surgery in the -- [ Indiscernible ] Functional surgery. I represent 400 neurosurgeons that do these types of procedures. Indeed, there has been 30,000 operations for parkin sewn's disease using deep brain stem lesion and many groups use multiple tracks, five per hemisphere. This is really a standard. Furthermore, the targets chosen in this nucleus probably have an increased risk in comparison to the PUTANUM. I think that both in experimental studies in the past involving fetal niingeral transplants, the cells and clinical usage, there are many nurtured in thousands of parts that have had in access -- excess of four tracks per hemisphere. I think this is really the standard of our practice as it is today.
My name is Jeff chord overa, a professor of science at Rush university center and I performed the monkey studies shown here today. I wanted to address Dr. Martha Bohn's comments briefly. [ Indiscernible ] There is about a 55 to 60% loss in the parts of packinson's disease in the stage you see here. You often see quotes there is a loss of 80% of the neurons and parkin sewn's disease. That's not true. The loss of 80% striatal -- [ Indiscernible ] But in terms of the cells, that's about a of to 60% cell loss. Dr. Martha Bohn is correct. There are a number of ways to administer MPTP. In in my way, there is no way to administer to get a 60% loss and have stable deficits. Can you drive the cell death, can you inject the artery on one side and lose 90% of the neurons and go of a partial on the other side. That thadoesn't model what we're doing in our patients what. We try to do and we want to make this clear, the purpose of the studies is not to necessarily model what we're giving our parts, but to prove to two points. One is can we provide neuroprotection for the cells and can we augment the cells. What we did is reused the model we published with lengthy GDF and -- [ Indiscernible ] Finance in the year 2000 where we did a neuroprotection model. We did MPTP, waited five days and we know there was extensive striatal degeneration occurring and trying to protect against that. That was one of our goals. We wereable to show profound protection and as a side point, this panel was approved, the protocol of AAV and I did both study as well. The level of new protection in this study to have a level of efficacy shown in that study. The other thing we attempted to do was show them we can invigorate agent cells, which might be now to the model that took patients during the study and it shows that as well. So, I disagree, Dr. Martha Bohn, that we can provide an accurate model of advanced parkinson's disease that truly mimecs the status of the Niagara striatal system in GDF -- GDP. We can create for the deficits, not necessarily modeling. We can find the protection and provide extensive upregulation of dopea men everyone,ic. They're our goals from the -- dopeaMINERGIC. Those are our goals from the beginning and we will achieve theme them.
Dr. Abop, you have comment?
I think it was unfortunate that Niagara was put in the experiments. I think the aging monkey is the best, the close of the model.
Let me just address that point quickly. Certainly the rat data shows can you put in the striatum and get neuroprotection andingmentation of stri atal function. As you might suspect, a long and hard conversation of the actual design here should be going to the Niagara, shouldn't we go into the niingra. The issue is we're not going into parkinson's. We're dealing with a vector that has a ramp-up time.
I'm sorry, we'll save this for the discussion. We're going have to move on to the next reviewer. Dr. Howard Federoff. Are you on the line?
I'm still here.
Okay, so are we. All right, do you want to summarize your review and tell us how the investigators -- review and if you have any remaining concerns.
Yes, I might note that I have been having some difficulty hearing those at the podium, so if it would be possible when they reploy to some of the points that I make if they could speak more loudly, I would greatly appreciate it. Let me first start off by thanking Dr. s OSTRO, ALANO, Bartus, and -- I think the review of this protocol is extremely important because it characterizes in my estimation a landmark protocol and that is providing the -- unprecedented and providing an opportunity to evaluate the unrestrained production of bioactive molecule and neurotrophic factor Neurturin on the Niagara striatal system on patients with parkinson's disease. I found that the response to my questions and I'll try to be brief here, are largely well-addressed, however, I will make thought of -- note of those I thought required further elaboration and underscore in the rare case where the response I thought was inadequate. The first of my issues really pertain to an understanding of the potential toxicity that could be associated with the delivery of Neurturin by the recombinant AGE transfer. The first three address the fact that the investigators have made a chimeric protein probably to enhance the processing of Neurturin, which in the environment they wanted to know first whether there was indeed evidence for any response to that novel EPITOPE created by thefusion of the sequence of the nerve growth to that of Neurturin. Their argument was that given the sensitivity of the assays for Neurturin antibody detection being what that were and the absence of any data pertinent to that, they didn't feel it was necessary to characterize the potential hypothetical response. It still remains an unaddressed question. I think from looking at the data that they have provided, it would appear the ability to detect antibodies to nur tur sin not terribly sensitive and I just leave that as an inaddressed issue and may well become relevant should this protocol move into a clinical stage. The second was partly addressed and I think also brought up by Dr. Abop, and that is whether the pro -- by Dr. Aborntion and that is whether the proteins, if it's indeed -- epdeed secreted and process, although they mention that the vast majority, I think, was the terminology used in the culture studies which the recombinant AAV-carrying Neurturin was studied, was, in fact, mature Neurturin, I was interested in knowing whether that was true in the central nervous system and knowing particularly whether the protein that mean released from the transduced nurons was, in fact, exclusively mature Neurturin or perhaps could, in fact, have the appended pro sequence in incomplete processing. That point, whole addressed until cultural, the data I requested by western bloght wasn't presented still re -- bloght, wasn't is any asked and still remains an issue. On the scale of things, it's a relatively minor one at that. I was also interested in several other issues that were pertaining to the likelihood of having responsiveness in parkinson's patients that at later statements. And I asked whether there were information pursuant to the ent isors in this case, likely to be the GFR Alpha I receptor resident within remaining Niagara striatal dopeaMINERGIC neurons in the parkinsonian brain, and I think the data are not yet available. It would be quite useful because it addresses the potential clinical utility of the approach, and while the point was made that this was true in other diseases such as Alzheimer's disease, that is a very different disease entitty, and although it may be correct that one can extraf -- extrap late the absence of data makes that relative issue to me at present inknown. I had asked a variety of questions regarding the sensitivity of the detection of the conveyance of the CERE-120 outside of the nervous system because there was evidence there were vector genomes and the data that was brought back in response to my question was that there were, there was no evidence for messenger RNA detect -- detect, and I don't know what the absolute level of detection, the way the data were express side on a basis that I am not quite familiar, so in terms of absolute numbers of molecules, I really still don't understand whether we know the lower eliminate of sensitivity with the methodology that they proposed, but given the data that they did propose at that level of sensitivity, um, there was no detectable message, so the concern that was raised regard to potential lymph node or SPLENEC content of message in the opportunity for expression and maybe antigen presentation was addressed in that matter. I asked about antibodies that covered that before and I think that that was also raised in another question of mine. Now, the last point that I would like to make, and I think that this is one that has been danced around in a number of the discussions that followed Dr. Martha Bohn's review as a protocol, and may be if I could draw a slightly finer point on it, I will attempt to. The question as I see it really relates to the utility of the non-clinical animal models to predict response in parkinson's disease, and from a bioactive perspective, the point that has been made is that the models are not, two models of parkinson's disease, but rather could be used to look for bioactivity of the expressed secreted Neurturin. I think that that probably is the best that one can hope for given the limits of current parkinsonian animal modeling. However, I think it's in that same regard, relevant to make two additional points, and I would like the one or several of the presenters to address this in a traditional pharmacological setting it's not peacock setting one is concerned about, but the chronicity of the bioactive molecule, whether it be in this case a protein or polypeptide versus a smal mol -- versus a small molecule, and I think one of the issues that Dr. Bartus was trying to address was the lack of need for being able to rescue or to extension wish the expression of the transgene once it's in residence. To my way of thinking, there is no current data presented by this group or others that really addresses the longer-term toxicity that meet accrue from the cumulated and persistent bioactivity of this molecule. Now, the data that they have collected to date would suggest that within the limits of its current presentation that there is, indeed, no overtoxicity. I remind you again that the parkinson's brain is different than the animal model brain. And I, I think the point that I was trying to raise with regard to the immunogenicities to brain inflammation. The last point that I would like to make in that regard is to ask whether the reviewers could tell us about their understanding of whether the unrestrained production of nur tur sin likely to contribute in any way to promoting inflammation. If so, did they believe that any of the modeling they have done, which they have admit side not truly modeling of parkinson's disease is going to be prckive to be copfeddent if they can't turn off the Gene, they won't create a pro inflammatory environment. Thank you .
Thank you, Dr. Howard Federoff. Would someone from the team like to address Dr. Howard Federoff's concern regarding the possibility that accumulated NTM would cause toxicity or inflammation .
Thank you, thank you, Dr. Howard Federoff for your invith -- epsightful comments. We appreciate your perspective that there is no perfect way to model parkinson's disease. All one can do is set up models to look at the bioactivity. We appreciate the effect that there is a no you in CNS. Different from the no view of models. That's why we have used agent rats and monkeys in part, except part of that because ageing is a risk factor for parkinson's disease. We're also aware the neurotoxit -- toxicity and MPTP produce a bit of an inflamitory action, that show the inflammatory newU in the brains.
Excuse me, Dr. Bartus.
Yes.
Dr. Howard Federoff, can you hear Dr. Bartus in.
I'm struggling to hear him. The last bit of that, I didn't hear. If it were at all possible, if he could speak slightly louder, I would appreciate it.
Okay, we're solving the problem. I have changed microphones. I won't repeat everything, of course, Dr. Howard Federoff, but I will say that we understand that, and appreciate your comments that it's impossible to monitor of course in the parkinson's brain with animals and we need to strive to do that as well as we can. We do that by using a collection of models, including agent rats and agent monkeys that have the character of thic age-related changes, since ageing is an important risk factor for parkinson's disease and parkinson's patients are agent, and recognizing that MPTP and six hydroxydopamine in the rat and monkey respectively that may mimic part of the inflamitory new you characteristic with the parkinson's brain. There were two points you raised in that regard. The first is the spread of protein and the long-term consequences and the coreulary that was whether or not -- [ Indiscernible ] The reaction to long-term Neurturin expression. I can say I hope you'reable to see this, the data we presented today. I assume you saw everything.
I did see it.
Great. You saw how nicely we can control the spread of protein. The interesting thing is those data showed reasonable correspondness from rat to monkey, independent of the six hydroxydeepa -- dopamine. Independent MPTP, from rats to manchy -- monkeys. But normal healthy monkeys. The point is we do capture a rainfall of CNS -- with the various model systems and we see comparable expression and spread of protein. So, that gives us some copfiddept -- confidence, at least, although we can't predict with great certainty that the spread of protein will be the same in parkinson's disease patients, we can presume that it should be similar to what we have been seeing. No data suggests otherwise. We have seen absolutely no problems from long-term expression of Neurturin and in rats, we have looked at a six-month time point and a dose of hundreds of times higher than required by efficacy in brain wave in humans. No consequences at all. Importantly as you look at the gradient from where you inject the vector, it's ground zero to use the local term these days to the number of protein expression. There was no different -- difference in the response. Our studies over the last few years have come to the the point that we can't have too much growth factor within the -- [ Indiscernible ] Of the brain. Since that harm is done. Harm is done buzz you do outside the target. Not because you have a toxic effect of too much vector. The last point is inflammatory reaction. We have any indications of the inflammatory event. Both in the lesion models as well as the agent rats and in healthy rats and monkeys, long-term, after the expression. We have seen no evidence of inflammatory reaction. No exacerbation with the neurotoxic inflamitory reaction exists and no exacerbation with agent.
let me just make the more, the direct point do you feel extremely comfortable to understeak and -- [ Indiscernible ] [ Indiscernible ] A Neurturin delivery. [tauz pausing to switch captioners] .
Determine whether there was an immune response to in your your rans. Those are the points that I raise at the very beginning and it remains interesting questions that I would like to have answered at a final level.
Okay. Just a few points on this. You know, classed by our distribution studies with Al vector in rats, I want to point out that the rat brain is very small, obviously compared to nonhuman primate and human brain and hence there was we believe a small amount of leakage that was seen in the draining lymph node, but we're talking hundreds of copies. We're putting in billions of copies of sensitivity of 10 copies, per microgram of DNA which I assume would be the standard for most researchers. We can detect the DNA fragments. It's in our case we use random prime dt second strands synthesis, wear not a hundred sure of the efficiency of that reaction but in no case do we see expression of nurtured m RNA and this is human and we do not see antibodies against into your cheurant. One would the protein to be human no general Mick. We know the rat can map the human response. We do see it in those studies. Being we can talk more about sensitivity later. It's a detail that if we want to learn more about it we can. But it's not the most Jermaine right now.
Thank you.
Thank you. We're going November on to our next review. We have to move on our next review, miss -- Ms. Quan.
Thank you. Before I begin my review, I just wanted to remind everybody here particularly because I heard the presenters as well as the patient advocate talk about our approving this protocol and I really want to clarify and remind people that this body is not a regulatory body. We are not here to approve or disan a -- disapprove any particular protocol but allow a public forum to discuss things that scientists as well as nonscientists may see related to any particular protocol. The presenters, the p PIs, the FDA and rib's are informed of our conversation. But any and all of them are free to choose to totally ignore what we say here. So I just want to make that clear for the record.
My review concentrated mainly on the abstract and the informed consent document and I want to note here that for protocol that was a scientifically complicated as this one is, the informed concept had unusually well written language compared to other things that we have seen, and, in fact, the documentation of the request for all autopsy was probably one of the nicest explanations that we've read. Nevertheless, a number of my comments had to do with clarifying and then perhaps changing the neurons implied implied benefits of this to anybody considering participation. And there was a fairly extensive revision of the informed consent document that seemed to take care of most of these things. In particulars I was concerned that a participant not anticipate a greater relief or treatment value from this Phase I protocol than was justified and I believe a lot of that was modified and corrected in the informed consent document . There are three areas I would like to discuss if you were the one is fairly simple. And one is on various pages there is reference to a 28-day period between dosages and between cohorts and in other places it refers to one smooth. This is very minor but this is the kind of thing that where somebody should just really make sure that it's consistent through the because the wording in the informed consent document according to the response has been he revised to be consistent throughout the document which is 28 you days and yet we saw in the presentation mention of the documentation by month and perhaps if you used weeks that would make it easier because a week is always seven days long. Then I also ask that there be greater explanation concerning the fact that the making of m TM by the body cannot be stopped because the brain cells may have been permanently and genetically changed when gene transfer is done and I mention that this is a very serious consequence and deserves a section or paragraph of its own for understanding. There was additions made to it and I think we saw it in the presentation what was added was a chart showing all of the anticipated possibilities that the presenters thought could happen from permanently and genetically changed brain cells. But I think what concerned me was also that this was the response that was called rescue. And I think in the-in our use of the term rescue in all the protocols that we have reviewed and I think also in a more general population, what they provided was -- what they would do to address symptoms that would happen if something went wrong, and what we're talking about is how to remove what's causing symptoms would be the correct definition of rescue. So I think that there still has to be a clarification and it has been made automobile clear to anybody considering participation that once that is inserted, there may not be a way to remove what has been inserted and that constitutes a permanent change, that you could possibly address consequences of that but you could not reverse and remove that. And I think that needs to be made really clear. And then finally I raised the question, I actually parsed the statement in the scientific abstract and this is a quote to be most safe and factors neurotraffic should cover as much. A without affecting nontarget sites. And I asked am I correct in parsing the sentence as follows. A to be most safe the therapeutic protein neurotrof if I can factors should not reach nontarget sites and to be more therapeutic the neurotrof if I can factors should cover most of the target as possible. If I am corrected it is Phase I to assess safety and powerAbbott and requires that the extent of exposed tissue be much more limited than described in the rest of the protocol, possibly never arresting the level described as the dose currently planned for the first dose subjects. I'm going to read the response that was given taking out some of the details. But this is pretty much a quote. In order to justify the risk of the neurosurgical procedure required to deliver this therapy, it seems reasonable that even the starting dose should have some potential for resulting in a clinical benefit. And then there's more detail and I'm skipping to the last sentence of the response. The proposed starting dose of Seri distribution is smaied to be at the lowest level that might offer some potential therapy without extending beyond the boundaries of the target tissue thus the starting dose balances the need to minimize risk while at least having a minimal potential for some benefit. I raise this because it seems to me that this may be a Paradigm shift in terms of the definition of Phase I. We have had Phase I flash Phase II protocols in which they start very slowly but within the same protocol then go to levels that presume to provide some efficacy but it seems to me that this is the first time that they say they decide the starting dose, not based on the escalation of safety but to begin at the lowest possible dose where they might -- they believe they might find efficacy so I have one question for the presenters and then some for my colleagues on the rat. Question for the presenters is do you, indeed, believe that this should be a shift in terms of the way how we define Phase I protocols for all human subject research or just for this particular protocol and if so, in Iraq case why? And then for my colleagues, I correct in assume that I think this might be significant change in the definition of Phase I or even Phase I/II and how do we feel about it .
Can someone address Dr. Quan's question?
Thank you very much. Your helpful comments and compliments on some of the ethical as pictures of our protocol. We have selected a starting dose as you describe that we believe is sufficiently low that it should provide minimal or no risk to patients based on extensive clinical data and try to capture an element that could provide efficacy. With all the studies that have been on growth factors we actually believe the greatest risk to the subjects will be the surgical procedure even though that's extremely small. And the point of subjecting them to that potential risk while having any upside at all for them as victims of Parkinson's disease seemed appropriate. To what extent that's Paradigm shift, I suppose depends on semantics because I'm aware as many are aware of many Phase I trials beginning at a lower dose but one conceivably could provide efficacy, whether they chose to define those as stage one/two is purely semantic I believe. The agency has discouraged us from using stage one/two which is a selected.. Even though we do have an intention of trying to provide some hope of efficacy in these early volunteers.
Dock.
Can I ask a question, why was it, could you justify why you're doing bilateral injections so in terms of safety it seems to be better to give it on one side and in terms of looking for any efficacy you've had a internlts internal control.
Yes, we thought about this they hard.
Go ahead.
There's a real problem in Parkinson's disease with lateral treatments. First of all, you're dealing with a bilateral disease. Secondly you're dealing with a side-effect profile. One of the problems you run into is if you do unilateral disease, how do you treat them. If you use treatment that controls the bad side you may get overdose side-effects on the good side, if you drop it to avoid side-effects then the bad side is poorly controlled. So when all is said and done this will be a bilateral therapy. Ultimately we need to know if it's feasible and if this needs to work that's the most reasonable way to approach it.
Dr. Johnson.
Well, first I will read my statement for the record. Before I begin my review I'd like to make a disclosure, rot column targeted Jeanette he tick as and uses this virus as a vector construct in its clinical trials. While none of the target genetic trials are currently aimed at Parkinson's disease I, nonetheless, between disclose the fact that I invented to av vectors and a vaccine vector that was patented by my former employer and licensed to targeted genetics. He received royalties and some of those royalty moneys are passed on to me. Okay. Well, given the hour, Neil, the way I looked at this protocol was in two buckets and the first bucket has been reviewed extensively this morning, that is the neurobiology of this whole concept. The second bucket has received no review which is the whole production and use of the vector as well. And this is a very group provided me with plenty of information both in one temp protocol and this rot column to ensure me that they, in fact, have a product that they can qualify and get through the FDA so I had no concerns about the vector or the production methods.
Thank you, Dr. Johnson now we're at where we've thoroughly discussed this protocol and I'd like to ask members of the rack if they have any additional questions or concerns.
I just wanted to follow up on one thing that Dr. Bone asked about and that was the increasing the delay between the patient enrollment and I wasn't sure if that was really responded to or if there were any thoughts about that as currently scheduled the 28 days and Marty's suggestion was to consider whether that should be a little longer.
Thank you. We believe that the 28-day period between patients enrollments is appropriate given several things. If I was of all that's rather conventional and it was exactly what this economy had approved a year ago and we see little differences between those protocols, the data protocol is more aggressive more extensive and more convincing. Secondly, we've demonstrated very clearly I think that the expression of nurtureant occurs in Broom, and a week it's quite robust. Within a month it reaches an asentoet while it's clear we're not sure how long it might take to get the biological responses that nurtureant might I know during once it rams that stage for 28. We look at eight months in monkeys, we've looked at long time points. We don't see any evidence of any toxicity at all. So how long is long enough? The data of growth factor sucked the liabilities is the ventricular areas and certainly less than four week. We can get miss targeted delivery in principal being transfer. We don't think it could happen within W any reasonable sense of probability with sairra. 120 but hundreds involved multiples between the animals tested and the proposed human doze. I would ask you to question whether you've seen similar dose mustless in your other studies. We're very proud that we're able to achieve those dose muttless because I think they're nearly unparened. So there's no data suggesting that there is any reason to wait longer. If you start thinking okay maybe longer than the question is how much longer, is two months make a difference, does six months, does a year? What will happen is that we'll never be able to effectively test this, get it into the subject and bring it to the patients who need it. This is advanced say the that deserves more treatment than it currently has.
Thank you. . Any other comments, any other comments from members of rack on file?
Could I just ask the restriction of the protein expression even with very high doses of virus is very impressive. What is the basis of that restriction?
That's an an excellent question. Av binds to most surfaces endogenous sites so we get very little diffusion. We are not using convection enhanced solution which is intended to spread the vector. We use something that gives better control, multiple injection sites. The protein doesn't diffuse does not diffuse that far from site of transducks so by selecting the target and having protein spread we get with the various rings of doses can be tested we can hone in very nicely because we have that control. It's an empirical fact that the protein stays relatively localized to the site. You get some diffusion. We can quantify that. It's a function of dose and we can actually control it.
The virus is restricted to that area or does the virus -- I mean, when you're pushing in lots of virus, I would have expected it to just by pressure elements would --
We see wired distribution in the monkey by the vast majority of the vector is restricted to the injection site. We do see some evidence of vector genome, it's minuscule amounts and transients. Most of had a is probably fragments that have been broken down. There's no evidence of transgene expression in other places besides the targeted area. And so if vector is being pushed out some place else, it's not transducing the cells into any biologically meaningful level.
Doctor. So I have a couple questions. In the first study that you showed the mtpt monkey model, you talked about the control and I didn't really fully appreciate what that was. Have you ever tried an empty control.
That was a safety efficacy study done in combination and agreement with the agency, of course, because we're moving towards developing a product for Parkinson's patients, and so we actually split those control animals in two groups. Formulation buffer which the agency wanted to include as a control and gfp vector so there was vector in there and a gene that -- and as the standard scientific studies.
And just one other question. Do you have any sense of what the vector, the multiplicity of infect is as far as the vector to neurons in these tissues?
We really don't. All we can do is try to estimate that, but it really doesn't answer the question. It's probably somewhere in the range of a bit more than one vector per neuron but the range could be anywhere along that -- all we can do is talk gross averages for the chunk of tissue we're able to extract and dissect and analyze and it done really answer your question.
Any other questions from the rack.
Say quickly, you went to great pains to talking about avoiding uncontrolled spread to the ventricles. What would happen if you did get that?
We don't know for sure but the worst-case scenario is the studies in animals and humans have looked at that empirical, in animals studies it's controlled, in human it's efforts to spread the protein into the brain by way of injecting it into the vents cl and the responses that are characteristic of growth factors, you get a thickening of the pia the layer of meninges, you're system lake swan cells in that area to grope. And you have fiber in-grown, fibrous grown in because they are what's interesting is in animal studies that have actually injected them into the vents weather the paren can I ma, in our own we paren.
And we have casino evidence of those side-effects. So there's a question of whether or not transfer near the ven cl would induce the same spontaneous. We're taking the worst case most conservative approach in assuming if we got protein that spread to that area, we'll get the results. It's the just the appropriate response to take. When you look carefully at brains of those animals you actually see barrier between the protein extension and the ventricle and that's call the apendymall cells. That's analogous to a blood brain barrier .
Any further questions from the rack. Any further questions.
I just like to point out miss Quan noted that the reference to the gene transfer's treatment should be changed and you mentioned that it was although I believe I have the revised inform consistent send treatment inform consents treatment. One of them is on page 36 of your response, and the other is on page 50 of the response.
Thank you. For pointing that out and we'd be happy Tony corporate all the suggested changes to the -- Those will not be an issue. Any more concerns from the rack.
Okay. Any public comments?
Can I make one more brief comment on protocol?
Is it a public comments?
Sure.
I've seen some of these studies going forward and I just wanted to make a general big picture point about this. As I've heard the protocol I think there are two main issues that we delegate with and I don't know if the big picture emerged. Was the concern that about the efficacy of the newer churants and I wanted to point out that we have more protection data with the into your cheurnt given first, we have respect. We have aged monkeys that have shown a biological response in terms of pet scan. We have aged rats that have shown an aged response so we have neuroprotection reenervation we arced about mine cha of those models but I was wondering if Dr. Bow went has proof of efficacy given function recovery in the best row deny and primate models we have of Parkinson's disease.
I wanted to see if we resolved that rack issue or not.
As Dr. Quan pointed out. I don't think there are a minutia that the animal moms used were not ideal and did not completely reflect the best model parallelling the design of the protocol.
I didn't be mean that critically at all, Marty from. a Big picture peck spiff, we have that body of data are there remaining concerns about efficacy. In deference to the next group we have to wrap this up. So what I, if there are no more public comments what I propose we do is adjourn for 10, 15 minutes. For 15 minutes and iq that the rack reviewers remain here so we can draft draft recommendations that we'll revisit.
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We have decide for reasons of practicality to defer the public vote on the last protocol until we have finish our work this morning, and we're going to go on to the second protocol this morning wrist ended Phase I trial of systemic of virus genetically engineered to expressness with or without cyclo Foss flow my with patients with multiple myeloma. The presenter is Dr. Gurts from the mayo clinic who is just about to begin.
I'm going to sign off now.
We do have a group of people here involved in the project. We unresponsive for this project from mayo clinic and the other individuals who are here from mayo clinic is the principal investigator for the protocol. If you'd like to raise your hand, Angela. Dr. Eva guyLANis who is an investigator who was a Miece sell's various the domain of and general, David dingly the lead scientists in this project who constructed and did initial testing of the virus. Mark stepfeld is the person running the facility at mayo where the vector will be produced and the toxicology studies. We also have here Karen sly kert from the rate program and Karen is looking after the toxicology aspects for us. Okay. So this is about multiple myeloma which is a devastating incurable malignancy of Plasma cells characterized by infiltration of the bone Maiero, painful bone destruction. A reduction in normal immunoglob luns in the blood and it remains incurable, it's response for 11,000 deaths per year in the U.S.A. and it's disseminated from the outset so it needs to be treated systematically. Viral therapy is the approach that we're exploring for this disease. The virus is to destroy tissue and maybe we could harness that capability for cancer therapy. We've elected to work with measles virus for a number of reasons. You can see in the picture there this is a 10-year-old boy who had a spontaneous regression of a retroorbital Burkket limb Omaha in the course of the measles infection. We've explored the use. A 10 waited vaccine strain which in contrast to the wild type is again no cells and if kills myeloma cells. It spares normal cells and it has variety xeno graph moms. This is just the linkage from which the he had monson virus comes. And the vein was derived from 1954 through the throat of an 8-year-old boy who had a measles infection and his virus was then passed on a variety of different human and lines to generate all of the currently used measles vaccine strains which differ from each other in a variety of point mutations but they're all from the same lineage and the virus we've been working with is derived from this spud which came out the he had monson I know angle and from an infection molecular clone was generated the way in which the virus kills myeloma cells is by infecting a small number of cells and causing them to fuse with their neighbors resulting in the generation of large multinucleated. Green dots which the a myeloma cells and then a lot of these much larger green spheres which are multinucleated. And then you can see in the right hand panel there that those large spheres become incapable of excluding try pan blue when they die. The basis for the measles virus oncology specificity resigh in the h attachment protein and the s fusion so h immediate Yates attachment to slam and then f triggers fusion and slam is expressed on cd 46 is ubiquitous. But cd 46 is over expressed on human myeloma cells and we believe that provides a basis for the toxicity of the virus. If we look at multiple myeloma patients bone Maiero, you can.
Cd 46 staining is on the x axis in those dot plots, and you see in each case there's a little cluster of myeloma cells with high levels of cd 46 compared to all the normal bone Mario elements and when we Kwan Tate that in 18 patients here that in all cases the near plastic Plasma cells have higher levels of cd 46. We've conducted studies to show that measles virus can discriminate cells with high density from those with low density. And this data just shows us a panel of krelgs engineered to express increasing cells of cd 46. And you can see when we infect these cells with measles virus we see that there's a threshold density of cd 46 above which the cells begin to fuse and die. And this threshold effect is very important in the antitumor affect. Myeloma cells have higher levels of threshold in the fusion for killing and then there are lower levels. The specificity of the virus is illustrated here. In the left hand panel at the top, the broit green multiple thuk cleated fisher measles virus can see, can be seen. Pevrt ral blood lymph sites were not did limb sites sinfisha, we were able to completely e raid indicate large zero no graphs by large administration of virus these in mice xeno graphs. Now we did not engineer the virus? Because there are some problems with the virus as is. And in particular, we were concern if we're going to use in the clinic we need to monitor its spread. There are also problems which I think will be clear to everybody here that everybody has antimeasles and it's bodies which may block the ability to deliver the virus by the vascular route and also once delivered the spread of the virus ma