Dr. Berstein: parkinsins disease Silver bullet?

Transcipt: (to be tidied up)

0:00 so welcome everyone here we go welcome everyone my name is michelle 0:05 thank you very much for joining us today for this rescheduled session and thank you very much for your patience 0:11 i am delighted to host dr jonathan zacharin who study published in the journal of parkinson's disease offers a 0:17 new theory about the causes and potential treatments for parkinson's which of course has been a topic of big 0:23 interest to everyone who suffers from the condition i would like to start by reminding everyone that this session is for 0:29 information and education purposes only so if you're seeking medical advice diagnosis or treatment you should really 0:35 consult a medical professional um as you can figure out through the the 0:40 screen that you see there's a q a button at the bottom please enter your questions using that function there will be time for 0:46 questions at the end of this presentation so just a few words about us for those who don't know us mark lumber and now 0:52 i'm made a tutorial at the tutorial on nutrition and parkinson's in the summer of and decided to stay in touch with a few 0:59 other people we named our small group no silver bullet and that was basically a reflection of our belief that uh we need 1:06 a holistic approach to managing your symptoms that not no one single solution is available but there is an array of 1:12 various solutions that we can tap into to help ourselves manage our symptoms 1:17 since then we've been hosting external speakers every few weeks and this is really to help us think holistically about the various ways of 1:24 managing your symptoms so in addition to our youtube channel that we mentioned a second ago 1:29 this is where we post the recordings of our sessions we also have an instagram page and a twitter feed the details are in the chat 1:36 let's come back to today's topic motivated by frank suffering from parkinson's dr zachar bernstein decided 1:42 to look more closely at the disease and focused on the gap in our understanding actually no one had so far measured the 1:49 amount of dopamine in the dopaminergic neurons of people with parkinson's and this is critically important because 1:55 dopamine can be toxic to these cells which would then be a driver of neuron dysfunction and death leading to disease 2:02 progression jonathan published his analysis last summer in the journal of parkinson's disease and he showed that these 2:09 critical neurons do not lack dopamine they actually have excess dopamine which this is something that led him to 2:15 design a clinical trial to test a drug that addresses this newly defined mechanism of 2:20 disease jonathan was a renewed renowned clinical trialist in cardiology before 2:26 leading academics to pursue medical product development he served as an associate director of the fda device 2:32 center where he led diverse programs under collaboration with dhaka after serving at the fda jonathan 2:38 consulted for darpa and supported the launch of the biological technologies office with a primary focus on 2:44 neuroscience and big data programs champion's academic experience ranges ranges from first and human to 2:50 international trials both as a clinical investigator and a trial leader we're very fortunate to be able to listen to 2:56 you today jonathan the stage is yours 3:01 thank you very much michelle thank you mark and i appreciate everyone taking the time to join this conversation today 3:09 um i'm going to bring up the slides if you give me a moment 3:41 we've all been there or at a minimum we can imagine the situation 3:47 faced with the prospect of suffering from a degenerative disease we yearn to find a way to change our 3:53 fate or the fate of our loved ones those of you who are scientists on this 3:59 call today may recall how alexander fleming accidentally discovered penicillin and 4:05 hope for such fortune or perhaps you hope your doctor sees something that others can't the way 4:12 edward jenner noticed how dairy workers who contracted cowpox were immune to 4:17 smallpox leading to the development of a smallpox vaccine perhaps you bring in articles to your 4:23 doctor asking whether a report offers promise perhaps you search the reports of how 4:29 changing your diet or taking a supplement could change your fate in each case 4:35 the motivator is to address the risk of disability of suffering 4:40 i faced a similar situation my buddy ivan was diagnosed with 4:46 parkinson's disease and i watched as his condition started to worsen so as a doctor 4:52 albeit a cardiologist and not a neurologist i ask myself 4:57 what if i could discover the silver bullet for ivan for parkinson's disease The Silver Bullet 5:06 to do so i would need to teach myself about the disease and available treatments and what did i learn 5:13 well for current treatments there really have been no major advances since the 1970s 5:19 all of these therapies focused on dopaminergic stimulation or dopaminergic 5:24 support are palliative affecting symptoms and none are shown to affect clinical 5:31 progression or clinical worsening so then i define the process i would 5:37 follow how could i tackle this in a way that gave a chance for a meaningful impact 5:43 and a meaningful discovery well first what i would do to evaluate the 5:48 possibilities is i would resort back to first principles the foundational assumptions underlying 5:54 disease understanding next i would apply systems analysis a set of disciplines learned as an 6:01 undergraduate studying engineering and then i would look for parallels to other settings 6:08 with the perspective that perhaps the solution is possible based on the work of others 6:13 i'm going to share the highlights of my path using this three-step process 6:19 and i'm sure in many ways it will raise more questions that we can discuss afterwards 6:24 or at a separate session but again the first principle The First Principle 6:30 that i attacked initially is that parkinson's is a state of dopamine deficiency as this is the basis 6:38 for virtually all the therapies developed since the 1970s Dopamine Deficiency 6:44 so that leads to the question if parkinson's is a disease of dopamine deficiency 6:50 why don't dopaminergic therapies change the course of disease since they replace 6:55 dopamine well we know that dopaminergic therapies do not fix the disease 7:02 so then a related question would be getting back to the very basis of our 7:07 understanding is whether dopamine or dopaminergic neurons are actually 7:14 dopamine deficient and of course that's what seems to be proven true based on 7:19 textbooks and standard of practice in order to address these two questions 7:25 and really start to focus on the second i started with the papers that established the current model published The Swiss Model 7:32 in the early to mid 1960s by a swiss group who published all of 7:38 these observations in german now i don't know how many of you are fluent in german 7:45 but you can imagine that it requires some insight in order to really tease apart 7:51 detailed scientific papers that are considered the foundation of our assumption that we lack dopamine 8:00 in parkinson's disease well let's take a look at what these studies taught 8:06 um in any paper the results are typically pretty easy to 8:12 understand when they're presented in table form or graphical form so as an example 8:18 here's a table taken out of the first publication and you know numbers are numbers and the 8:25 the latin names for anatomic structures are the same whether written in a paper in german or in english or in spanish 8:33 you can look at the top and it doesn't says who it's in but it doesn't have the word parkinson's so we can infer that 8:39 this is from normals we can see that the regions of the brain of interest 8:45 relating to parkinson's are easy to identify the levels are easy to identify of 8:51 dopamine that's at the top of this so we can extract these numbers and draw a set of conclusions 8:58 but scientists know that the key part of any study is the method section 9:04 and if you don't know german understanding the nuances here is much 9:09 more difficult my advantage over people of my age group who started out in training as 9:15 neurologists and parkinson's experts is i'm starting now in an era where i can use google translate they didn't 9:22 have that so believe it or not of the four landmark papers that were published in 9:27 german in the 60s only one has ever been republished in english so i went back to see what these papers 9:34 actually measured by dissecting out the methods and here's a way that people would look 9:41 at this you can see the three of the first three papers are listed here the amount of dopamine in normal brains 9:49 and in parkinson's brains and you see that basically the amount of 9:54 dopamine in parkinson's brain is reported to be about ten percent of normal the caudate 10:00 and seven percent of infotainment okay so now we understand why the 10:06 conclusion has been drawn and why all of investigation is based on the fact that dopamine is 10:13 deficient in the basal ganglia Why Scientific Methods Matter 10:19 i'd like to explain um for a moment um why scientific methods matter in this 10:26 particular setting and i'm going to try to do this with an analogy that i think is fair um and and hopefully will help 10:35 communicate what i observed as i started to tear apart these data and the methods 10:41 of these studies let's say it's a parallel situation where we're interested 10:46 in the economic standing of a community and that we have a way to measure the 10:52 amount of money that is in savings in every household 10:58 maybe it's in every building so if we take the total amount of money 11:03 and divide it by the number of buildings we would theoretically know what the average amount 11:09 of financial reserves financial security is for each family 11:15 but if in fact when we did the calculations our methods were such that we counted every building 11:22 and we didn't discern between a bank building and a single family 11:27 house well that bank building would have hundreds of thousands or millions of 11:33 dollars in reserve and would throw the average off for the entire community making the community 11:40 appear wealthier than it actually is and so the key here is that if you want 11:46 to know how how secure financially a community is at the level of a family 11:52 your methods have to include only measures from the families not from 11:58 every building that could include a bank or a business or a credit union and that's the same problem that 12:05 happened in these particular studies and those that followed when people were 12:10 measuring dopamine they were measuring dopamine in the entire region of a brain 12:16 instead of what's inside the individual neurons and i'm going to explain to you why it's 12:22 important to know what's going on inside the neurons the reason is 12:28 and this is probably going to be a topic that people are going to want to dig into is that when dopamine is freely floating 12:35 within the cytoplasm within the cell body of a dopaminergic neuron 12:41 it is toxic to these cells primarily through its breakdown products but also through direct effects 12:49 this is not controversial we know that if we take cells in the lab and we do 12:55 these measurements dopamine is toxic we don't know and there's not proof 13:01 as to how this manifests in a person over a long period of time but on a 13:07 scientific basis we know that dopamine is toxic 13:12 we also know getting back to this analogy with the wealth of families that if dopamine is 13:18 outside the cells is extracellular it does not damage the cells it does not 13:23 damage the mitochondria in the cells which is basically the part of a cell that produces all its energy and it's 13:30 necessary for the cell to function and it does not affect cell viability so extracellular dopamine 13:37 doesn't really matter if we're trying to understand its role in disease severity or progression 13:46 so tissue dopamine is not the most important variable even though all of the 13:52 science all of the therapies have been based on the assumption that 13:57 those tissue levels reflected what the cells were experiencing at the site of their toxicity 14:03 so what we need to know is dopamine in the cytosol in the cell body 14:08 in order to understand exactly what's going on so to to figure that out What Do We Know 14:15 i went back to the literature and said what do we know about the amount of dopamine inside the neurons of people 14:22 suffering from parkinson's disease and what i found is that the amount of intracellular dopamine 14:28 is not reported from any clinical study any samples of from autopsies 14:36 nowhere neither by direct measurement or by indirect calculation and i i 14:42 actually found some people have done some measurements of dopamine in animal cells not from parkinson's models 14:48 because not there's no publication in parkinson's models and tried to talk to them about how easy or hard it would be 14:54 to do that and really was not able to get a lot of traction but clearly no data 15:00 so i have to try to figure out how to understand how much dopamine was 15:05 inside the cells and the way i did that was by a review of the literature that showed that all of the components were 15:12 necessary to do the calculation now it's not just you know dividing a by b by c and you have your 15:19 answer there's some modeling there's some statistics there's some meta-analysis methods that i was able to 15:24 to bring to this this question but what i found was that indirect calculation is actually pretty 15:30 straightforward mathematically because you can account you start out with the tissue dopamine you account for 15:36 the number of a reduction in number of dopaminergic neurons the reduction in number of axon 15:43 terminals and the reduction as well as dysfunction of the vesicles inside the neurons which are critical 15:50 for holding those securing those um and and also involved with neurotransmission the 15:57 signals uh spread from one nerve to another using dopamine cytosolic dopamine 16:03 so by doing that um then this was the paper that that michelle mentioned published in journal 16:08 of parkinson's disease this this past summer what i learned is that cytosolic 16:14 dopamine is not reduced it it it is if anything 16:19 elevated and and here's the data compared to cytosolic dopamine in the brains of 16:24 people without parkinson's in the caudate parkinson's patients have 16:30 almost have about 89 more cytosolic dopamine than normals and you 16:36 see the p-value is a is a a trend statistical trend and in in the um 16:43 putamen it's 460 percent higher and here you'll see it's highly statistically 16:49 significant included in this analysis was breaking down these studies by whether the 16:55 patients were on any therapy or not and it basically showed the same result 17:00 whether they were on some sort of dopaminergic therapy or not because dopaminergic therapy was starting in the 17:06 mid 60s in some of these studies and became standard of care in the mid 1970s 17:13 so what we know with this first analysis 17:20 of how much dopamine is inside the cells which is critical to determining whether dopamine plays a toxic role a 17:27 mechanistic role whether we should supplement it for the sake of the cells or not 17:32 is that dopamine is not deficient for the dopaminergic neurons from their 17:39 perspective those average the average neuron has excess dopamine and therefore 17:46 parkinson's is a disease of dopamine excess in the dopaminergic neurons 17:52 not of dopamine deficiency now systems analysis 17:57 that may seem a little a little tough to swallow especially for those of you who are familiar with the fact that if you take 18:03 levodopa or you take a dopamine agonist or or maldi inhibitor etc that you can 18:10 experience a prompt improvement of symptoms now it doesn't 18:16 last for years in most people but it certainly happens you take the dose you feel better you can move better 18:22 that's the typical experience in parkinson's so so how can this be if i'm saying dopamine is bad 18:29 how could let's just say for the sake of discussion i'll talk about it from a levodopa point of view how does levodopa 18:34 actually do good and and really applying systems analysis and 18:40 pharmacology insights tell us why so let's talk about systems analysis 18:45 this is typical of what doctors like me like to do we like to put on these complex figures i'm sorry for that but what i'm 18:52 going to do here is focus on a couple areas you see the top part is the presynaptic axon terminal the bottom 18:59 part is the postsynaptic dendrite what i want you to focus on here is first of 19:04 all this red circle l-tyrosine is converted to l-dopa by th 19:10 tyrosine hydroxylase tyrosine hydroxylase is the rate limiting enzyme 19:16 in the formation of dopamine this particular step right here 19:22 i'm going to touch back on that in a few slides the second thing to notice is here you 19:29 have d a which represents a few hundred thousand molecules of dopamine inside this little 19:36 ball which is a vesicle some of you may have heard of something 19:41 called vmap2 which is a protein that enables the vesicle to form and function 19:48 dopamine is sequestered inside these vesicles and that's what prevents it from being toxic 19:54 it's only toxic when it's floating around in the cytoplasm not when it's held inside the vesicle vesicles 20:01 eventually attach at the surface they open up and they let dopamine come out 20:08 okay where it then um will bind uh at a here showing the dopamine 20:15 one receptor there is five dopamine receptors really categorized mostly as 20:20 type 1 like or type 2 like and you see there's something here called the g protein 20:26 and and this is g protein mediated receptor means that the dopamine attaches here 20:33 and through the g protein sends a signal that tells this cell whether it be excited or whether to be inhibited 20:39 active or off um g protein mediated receptors are all over the 20:46 place including the heart and throughout the body on your white blood cells that fight infection 20:52 and so they're extremely well understood and it's their pharmacologic principles 20:58 that tell us why levodopa works so here's the kind of curve that people 21:05 who study pharmacology like to show they usually have it with all sorts of little numbers and figures and all that sort of 21:10 stuff on it so i'm stripping it down just to show that the relationship for dopamine for a g-protein coupled 21:17 receptor you see as you go up on the dopamine to the right there's not much of an 21:24 increase up and down and eventually you get past the curve and there's a steep section so that as 21:31 you go up on dopamine a little bit there's a big difference in receptor activation and then you get to the point 21:38 where the receptor is completely saturated with dopamine and you keep going up in the dopamine and it 21:43 basically doesn't go above 95 okay so in the normal person 21:50 the cells are operating down here and very small changes in dopamine wouldn't 21:57 do much but there's nice dynamic range this is a very active system 22:02 can put out millions of dopamine molecules at a time which is enough to 22:08 cause an increase in receptor activation and things happen in parkinson's 22:16 you give levodopa and the base the average dopamine level shifts to the 22:21 right from the red circle to the green circle and now it's still on the curve 22:27 and you can see that by operating up here going even letting a little bit of dopamine 22:33 out can cause nice receptor activation so you're not really changing the active 22:41 um dynamic nature of dopamine neurotransmission 22:46 by giving levodopa you're shifting up on the curve to a spot where a very small amount of 22:53 dopamine being released can have impacts and that's why levodopa would appear to 22:59 work based on a systems analysis and pharmacologic principles 23:05 now i hope this isn't getting too far into the weeds but i i did want to make 23:10 sure i took some time to show you that the model of dopamine being in excess in parkinson's 23:17 is completely compatible with the fact that levodopa or other dopaminergic agents work 23:23 for symptomatic relief acutely after a dose and for a period of 23:28 what could be months to years before the effect starts to wane because the other thing about g 23:34 protein-coupled receptors is that they get desensitized over time 23:41 the the last part of of the analysis that led me to this approach is by drawing parallels 23:47 and one of the things i realized as i started to read about parkinson's was that it was strikingly similar to the 23:54 work i did as an academic cardiologist with a class of medicines called beta blockers 24:00 as a treatment for congestive heart failure or chronic heart failure now at the time i started doing this work in 24:06 the early 90s beta blockers were contraindicated they had a label 24:12 in their approval from every country that said don't use beta blockers 24:17 because if you give them to a heart fair patient in a standard dose by the end of the day 24:23 you'll have them in the emergency department because their symptoms will worsen 24:29 but a few cardiologists in sweden actually thought well maybe the problem is how much is being dosed at a time 24:36 and so they started out with about a tenth or twentieth of the dose and gradually increased over the course 24:44 of weeks to months and what they were able to show was that all these patients tolerated the blade of blocker quite 24:50 nicely and seemed to have improvement in their heart function and their symptoms 24:56 i was fortunate enough to be starting the first phase two trial of a beta 25:02 blocker for heart fair where again we saw the same thing starting at a low dose gradually going 25:07 up um allowing the body to respond over the course of a few months 25:14 as opposed to expecting an effect over a few minutes led to the appearance of data 25:21 that showed that the drug slowed halted and in some cases reversed 25:26 disease progression and now beta blockers are standard of care for heart failure 25:33 so um uh what what i just summarized was their dopamine and norepinephrine 25:39 their similarities they are um really do have related peptides dopamine in parkinson's and 25:46 norepinephrine which is synthesized from dopamine in heart failure 25:51 if you give too much you're going to make somebody sicker in all probability 25:57 if you look at the laboratory data for each what you show is that antagonizing that 26:03 respective peptide improves the biology and function in a number of cell models 26:08 and then eventually in heart failure the drugs are proven to work um and and i think that that's the same 26:15 kind of thing we could see if we picked the right therapy to block the toxic effects of dopamine 26:21 in patients with parkinson's disease so um excess dopamine 26:27 while levodopa enhances neurotransmission across the synapse the dopaminergic neurons are not dopamine 26:34 deficient i'm sorry to be redundant but it's important for me to emphasize that they have excess dopamine 26:40 and excess dopamine is toxic to dopaminergic neurons supporting the importance of testing therapies that 26:47 will reduce cytosolic dopamine that's right uh what what i'm advocating is based on 26:54 pre-clinical data and careful review of these foundational studies about parkinson's 27:01 and show that it is scientifically rational to treat parkinson's 27:06 with drugs that reduce intracellular dopamine 27:14 so um really as as i think about this it certainly unfortunately is too late 27:21 for ivan but perhaps not too late for you and for others and so what i want to do is share the 27:27 data um that show how reducing dopamine 27:32 addresses the pathologic processes that are experienced by dopaminergic neurons 27:39 a drug previously used in the u.s but to date not approved in the uk 27:44 for a rare cancer complication is shown to work in two preclinical models of parkinson's disease 27:51 by blocking tyrosine hydroxylase i mentioned tyrosine hydroxylase earlier 27:56 that's the rate-limiting enzyme that um involved in the formation of dopamine so 28:02 that's by blocking that would be a very logical way to attack this problem now 28:07 you may say how can i be so confident that this is logical well before we got into the days of 28:13 looking at genes and editing genes and using cell therapies and programming 28:18 cell therapies almost all of our treatments were either to block the effect of something at a 28:24 hormone or block the rate limiting enzyme so ray living enzymes are used 28:29 widely most antibiotics affect rate limiting enzymes that determine whether a 28:34 bacteria lives or dies anti-hiv meds are all about attacking 28:39 rate limiting enzymes the most widely prescribed class of high blood pressure medicines ace inhibitors 28:46 blocks rate limiting enzyme viagra one of the most successful drugs 28:51 ever developed in terms of how much people want to keep using it is again an enzyme inhibitor and the class 28:59 of stat the statins are all again enzyme inhibitors of the rate limiting step so this is a very 29:06 well-known effective way that we can modulate how 29:12 the drugs can work that we're going to use to try to reduce dopamine levels in the cells Materiacine 29:19 so the drug itself is called materiacine in the u.s the trade name is denzer it was approved in 1979 for treatment of 29:26 hypertension due to dopamine excess from a kind of tumor that makes huge amounts of dopamine so a 29:34 systemic dopamine toxicity and this drug does penetrate the blood-brain barrier and is shown in a number of studies to 29:41 have effects on dopamine synthesis in the brain high doses are required for patients 29:47 with rio chromosatoma between 250 and a gram uh four times a day 29:54 in parallel to the beta blocker with heart failure experience i alluded to before i would not advocate using high dose and 30:02 to be honest i don't know what is too high a dose quite yet that's what we want to test in the first study 30:08 is identify a low enough dose where there's no side effects and then gradually increase Materials 30:17 so i mentioned that materiacine works most um drugs that are developed for 30:23 disease go through a whole series of pre-clinical study toxicology studies drug interaction 30:29 studies genotoxicity which affects the things that affect the genes 30:34 then they go into phase one studies where the drug is seen how to how it gets absorbed how it interacts how it's 30:41 broken down um basically all that stuff's been done with the tyrosine so it literally can go 30:48 right into a phase 2 clinical trial here in the us so in terms of materials let me just 30:53 briefly show you these two studies one is published in the journal science 30:59 you don't get a paper into a better journal than science i mean that's probably one of the top two 31:04 or three journals for scientific publications in the world and they use something called ips cells 31:11 we were discussing those with roger barker in the last session induced pluripotent stem cells which you make 31:18 from taking a skin biopsy on somebody and then treat it and you can turn it into dopaminergic neurons for that same 31:26 person um so ips cells were obtained from people with 31:32 spontaneous pd and genetic pd a dj one homozygous um 31:37 population as well as people without parkinson's disease and what they showed in these cell cultures that 31:44 lasted from two to six months is that oxidative stress was reduced with 31:50 materiacin that alpha synuclein deposition was reduced with patient and that 31:55 dopaminergic neuron survival was improved with material scene the effects were seen 32:02 within about 60 to 90 days in the dj-1 mutant ips cells from dj-1 32:10 mutant parkinson's patients and in the sporadic patients it took about 120-150 32:16 days so it's a little slower before the toxicity showed up as well as the benefits showing up but showed it in 32:22 both populations in a study of journal biological chemistry a couple years earlier a mouse 32:29 model the mtpt mouse model was used and what this showed was dopaminergic neurons survival was improved 32:36 with patient therapy in this model so two 32:41 uh documented and accepted scientific models of parkinson's disease um 32:46 i can't show you anything that didn't work because there's no model using the tyrosine that didn't work two 32:53 for two which is pretty good um for those of you who like uh graphical 32:59 representation you can see that about a point six fold drop in in oxidized dopamine and alpha synuclein 33:06 deposition and about a one and a half fold increase in their own viability Barriers 33:14 so if i'm so confident uh with the use of materials that the use of materiacing to reduce 33:21 dopamine levels will help you may wonder why i don't already have a list of study sites ready for you to 33:28 approach for enrollment well what i'd like to do is explain some of the barriers which i'm working on 33:34 um the first is it clinically uh i think i figured out the right dosing regimen um 33:41 i submitted uh uh and engaged with the fda over the last 33:46 nine months about the approach i want to take a clinical trial design dosing regimen 33:53 they seem to be comfortable with the dosing regimen that i proposed which is again very low at the beginning and 33:59 increasing at weekly intervals uh i i'm pretty close to a formal agree 34:05 with the fda but there's some work that they asked me to do in a submission that work will also require me to secure 34:13 a source of drug so either have to start manufacturing or figure out 34:18 how i can buy it from a source when there really isn't much to buy so because again it's for a very unusual 34:25 condition so i'm working on those in terms of the regulatory summary as i 34:31 mentioned i'm seeking the fda permission to launch a clinical trial i expect that i could have that uh request in within 34:39 the next few months um and that generally i think that'll probably take 34:44 probably by the end of the year i could get get that trial approved of course 34:50 that still requires me to get money i can do this work it doesn't cost to submit this to the 34:56 fda but but to actually do the work after getting fda clearance to start the trial 35:02 requires a pretty substantial amount of money and that includes money to establish drug manufacturing or secure supply so 35:10 that's why the financial issues are really the biggest barrier and i've been out 35:15 um trying to raise money for the last couple of years most investors do not like to invest in 35:22 repurposed drugs because they feel like the business model is not their usual um so when i ask for 10 35:28 million dollars to complete phase two um it's it's hard to get people to to 35:35 make a commitment i've had a few that have started to do a little diligence but have not been able to close that and continuing to work on that Development Process 35:43 so in terms of the development process that i see over the next three to four years 35:48 um you know pre-clinical validation is already done pre-clinical toxicology is 35:54 already done define the metabolism and drug interactions through phase one trial is 35:59 already done submitting the pre-ind already done i'm currently working on the final 36:05 design for the phase two clinical trials then i'll have to continue to work on 36:11 site selection although i already have identified um three perkins 36:17 investigators who are interested in being part of a trial um i've got to 36:23 then of course execute the trials and i've done that before working for 36:29 companies working in academics i can get the operations in place once that happens there's something 36:35 called an end of phase two meeting that you have with the fda to define what the 36:40 endpoints would be and what the trials need to look like for phase three those have to be performed 36:46 if you complete those submit a new drug application which generally takes somewhere between nine to 12 months and 36:52 that's commercially available so a lot of steps um once uh funding would be secured i would 36:59 expect that um within three to four years i can certainly get through the fee end 37:04 of phase two meeting and i think with positive data it'd be really easy to get the money for phase three even 37:11 though you're talking nine figures of investment um with a drug that actually showed it 37:18 could have an impact on people with parkinson's disease through a novel mechanism there would be a lot of 37:23 excitement so uh what ends up happening a lot of times Key Challenge 37:29 when i'm talking to people is they ask me what the key challenge is um and it's really pretty simple 37:36 i'd also need to make sure that i provide the proper warnings it would be a mistake and potentially a 37:44 life-threatening mistake for any of you to go home and call your doctor 37:50 to start treatment with the tyrosine we need to do the studies that demonstrate materiacine works and 37:57 if so how to make it work work safely so there are several warnings that i 38:04 just want to make sure you're paying attention to Warnings 38:09 the scientific studies and peer-reviewed data strongly support 38:14 launching the investigation of the tyrosine as a treatment for parkinson's disease 38:20 a phase ii clinical trial could be launched within a year of securing funding 38:25 and over a hundred failures that i've experienced pitching vc funds angel 38:30 investors and foundations well i'm not going to let them define me or this project Silver Bullet 38:37 because the key thing i keep asking myself is what if my tyrosine is the silver 38:42 bullet because i believe that this discovery is a silver bullet for parkinson's disease 38:48 it won't be a cure but the science suggests that using the tyrosine can slow stop or reverse 38:54 the clinical worsening that appears to be the destiny of people like ivan and many of you who have parkinson's 39:02 the trial will start this week but it could start this year and i plan to complete it quickly and 39:08 with the highest quality so that hopefully we'll learn that the drug will be useful for you 39:14 it's what the data say is more than just a possibility thank you Questions 39:20 gentlemen thank you very very much for this fascinating presentation and definitely thought stimulating 39:25 thank you very much um for questions and i see that some of you have already posted your questions 39:31 on the q a i'm just engaging those who haven't done it yet and have questions to look at the bottom of your screen there's a section that says q a this is 39:37 where you can post your questions before we go through those questions mark we got a couple of questions from people 39:43 who were unable to join i think audrey and ann would you like to take us through those Medication Toxic Neurons 39:51 michelle i'll just copy and paste the first one in there pretty soon the question is leveled over medication toxic neurons 39:58 it also is known to raise kind of a word which is toxic to the brain in the heart what was your view on that jonathan 40:04 i'm sorry mark i'm having trouble hearing the audio is not great could you try that again can you see the chat 40:12 yes i've just typed the question into chapters that's clear thank you from the previous 40:19 um we're i mean there's a lot in the chat i'm sorry we're 40:27 okay great thank you so um the question is whether it is is 40:34 a request to confirm that what i'm saying is that l-dopa medication is toxic to neurons 40:40 so what i can tell you is that when neurons are are taken from animal models of parkinson's 40:46 disease in a laboratory and then in isolation so they don't have 40:52 the whole system there that could potentially have compensatory factors that we i don't 40:57 even that nobody understands but when you take those cells out of animal models in a lab and expose them 41:04 to dopamine or l-dopa you will see evidence of toxicity 41:11 now is that something and i and i want to be careful here because i find that 41:17 the way those papers are written doesn't seem like the authors have any questions that they're raising in their 41:23 mind as to whether this is actual toxicity but if you talk to parkinson's experts 41:29 in the clinical arena what they'll tell you is we've had people and studies that have 41:35 said l-dope is toxic and it's gone back and forth over the last 30 or 40 years where 41:42 if you go back to the history what you'll see is that there was a time where people would advocate for 41:48 levodopa holidays that you wanted to take patients who were who had parkinson's disease on 41:54 levodopa stop them for a few months and then give them a holiday let this the body recover and then start up again 42:01 um there are some clinical studies that experts will say demonstrate that l dopa is not toxic 42:10 and therefore these laboratory data although there's no controversy about what they show aren't relevant to what's going on 42:17 clinically i don't believe that the studies that those experts are citing 42:24 to to disprove that l-dopa has potential toxicity are valid 42:31 ways to prove that point because they're just not designed in a way to test that as an 42:36 example in cardiology when we were concerned about the equivalent something you know 42:42 basically a beta agonist instead of a beta blocker studies were done with two or three thousand people 42:49 followed for two or three years and those showed that those drugs had toxicity clinical toxicity 42:56 in parkinson's disease the there are two placebo-controlled trials with levodopa 43:01 neither one longer than nine months neither one of them bigger than a few hundred people they just they aren't big enough to 43:08 detect a problem if there's one there so while i believe 43:13 dopamine and l-dopa have potential for toxicity i do not i cannot 43:19 stand next to a parkinson's expert like roger barker who was here last time 43:24 and convince him that i'm right even though i i think i could convince him that it's good to explore this approach 43:31 because the data say this is approach is scientifically rational Dopamine Toxicity 43:36 thank you jonathan um if you don't mind joining me in just checking the questions on the q a if you 43:42 can do this with me that would prevent me from having to read sometimes quite lengthy question not the first one from christy is quite short 43:49 christy is asking us what does dopamine toxicity look like in a healthy person 43:55 in a healthy person i'm not sure i'm not sure what the relevance would be of that i mean we're 44:00 talking about what's going on in parkinson's um so if the person is asking me what does 44:06 dopamine toxicity look like in a parkinson's patients who's starting out 44:11 relatively well yes what i would say is that i believe but i cannot prove and i don't 44:18 want to be quoted as saying this is absolute truth but i believe 44:23 that we will eventually learn when proper studies are clinic when proper clinical trials are done 44:29 that l-dopamine does improve symptoms in the short run but exerts toxicity over the long run 44:37 and is a contributor to disease progression now if there's a parkinson's clinician a 44:43 neurologist on the on this call uh shear he is going to be jumping up and down wanting to get on this 44:49 conversation saying that i'm being irresponsible by making that statement 44:54 yes i'm trying to qualify it by saying i believe that that's what clinical trials would show 45:00 what i can say with a hundred percent certainty is that there is no clinical trial that has been performed to date 45:07 with levodopa or any other dopaminergic therapy that's placebo controlled that's designed in a way 45:14 that could prove that those therapies are safe that gets designed in a way that can prove to them though those therapies 45:22 don't potentially worsen the natural history of disease they just haven't been done Question from Randy 45:28 thank you very much you have a question from randy if you don't mind having a look he's asking us about the method 45:37 i'm looking for randy's right now i'm sorry yes the first one on top 45:44 okay wait a second i think i'm looking at the chat instead of the computer 45:50 open questions first one 45:55 i can read it if you want okay i'm just talking about getting off of the okay so so it's quite the lengthy question let me just read it to you how 46:02 were you able to establish a method of measuring the number of dopaminergic cells still alive in the living 46:08 parkinson's brain to calculate the cyst acetolosic dopamine being excessive from norm 46:14 he thinks that the method would seem very difficult to validate and secondly he's asking if the dopamine tracer dat 46:20 that scan shows diminished dopamine in the neuron how does that correspond with your findings 46:26 okay yeah i mean to to create a method to count neurons 46:32 is really really complicated and really hard and just to go through a little more detail how i did it i relied on 46:39 peer-reviewed publications that had done this so in in the peer-reviewed literature 46:45 i don't remember the exact number i think there are seven or eight papers that measure the number of neuron cell 46:52 bodies and they measure them by staining for specific components that are seen in dopaminergic 46:59 neuron cell bodies and then um using a standardized 47:06 magnification and a standardized number of fields and a standardized shift in 47:12 how deeply they went up and down as they looked at those fields they came up with a number and calculated the number as a 47:20 ratio using the same methods between dope brains from patients who had died with parkinson's 47:26 and undergone autopsy um and normals age same age again who had died and 47:32 undergone autopsy and they were able to get brain tissue from each of those populations so these are methods 47:39 that have been validated for which there's great literature um they uh are 47:45 validated for measurement of tissue dopamine they're validated for number of cell bodies 47:50 they're validated for the number of axon terminals they're validated for the 47:56 amount of vmat2 protein as a surrogate for how many vesicles there are so those were the four parameters that 48:03 were used to do the calculation and then it's standard math using meta-analysis methods 48:10 thank you very much anthony jo milne is a lady who can smell parkinson's she suffers from a condition 48:16 that just allows her to detect parkinson's through the smell and she basically says that actually 48:21 from the volatiles that she can smell they have discovered with the university of manchester if i remember well that 48:27 there are some dysregulated levels in most mitochondria in the body in terms of cardiolipids and different 48:33 types of glycolipids and others will this address the problem with the the drug that we're talking about that's 48:39 the problem well one of the things that we see in people with parkinson's 48:46 um who are the the exact kind that were the basis of these studies that allowed 48:51 me to draw the conclusion that the levels are in excess not deficient 48:57 within the neurons is that when dopamine is in the cytosol in the cell body and then gets broken 49:02 down in the cell body and forms these metabolites one of them the main effects is the 49:08 toxicity on the mitochondria so mitochondria drop out and that's really what's 49:14 what's i think the major reason for disease progression is that as you lose 49:20 the mitochondria and you've got these dopaminergic neurons that are amongst the the most metabolically 49:27 intensive requiring cells in the body with thousands of branches of these axons all 49:33 interconnected they lose a little bit of their mitochondria which are producing the 49:38 energy that keeps all this neurotransmission going you lose the axons you lose the neurotransmission 49:46 so yeah i think that if we can knock down enough of the 49:51 dopamine we will reduce the levels of oxidized dopamine and with less oxidized dopamine 49:57 and breakdown products of dopamine we should spare mitochondria will we restore them to normal 50:03 i i think that would maybe maybe you you'd get upset with me saying this is a silver bull but it's not a 50:08 gold bullet you know a gold bullet would restore them i'm just thinking we have a silver bullet that can reverse this 50:14 process thank you jonathan another question from randy actually who is asking the following question are there not Question from Rhonda 50:20 already patients who are taking drugs like methyl resin that already have pd and and where we 50:26 would have seen an effect of the drug on their on their condition an excellent question so this was one of 50:32 the first things that i thought especially because if you were to read the product label from a tyrosine it 50:38 does have a warning about the drug worsening parkinson's um which would be appropriate if you took a dose of 250 50:44 milligrams or a gram and you had parkinson's i think you'd probably be in the emergency room later that day or the 50:50 next day um so the first thing i did was i went to the fda's fares database which 50:56 is a database that records spontaneous reports of adverse events couldn't find anything 51:04 um not one report of a parkinson's patient taking the tyrosine 51:09 then i contacted the medical affairs department of bausch health here in the u.s 51:15 balsh health is the company that owns materiacine they didn't develop it it was actually developed by merck back in 51:20 the 70s but bounce health owns it now badge health medical affairs department did a search on all their case reports 51:27 and came back to me and told me that they had not one report of a parkinson's patient taking the tyrosine 51:34 or could they neither could they give me even a report of somebody taking the tyrosine who developed parkinsonian 51:40 symptoms um so uh those were the two best ways i could do 51:46 it i did also manage to convince um a drug research group 51:51 to um to do a search of whether they had any evidence of materials in 51:57 prescriptions being filled in people who took parkinson's drugs 52:02 and they found like three or four um and none of them were refilled and they had no way of telling me whether they were 52:07 adverse events or not so i've tried to figure out if there's any real world data of materiacing in 52:15 parkinson's patients and i've hit the derricks thank you for trying Question from Ali 52:20 and jonathan a question from ali he's basically asking whether you have any concerns that metarosine might worsen 52:26 motor symptoms in patients as it will deplete dopamine even if in the long term it slows down the progression 52:32 um well i mean the the one thing that i'm very comfortable saying is i worry about everything so yes i worry about 52:39 that um and i think that that's why um i've spent uh an incredible amount of 52:45 time going through pharmacology papers from the 70s and 80s to try to figure out both animals and 52:52 people to figure out what dose i would be comfortable wouldn't do anything 52:58 and then cutting the dose further so there's a whole bunch of studies and in fact i was able to get the medical 53:04 review by the fda from 1979 through a freedom of information request it took about six months before it 53:09 showed up but that was incredibly valuable as well because with between that review and all the data in it 53:15 and what's published in the literature you can you can see that um there's a 53:21 dose that the likelihood of it doing anything is is pretty close seems pretty close to 53:27 zero i mean god you know god knows it could do something bad and that's why i tell people don't don't try this at home 53:34 it really should be done under a very very controlled environment um and that the way i would say this 53:40 controlled environment not just picking a dose right but in the way i've written the protocol is every time somebody takes a dose the 53:46 next highest dose is in the clinic and they have to stay in the clinic for three hours under observation after they 53:52 take the first dose of that level so am i worried yes do i believe i figured out the ways to 53:59 mitigate that risk yes because say they get into trouble in three hours i give them some droxy dopa or some 54:05 levodopa and it should reverse because the pharmacology is not an irreversible 54:11 100 percent blockade of the rece of that enzyme thank you very much anthem 54:16 mark is asking a question about um potential post-mortem analysis that could have measured that i mean in the 54:22 cells it's a good question actually because why would we not just do it isn't that isn't that amazing that 54:28 nobody's ever done it i i found that the one study that i found that was really 54:34 really terrific um was a study that looked at intracellular 54:39 dopamine levels in cells that are that have some dopamine they're similar to dopaminergic cells a 54:46 little bit pc12 cell line but um not in people and i contacted that 54:52 author and i said oh my god this could be so cool let me tell you about this paper i just submitted 54:57 i think it's going to get published you could do like a great study you should you should use your your pc12 55:03 method in some human brains maybe i can help you somehow i don't know 55:08 and basically uh what i learned was that um experimental prep was so complicated 55:15 that they used it it was very hard um i think that they were um 55:20 they were convinced that unless there was going to be some big series of studies that they just couldn't keep it 55:26 up and keep it working so they don't even have a setup anymore so i think this would be an amazing 55:31 study to do but by the time you found somebody to do it um and by the time you you got going i 55:39 could have the answer faster by giving the intervention thank you gentlemen just just a comment 55:45 to our audience because i see i think that some people have been posting questions on the chat if you don't mind 55:50 cut and paste your question in the chat if that's the case and put it in the q a where i'm handling them so that i don't 55:56 have to toggle between one and the other if you don't mind if i can ask you please to do this going back to the questions audrey is asking probably the 56:02 most the most basic question at all that everyone has on the back of their mind should pwps avoid l dopamine 56:11 well audrey if i could get funded within um two years i'll be able to answer that 56:16 question good well actually i'm just thinking you're looking for 10 million dollars we 56:22 have we have 10 million parkinson's patients in the world we should be able to match both there you go 56:28 we'll set up a profit sharing plan for everybody a comment from joey who was asking about 56:33 mitochondria is not a question it's just a comment to say that in 1922 dressler and frederick louis of the famous udui 56:40 bodies wrote about this mitochondrial dysfunction and toxicity but it was a paper that was squashed as you like you 56:47 like looking back at old papers you might just have a look at that one if you haven't already i am definitely going to pull that one thank you john 56:55 um he has a question from jono john moore who is asking basically is there a natural form of methylzine 57:02 that we could basically access through dietary supplements you know if there were a and i don't 57:09 know if i don't know the answer to the question but if there were um and it was 57:15 chemically likely to be effective against the enzyme the way materiacine is 57:21 i would find it to be no more comforting than just metyracine 57:28 the goal here is to figure out how to block the enzyme and i don't mean 100 i mean one of the things about materiacing 57:35 that i like which i've had some pharmacology people tell me is a is a weakness 57:41 is that it can't block tyrosine hydroxylate 100 the highest any study attempt 57:48 studies are done when drugs are developed to say you know at what level you get to 50 at 57:53 what level you get to 100 and what ends up happening is you see how effectively you can block an enzyme this 58:00 can only block it at 65 that's the maximum it can go so 58:05 i actually think that's good because you want to have some tyrosine hydroxide function you still need some dynamic 58:11 activity if you were to take a dietary supplement that only gave you five percent 58:18 i doubt that's going to be enough you might as well not take it um if on the other hand five percent inhibition 58:25 turns out is enough to make somebody worse and we really should have started out at one percent 58:31 well i i wouldn't make myself the you know sort of um 58:37 guinea pig number one without it being very controlled and without having some understanding of 58:42 what that natural supplement might actually do uh in terms of its potency relative to 58:47 materials thank you i found a question from john moe who's asking whether there is a bowel marker for presence of methyl 58:53 asylum um i'm not sure that i understand where you're going out i mean that um to you a 59:00 biomarker to see whether you've got taken enough materiacine um 59:05 i mean biomarkers i i just don't understand the question i'm sorry maybe you can rephrase actually 59:11 if you yes feel free to just basically just add a more detailed question so we understand exactly what you're looking 59:16 for sorry for this um actually i will just skip one question for now because you remember christy was asking about 59:22 toxicity in a healthy person and we were not exactly sure the logic of that question actually she's kind of fine in a very useful way 59:29 here she's basically saying that and actually i've been asked myself that question quite a few times if you give a healthy person too much level dopa 59:37 so that they get more dopamine in the cytosol what will their symptoms look like if they get parkinson's symptoms 59:43 you can't you can't support it if someone who doesn't have parkinson's gets dopamine and gets gets parkinson's 59:49 symptoms then that would support your case yeah i mean uh i i think that what you can 59:56 um i mean it's not a study that i'm thinking of doing is taking it normal and trying to 1:00:01 induce parkinsonism um i'd rather take the other approach i mean i don't think that it's 1:00:06 scientifically invalid it's just not the direct path so that that's not where i've been 1:00:11 headed but it's an interesting thought so ingrid is asking about something slightly different here you may have an 1:00:16 opinion or not but just just in case she says that her mom basically has parkinson's and she's been doing 1:00:23 research for almost two years and she's not a big fan of the medicines the medication that she gets at the 1:00:28 moment um and she's basically she started vitamin b5 phantomic acid and it seems 1:00:34 to be very good is this something you would be familiar with oh it's not something that i have familiar with similarly 1:00:40 i'm sorry no problem thank you very much then now a question here uh from albert right hello albert 1:00:46 um he's asking is is the problem of high-freque related to a failure va 1:00:52 storage vesicles i do not understand the question myself i hope it makes sense for you it makes perfect sense so it's 1:00:57 good as i showed you on the complex the complex figure at one point in the middle um 1:01:03 the the way a neuron protects itself from dopamine mediated toxicity 1:01:09 is by packaging it inside these vesicles the vesicles keep it stable keep it from 1:01:14 breaking down and then also when a signal comes that they have to pass along they move over to the 1:01:21 membrane at the synapse and release the dopamine into the synapse 1:01:26 so that's what the these vesicles these storage vesicles which are driven largely by the protein 1:01:34 vmac2 do in the normal setting and yes in 1:01:39 parkinson's disease vmax2 levels are markedly reduced um and i think that's a big part of the 1:01:45 problem as to why dopamine is so much higher within the cytosol even without that it's certainly not 1:01:53 depleted on a personal basis but with that it's really the the elevations go 1:01:58 up dramatically so i think that's a big part and there are folks 1:02:03 who are working on drugs that could potentially increase 1:02:08 vesicle formation and improve function largely by modulating vmat too 1:02:13 that would be very a very exciting way to treat dopamine overload in the cytosol 1:02:18 but there really aren't any any molecules that are even close to going with clinical trials for that mechanism 1:02:26 thank you jonathan actually a question from dave and cedar they're asking if there are other ways to lower the 1:02:31 dopamine in your cells than taking the drug we're talking about um i'm sure there are i can i can come 1:02:38 up with a couple of hypotheses one would be to lower the drug lower the synthesis 1:02:44 another would be to enhance how quickly it's metabolized another would be as we've mentioned 1:02:50 before more vesicles increase vmat too you can also 1:02:56 think about the dac protein which is what's responsible for taking 1:03:01 dopamine out of the synaptic cleft and back into the presynaptic axon and maybe 1:03:07 by blocking that function you prevent the presynaptic axon from overload i'm 1:03:13 not sure that that's a great idea to leave super high levels in the in the synapse uh but i'm just saying 1:03:20 you know if you're trying to figure out how to reduce dopamine you just look at all of the factors that are playing a role and 1:03:26 you could say any of those are possible the beauty of of tyrosine hydroxylase is 1:03:32 that we can test it in people um and because it's already on the market at least in the u.s 1:03:38 and there are two animal models that show it improves cell function biochemistry and 1:03:44 viability so you've got a basic science support as well as 1:03:50 all the work done so you can move right into a proof of concept clinical trial so it's a very efficient approach to 1:03:55 take thank you jonathan question from sarah hello sarah she's asking whether you would like to 1:04:00 comment on the users of traptofan as a tarazan hydroxylase inhibitor 1:04:06 um it seems as though tryptophan is a very very weak inhibitor of tyrosine 1:04:12 hydroxylase um it there are some data that suggests it can inhibit the enzyme 1:04:18 um and and again it gets back to the idea of if if you're going to take let's say 1:04:24 let's just assume that it could work in a person with parkinson's disease so it it gets absorbed it's tolerated and it gets into 1:04:31 the brain and it acts there if you're going to take enough to try to attack this mechanism 1:04:38 then you're basically taking materialism and you have the same risks 1:04:44 associated with picking the wrong dose so if you want to try that um you know look people who are who are 1:04:51 affected by a can either be desperate or maybe they're sick of standard medicines 1:04:58 whatever the motivation is the key thing is if you're going to try something like that don't do it on your 1:05:03 own do it with a doctor make sure you've got a doctor who understands what to look for 1:05:10 and how to manage problems if they occur i mean i i 1:05:15 wouldn't do it outside of a clinical trial but you know i'm like conservative mainstream medicine kind of guy so i but 1:05:22 but that's what i would say do it in a clinical trial talk to your doctor maybe your doctor can do it as part of a of a 1:05:29 clinical trial um if they can get access to the drug and they think it makes sense so we have thank you very much and two 1:05:35 questions one from chris and one from alexander that are alongside the same topic about simultaneous use of l-dopa 1:05:42 and metaerosine so chris is asking if the terrazan works to stop progression would you expect that symptomatic 1:05:48 treatment like da for el dopa would be contraindicated indicated for simultaneous use with methyl sine and 1:05:54 alexander is asking so he's basically saying saying so how would the therapy with the tyrosine actually look like 1:05:59 would it be given in addition to eldopa so the way that negotiation 1:06:04 went with the fda is along these lines the fda felt most comfortable 1:06:10 with the drug being used in background of 1:06:15 of some dopaminergic therapy but not high dose they wanted it to be tested in people 1:06:20 with early stage parkinson's um who were taking maybe a couple hundred milligrams of levodopa for 1:06:27 example it's i'm willing to do that because i think that um 1:06:33 that at least will allow us to learn that it is a drug that is tolerated and 1:06:40 i think that if i were to show up at the uh at the michael j fox annual symposium or 1:06:45 the american association of neurology and present a paper showing that a dozen 1:06:51 people could tolerate doses up to 400 milligrams three times a day of methirism without worsening parkinson's 1:06:58 people would freak out like in a good way like oh my gosh this how could this be and then 1:07:04 uh the kind of attention and funding that would be a certain keep going would follow um what i've discussed um 1:07:12 with the advisors that i have in the parkinson's world is the idea of doing 1:07:18 that one study with the starting that study first showing the drug is tolerated on the background of the low 1:07:23 dose of l-dopa or dopaminergic um and 1:07:29 then starting a study right after again in mild patients who are not on any dopaminergic therapy 1:07:35 um could the two work together yeah i mean i could see that because as i showed you 1:07:40 before l-dopa or levodopa basically shifts you up 1:07:46 the curve of how the receptors are affected so it could be useful at the beginning 1:07:52 uh maybe people need to be on a little l-dopa to tolerate the tyrosine maybe that's what we learned and then 1:07:57 eventually it gets weaned off i mean the only way to know is to start doing the trials 1:08:03 thank you ashwani is asking actually a question about some he basically says would you 1:08:09 have a recommendation for a pd patient who is taking el dopa and he's not really sure if endopa is helping him at 1:08:14 all uh but he's been taking it to to be safe uh would you recommend 1:08:20 i mean at the end of the day that person should speak to his neurologist but what would be your your recommendation 1:08:25 i mean you know the only way the only way i feel comfortable answering questions like that is if i were to have 1:08:31 clinical trial data that's relevant to that situation or i could talk to somebody who's really an 1:08:38 expert in parkinson's disease and listen i mean i've talked to parkinson's experts who 1:08:44 just so to be completely transparent i've talked to parkinson's expert who think i'm out of my mind 1:08:50 i had one very prominent uh parkinson's expert who i read a few papers by who i wanted 1:08:56 to talk to about this who i couldn't get on the phone and he worked at a hospital with a friend of mine from a 1:09:01 cardiologist i had my cardiologist friend call him and say you know talk to jonathan we got on the phone he listened to me 1:09:07 for a couple minutes then he said to me so you're a cardiologist right i said yes 1:09:12 he said maybe you should go back to cardiology so i i bring that forward because i want 1:09:19 you to understand that what i'm presenting is not an approach that 1:09:25 has been embraced by parkinson's experts that i've spoken with um over time as i've talked to people over 1:09:32 a two three four year period i have people now who didn't really want to discuss it who say you know what this 1:09:39 makes sense we should do this trial you should do this trial um so i don't 1:09:45 even though i am convinced this is going to work and i am convinced i can 1:09:50 carry out the studies and work to demonstrate that um i i do want to give you the caveat that 1:09:57 uh people who understand this disease way more deeply than i do do not think this is a good idea so 1:10:05 when you go home be open-minded but again until we have clinical trial data 1:10:10 not only can i not answer the question that was posed by this last questioner about what to do about his or 1:10:16 her l-dopa but we really need to do the clinical trials that tell us what the 1:10:23 right answer is and i'm excited that eventually i'm going to get that started and then i'll share the 1:10:29 information with you thank you janet and linda you had a question along the same lines i will pass that question because 1:10:35 the answer that jonathan gave is applicable to this situation as well trish is asking um about um how would 1:10:41 basically uh i guess taking the terrazyn and uh with or without eldopa affect dyskinesia 1:10:49 uh i'm a believer with without any scientific data to back i mean i feel 1:10:55 like i have good scientific data to back up approaching parkinson's with this drug as a treatment 1:11:01 i don't have data with dyskinesia but from what i'm reading about what causes it and 1:11:08 looking at the parallels for tardive kissimesia in outside of parkinson's disease 1:11:15 i think it could help i mean again that's something that we can learn over time 1:11:21 and hopefully not too much time so that i have the answers at a time that's relevant for each of you 1:11:27 thank you very much mark is asking he's basically saying apologies if i missed something but why does the matara sign level come with a 1:11:33 warning that the drug could worsen pd i i think that it's it's a it's a pretty 1:11:39 straight straight path to say if i have a patient 1:11:45 who needs dopamine who needs levodopa and there's a drug that prevents l-dopa 1:11:52 from being made if i give that drug and shut off that synthetic pathway inside the neurons 1:12:00 i'm running just from logic a high risk of that person getting worse and that's the basis for that warning 1:12:07 it's it's not even based on data because there there aren't any i mean i'll talk 1:12:12 to some parkinson's expert who tell me oh you know we did this we gained materialism and it caused parkinsonism 1:12:18 in this clinical trial it's like i read that paper your paper doesn't say that it doesn't say you gave the tyrosine it 1:12:24 doesn't say it cause there was parkinsonism that was induced like can you share some data with me it's like uh i have to find it it's an 1:12:31 old paper uh there just isn't there there aren't data to support that statement but i think 1:12:37 it's a very reasonable statement to have on a label considering the mechanism of the drug and the 1:12:43 mechanism as we understand it of the disease thank you jonathan we still have a few more questions i hope you have a time 1:12:49 for another eight questions we have had like close let's go with 35 questions which shows a very strong 1:12:54 interest for for your topic here um an anonymous attendee is asking about 1:12:59 uh mao b rasagalli and rose galin basically saying if dopamine is toxic to cells how could now be rasagulin have 1:13:07 shown indications of neuroproject protection as one milligram dose do we just assume that the now the 1:13:12 neuroprotection trend was actually a false finding since after all it hasn't been reproduced i don't know if you're aware of this um you know i i'm not sure 1:13:19 i know exactly which study you're talking about but um there's been a lot of a lot of um 1:13:27 papers where neural protection is discussed i think that many of them relate to how 1:13:32 washout is done and then repeat or that scanning is is performed 1:13:38 um there's not a paper that i've seen and i've and i think i've read enough to say 1:13:44 this with confidence although it's i mean it's not like i've read every paper in parkinson's 1:13:49 but i have not seen a paper that has any evidence showing that the clinical course is 1:13:56 changed with any of these dopaminergic therapies well if somebody has a paper please 1:14:02 bring it forward because if i'm wrong about that then that's an important thing for me to know and certainly 1:14:08 undermines a lot of uh my enthusiasm for what i presented to you today 1:14:14 question from an anonymous attendee who is asking about dopamine that is produced in the gut is it something you've looked at 1:14:20 yeah really important question um because of how interesting it is physiologically and also how relevant it 1:14:26 is to parkinson's disease i have not looked at that at all okay interesting topic we'll keep in mind 1:14:32 um ann peyton is asking about evidence about herbals about the vasculside as th 1:14:39 inhibitor yeah i mean i i saw that question and and i i don't know that that compound 1:14:47 uh but i think i would i would say the same thing about um that compound as any 1:14:52 if you're looking at a compound which is essentially a drug whether you want to call it a dietary 1:14:58 supplement or a vitamin or whatever it's a drug because it's going to be affecting the tyrosine hydroxylase 1:15:04 enzyme function then you need to be careful because i think that to get benefit you have to 1:15:11 slowly increase your antagonism of that enzyme during addition of that enzyme but get to a point where you're really 1:15:18 meaningfully inhibiting that enzyme and whether you do with tyrosine hydroxylase or you invent a new drug or you've got 1:15:23 an herbal supplement that does it i don't think that the risk for any of 1:15:28 them is different if you are using a dose with the same potency against the enzyme that's what's 1:15:36 going to affect both the likelihood of benefit and the likelihood of her thank you 1:15:42 uh jiren is asking about anti-nausea medications that are blocking levodopa is it something you've come across 1:15:49 a lot of the drugs that i think you're referring to are ones that act at the dopamine receptors rather than at the 1:15:56 synthesis uh the rate limited enzyme of the synthesis of dopamine so it'll be different and 1:16:02 part of how i started this i actually started out looking for which 1:16:07 receptor i wanted to block because i was being very literal and trying to use the parallel from heart fair blocking 1:16:13 a cell surface receptor there i thought that's what i would do with dopamine what i found is the distribution of 1:16:20 dopamine receptors presynaptically and post-synaptically and elsewhere in the brain 1:16:25 is to me far more complicated than what i experienced with beta receptors in the 1:16:32 heart and i just couldn't figure out a way before i even look for a drug i couldn't 1:16:38 even figure out a way to affect those enzymes the way i wanted to to reduce presynaptic dopamine 1:16:44 and then i said well let me see how it's formed i'll attack the rate limiting enzyme and ended up uh going ahead and 1:16:50 finding um uh this drug 1:16:56 thank you question from randy about that scans he's basically asking can you see that question about trace or dopamine 1:17:03 trace of that scans whether they if they show the diminished dopamine in the neuron 1:17:08 how does that correspond with your findings well the the problem we have with uh 1:17:13 imaging uh in vivo imaging of the brain whether it be dad or pet is that you can't get the resolution to 1:17:19 see what's going on in the cells you're seeing and re-issue so um while it's it's interesting and 1:17:25 important it does not get into the issue of how much dopamine is inside the cells 1:17:30 versus in the neighborhood thank you a great question actually a great comment here from kevin mcfasting 1:17:36 if you see it because actually kevin is our next speaker in a month's time so we basically you are meeting one of your 1:17:42 colleagues so to speak um he's giving you the link to the study but i will also make sure kevin if you 1:17:48 agree that i will be putting both of you in touch after this call ingrid is asking whether you're aware of 1:17:54 any experts in the uk who are open-minded to the type of treatment you are contemplating 1:18:00 um i have not really been been um i'm just starting to really expand beyond 1:18:05 that initial set of docs but uh i'm not sure that i would even if i 1:18:10 had somebody i'm not sure i'd be comfortable telling you until they decided to advertise it 1:18:16 um and the kinds of people that i'm looking for are people who would be likely to say i want to participate in this clinical 1:18:22 trial i want to help you design the clinical trial i'm looking for people who are clinically trial focused because 1:18:29 that's what i want to do to demonstrate yay or nay 1:18:34 okay kevin thank you for for being very happy to be connected to jonathan albert had a follow-up question on the 1:18:40 day 3da is asking whether you would expect that producing dietary and tyrosine might help produce excessive 1:18:46 3da i think the likelihood is is not um because there's still going to be 1:18:52 enough in your body that's going to figure out how to take what's there and and make aldo 1:18:58 thank you very much and the last question for the day i think because we have we had plenty of time but we have been 1:19:04 going for quite almost like an hour and a half now um is a question from mark who is asking 1:19:09 what would the dopamine holiday look like so i think the the the best way um 1:19:16 to think about that would be to go back and and do some searches on the internet to find how people would do it i'm not 1:19:23 sure exactly um exactly how people prescribe to do it i 1:19:29 do know that when i've talked to parkinson's experts they tell me that the idea of a 1:19:35 of an l dopa dopamine holiday is something that is not viewed 1:19:40 as in the patient's best interest and i don't know if that's because what people have found is that when you 1:19:45 stop and restart that it doesn't work as well i think the theory initially was that when you stop and restart it works 1:19:51 better um but it's not something i know enough about in the nuances that i think you'd 1:19:57 have to discuss that with your neurologist and if your neurologist is over 50 she or he would probably know pretty 1:20:04 well what a dope meat holiday looks like thank you very much and i think i will take this last question from kevin um 1:20:11 um and then we will basically uh close the session for today he's asking you whether in your dream clinical trial 1:20:18 what kind of symptoms and side effects would you hope to be measuring accurately such as the fedex thermos 1:20:23 updrs objective you know measurement of movement yeah i think that you know the phase two 1:20:29 study basically what you're doing is you're testing which endpoints are going to be the most sensitive to detect the 1:20:34 effects you're looking for as you plan for phase 3. so the updrs is definitely going to be part of it 1:20:41 one of the things that has frustrated me about the way parkinson's is investigated and written 1:20:47 about um especially after watching ivan my friend is that he had a lot of trouble 1:20:53 moving around and that used to really frustrate him and what strikes me about clinical 1:20:58 trials and parkinson's is that i can't find one where people have actually measured how 1:21:05 well people can get around if if you want to say that i'm going to try to treat the movement disorder 1:21:11 grossly then i think one of the endpoints in a phase 2 trial should be how much a person walks or 1:21:18 how quickly a person can get out of a chair and walk there's something called the timed up and go test so i'm going to include a 1:21:25 few of those things as well as looking at overall activity by having people wearing something called an actograph that traces their 1:21:32 movements over the course of a week period so you really see whether they're able to move more 1:21:39 and i think those would be very interesting endpoints in addition to all of those that are typically measured in clinical trials 1:21:45 jonathan thank you very very much for your time today and for an extremely thought stimulating session i wish you 1:21:51 the best of luck with raising the necessary funding to the for the trial that you that you want to launch 1:21:57 um i will basically be calling you and just trying to see whether we can connect you with some of our partners and see 1:22:03 whether something comes out of it i would also like to thank our audience today who basically contained more than 100 people and was extremely active with 1:22:10 close to 40 questions which is really basically an all-time high so that really shows a very clear sign of 1:22:16 interest from everyone thank you everyone for this and then we'll be meeting again in a month's time for kevin mccarthy who will be talking to us 1:22:23 about some very interesting topics about the new new trials and therapies that uh that 1:22:28 can be of interest to everyone thank you all of you and we'll see each other in a month's time thank you jonathan bye-bye 1:22:34 thank you very much