The Current State of Alzheimer’s Research

so okay and and welcome all uh we have a wonderful collection today of board members and donors um uh for the 80 from the addf i'm mark royce there i have the privilege and honor of serving as the ceo of the alzheimer's drug discovery foundation we have a wonderful update on the current state of alzheimer's research coming from you today this is incredibly timely as last week there was a international gathering under the title of the clinical trials alzheimer's disease conference better known to those in the industry as ctad particular significance with the event this year one because there's been a lot in the news but two those of you have been supporters of addf for years know that just last year 88 of everything we funded because of your wonderful donations went into clinical trials and about 12 into pre-clinical uh but that overwhelming majority of what we're funding is all about clinical trials we were actually a gold sponsor of the event this year which started last tuesday afternoon and ran through friday it was in boston it was a hybrid event about three to maybe 350 people in attendance probably seven to eight hundred online across the world and uh we are very very fortunate today because we have two phenomenal doctors who are there for all of it dr howard phillip our co-founder along with the water family and chief science officer at the addf and dr jeffrey cummings who's a director of the chambers grundy center for transformative neuroscience uh and he's also he's a clinical trials expert and runs his own phase two study on a repurposed drug i suspect you might hear a little bit about that today i will tell you both howard and and and dr cummings were a bit of rock stars last week uh dr phillip ran two panels during the conference and uh those of you who tuned in a little early you might have heard me uh chit-chatting with dr cummings who served on at least three of the panels i think it was more but he tells me he was three um what we're going to do today i'm going to turn this over to howard in just a minute and he and dr cummings are going to speak for the next half hour plus uh just about what went on at the conference the key takeaways uh and then we'll open it up for questions and answers we'll have about 15 to 20 minutes to do that and then stop at the hour uh if you have when you have questions just put them in the chat feature so if you just click on the chat button and put your questions through and i will do everything in or we will do everything in our power to get your questions answered and if for some reason we don't get to them we will get you answers post the hour we're together today um so howard as i turn this over to you i i also had the privilege of being at the conference last week and and if i had to come away with three headlines and you and doctor comes to talk about anything you want but you know the coming of age of blood tests and alzheimer's seemed to be front and center uh there also seemed to be a lot about adjectamob and amyloid and tau and at the same time there was a competing amount about what i would call the biology of aging and that kind of starting to take a center stage so with that as a kickoff uh dr howard phillip i give it to you and you and dr cummings take it away for us here thanks mark um this was i believe the 14th annual uh clinical trials and alzheimer's disease meeting and uh i've been going to them i think i've probably gone to probably jeff and i have both gone to every single one of them or most of them and i always felt one of the criticisms of the meeting was that there were never any results um not too much on the way of positive data um and so often it was not a it it's the leading meeting uh annually on clinical trials but it wasn't the most exciting meeting i would say um and this year was definitely different it definitely had a different flavor there was a lot of results being reported a lot of trials that were being reported in the pipeline that would report out in the coming year or so so it was really in my way in my way of thinking um to me it was a landmark meeting i think in the field and it really reflected the progress that we've made in the field um and as mark mentioned there was a lot about biomarkers and how much progress we've made on biomarkers and particularly about the blood tests and there were some innovative studies i think where i'd like to start and then yes jeff or his opinion is that one of the headlines at the meeting was about the anti-amyloid antibodies and there was one sort of non-controversial panel about the controversy around adukanymab or adelhelm the biotin drug um but i think um and we saw some more data from that trial indicating that the mechanism of action uh to remove amyloid from the brain also correlated with uh a tau signal in in the spinal fluid and in the blood which indicates that again along this pathway of anti-amyloid therapies there really might be a a saving in terms of neuronal brain cell death and destruction but a really interesting part of the meeting was results on a similar antibody that's being uh developed by eli lilly and that antibody actually has a different chemistry to it even though they're both anti-amyloid antibodies to buy into drug and the little drug the lily drug actually has a different chemistry and seems to be more effective and so lily reported some of their results at the meeting which i thought were really quite interesting and also esai a japanese pharmaceutical company reported some of their results on their anti-amyloid antibody which is also a bit different and and roche reported on some of their data and i think taken together these are all beginning to support the idea that maybe maybe anti-m with their therapy really does work it certainly works to remove the plaques but maybe it really does work to help people in slowing the rate of decline and uh with that i think for the first discussion about the most advanced therapies and what was presented at the conference maybe i'll ask jeff what he thought about the general feeling about anti-amyloid therapies and the kind of data that were presented there thank you thank you howard and thank you mark thank you to adf it's really great to be here supporting an organization that i respect so much and howard's leadership has just been extraordinary over the period of time that addf has been growing into a really a major influential organization in the alzheimer's disease landscape i had the same sense that you did howard this was a meeting that turned the corner uh right we have been trying so hard for so long to develop drugs that would affect the underlying biology of alzheimer's disease and have that effect of slowing uh the progression or delaying the progression and none of them seem to do so until this this meeting and this year and i just couldn't agree more we now have four antibodies uh and they all look uh they're all dramatically reducing amyloid in the brain we can see that there's no question about it we can see it with these terrific scans and i think the clinical data are also increasingly compelling so atokanemab was kind of controversial because this trials were stopped early but the data that was harvested eventually supported the clinical benefit with uh the native map which is the lily compound that you mentioned they used a sensitive scale which is very important in very mildly affected patients and again you they are with a statistically significant slowing of decline uh in the latino map study which is the a-side drug again we used both the 8-s cog which was a a conventional instrument and the add comms which is again a sensitive set of measures for use in early patients and again you see the slowing of decline so i think this is very consistent and increasingly convincing and really exciting so i i just came away with a lot of enthusiasm from this meeting yeah and i agree and then the the next sort of drugs in the pipeline that seem to be mostly in phase two from big pharma you know so they're really being developed are these anti-tau antibodies but we kind of got less positive data out of out of the anti-tau antibodies i thought um you know we had this hypothesis that a tau which is a a molecule that's in the uh in the connections between urine neurons in the in the wiring of the neurons and also at the synapses uh that this was spreading through the brain uh the biomarkers indicate that tau correlates well with cognition because it's a neuronal degenerative biomarker and there was a lot of excitement i think theoretically in the anti-tau antibodies which were meant to reduce and remove this molecule tau which is in the tangles which is the other pathological hallmark of alzheimer's next to the plaques and so there was a you know reasonably good theory around that but the data that were reported at the meeting didn't seem as positive on the kind of supporting the tau hypothesis i was a little um discouraged about the anti-tau uh uh reports the anti-tau antibody reports what did you think jeff well for one thing let's let's tie that back to the amyloid question because i thought it was just so interesting uh that both the nenemab and adukanymab showed reductions in tau in concert with the reductions in a beta and just as you say that the relationship between tau and clinical decline has always been stronger than the relationship between amyloid and clinical decline so it it looks increasingly likely that the reduction in tau is leading to the reduction in a beta is leading to reduction in tau and that actually may be very important in terms of the clinical benefit that we're seeing but just as you say when you try to target tau itself with an antibody that has proven to be largely unsuccessful there was in the summer adam ab study there was one positive measure uh but it to me and i think to most of the people it wasn't quite a compelling story and there have been several of uh negative tau antibody studies uh before this uh so i think we we we haven't turned the corner on tau yet but you know one one lesson from a beta is don't give up uh let's keep going let's find the answer yeah and and the biomarkers like you say um the anti-amyloid antibodies move the tau biomarkers but what i think was really interesting and emerging is that there's more than one uh tau biomarker um so what we have is that um tau is a normal molecule in the brain it supports the axons and the synapses and it's a marker of neuronal degeneration and we can measure it with a tau scan actually just like we have a pet amyloid scan now there's a tau pet scan on the market now that was just approved for for use around the united states so now we have two scans we could talk about two brain scans that are already being used in clinical trials and and as we know from pathology uh tau correlates very well with with cognition so it's going to be a better biomarker than probably amyloid amyloid just kind of gives you uh whether or not alzheimer's is there but doesn't correlate with cognition whereas the tau scans uh we know from pathology and from the scans actually correlates with cognition but then what we see in the spinal fluid and in the blood now is is a molecule called phosphotal which is a basically a modified form of tau but there's different kinds there's phospho-tau p181 phosphotel p215 passport phosphotel p4231 and they all seem to have different properties so we're going to have we already have an amyloid blood test on the market we've already seen how that's being used in clinical trials which is another thing we could start to talk about how these there were reports of how these blood biomarkers are starting to be used like in the head trial that recess sperling reported on but also these tau blood tests how they're being differentiated into different types that might have different use or specificity and i wondered what you thought about that jeff yeah well thanks uh howard let me just emphasize the importance of blood-based biomarkers until now it was either expensive scanning or it was spinal fluid which of course means having a lumbar puncture to remove the fluid and understandably many patients don't want that and so it's been difficult to get as much of the of the biomarker present biomarker meaning something we can measure in the spinal fluid or in the blood that reflects what's going on in the brain and it's just fantastic now that we're getting all these blood biomarkers so as you say we have them for amyloid we have p-tower 217 which is being developed by lily which seems to occur to change very early essentially with the amyloid burden in the brain p-tau-181 also seems to be changing very early uh with amyloid in the brain on the other hand uh p-tau 231 appears to be changing later and then the scan that you described which is really a scan of the neurofibrillary tangle formed by tau is is even later coming on just before symptoms begin to appear so not only do we have multiple reporters but we have an emerging sequence of the biology changes in tau that are occurring in the earlier stages of alzheimer's disease so it's hugely hugely uh informative and i was so impressed with the biogen data that the ptau 181 had very robust correlations with the clinical outcomes so i i think these are reflecting in an important way what's happening to cognition in patients with alzheimer's disease and after all in the end it's all about the patient and these are stepping stones to helping our patients that's what we want and yeah and it shows us how you know we can really do modern clinical trials uh i like to call modern for lack of a better word but you know how far we've advanced in our ability to use biomarkers to really do much better clinical trials um in patients earlier even patients that don't have symptoms there's some trials going on i wonder let me say one thing about that howard i'm so excited about this but what we can see is that the amyloid goes very low and frankly i think uh as a as a as a a a group as a research group we don't really know what to do with that if it's very low do we need to continue treatment for example but what we can see is that the that the pital markers begin to rise in the blood during that time when the when the amyloid is still low and that may well be the indication that we need to continue treatment in those patients um so i think that the guiding of the management of the antibodies is also going to be very informed uh by these blood tests yeah that's a great point jeff that came out at the meeting is that it's kind of like cancer in a way the way we think about cancer treatment we treat patients we hope to watch their biomarkers with cancer it might be an x-ray of lung but it might be obviously these days much more sensitive biological markers but we treat them we see their biomarkers get better and then we wait and see and see if the disease recurs and that kind of model is actually what we're seeing emerging with alzheimer's disease which is really interesting because it might be possible that we see the amyloid disappear after six months of treatment and then as lilly was suggesting and some others you could actually stop treatment and we saw data that really going out almost two years there's almost no or very little increase in the recurrence of the amyloid which means the disease can take a long time to come back and cause uh symptoms or you know to to create havoc in the brain which really changes the clinical model because i think the thinking that you had to go on infusions for the rest of your life was really quite something difficult to imagine especially since we haven't talked about the the side effects of these drugs which is actually pretty serious i suppose and we saw some data on that jeff i wondered if we could maybe move on to some of the other things that we saw one thing that i was excited about was the semi-glutide trial and we we haven't seen any data per se from that trial but adtf sponsored a a clinical trial of a similar drug called lyric glute which was on the market before semiglutid uh the lyric drug is an injectable and what it does is it basically improves metabolism and insulin resistance in people with diabetes but of course in the in the aging brain we we see insulin resistance and we we thought the the theory from both epidemiological data and animal model data was that lyric glute could actually improve symptoms so we sponsored a clinical trial at the imperial college of london with paul edison and we saw results on ftg glucose monitoring looking at better metabolism from the drug and so on which inspired this novel this large normal nordics trial of uh of semiglutid and i'm pretty excited about that because again you have bieter which is um one form of of a glp-1 agonist which is the class of drugs we're talking about you have doula glutathione you have semi-glutathione and you have lyric glutathione and all of these drugs both in epidemiological studies and in clinical studies seem to show improvements so there's a body of evidence that this kind of improving metabolism by improving insulin resistance could really work to slow down the course of the disease and i was pretty excited to see the semi-glutai trial because semiglutite is the only one of those drugs that's orally available but i don't recall seeing any preliminary results or biomarker results from that um i guess i'd ask you what you thought about the data presented on semiglutid if they're you know or the whole proposition of semiglutid as a potential drug for alzheimer's and you know it's not just in diabetics if this is a drug that could also be used in non-diabetics uh to slow the the disease down yeah uh i agree completely howard i mean it's just uh so exciting to see this new class of drugs coming in uh this there were no data presented they presented a lot of the background of the trial and one of the things that i found particularly interesting is that there are now four registries where people have been followed over time mostly diabetics without being followed for cardiovascular disease and all four of them show a reduction in the mur in the emergence of alzheimer's disease and one of them the reduction was on the order of 50 that was very robust uh so um i share your enthusiasm for this i think there's animal data that supports the the glp one agonist there's epidemiologic data that that supports their use we know that there's insulin resistance in the brain and the main effect of sumagletide may be on inflammation in the brain because diabetics have a lot of inflammation and when you give them some magletide you reduce the measures of inflammation like c-reactive protein so we know that's happening and that may well be a key to what they're doing in the brain as well yeah that's a great point i i wasn't thinking about that but they when the presentation they actually postulated neuroprotection and an inflammatory effect as part of the way the drug worked and it's a good example i don't know that people really thought about it but it's a good example of repurposing because this is a diabetes drug that's being repurposed for alzheimer's disease and maybe that's a good segue to talk a little bit about our panel which i thought was great of course we were both in it so we're going to think it was great but but um you know we had you presented on the study we supported our sagittalin and anna pereira talked about her studies of early azole and emmy giacomo flew in from rome to talk about the studies we supported with his drug which was repurposing a parkinson's drug called roticotine and the whole purpose of the panel was not just to report the results of these drugs an als drug and two parkinson drugs but also to talk about commercialization because the theme of the panel was very often in repurposing you see an academic study uh reporting the results of a small clinical trial repurposing a drug it goes into the medical literature and then it kind of dies there and nobody prescribes it offline there's a lot of off label there's a lot of challenges in prescribing off label these days insurers don't like to pay for it and i thought we had a really good discussion about not just the results of these three addf supported repurposing studies but also where do we go next um and you you talked about your your pathway and maybe you could comment a little bit on the panel because i i think we got a lot of kudos on that panel particularly yeah i think it's it's really important repurpose drugs just to be clear are drugs that are approved for one disease maybe parkinson's disease or als in the drugs we're talking about uh and then they have promise for use in alzheimer's disease so they are repurposed for use in alzheimer's disease but of course they're not approved for use in alzheimer's disease so one could use them off label but you can't market them you and you don't have as much information the importance of repurposing uh is that much of the original work is already done uh the animal work is all done the dose finding is all done phase one safety is all determined so you essentially begin the development program at phase two cutting off at least half of the length of the of the development program that is so important we need drugs fast uh so if we can cut the time down by 50 percent that's great but it it is true that very few of those drugs have made it into phase three and part of that is the intellectual property uh problem that is maybe maybe they're already generic um and so uh pharmaceutical companies have shown less interest them but the panel was so instructive uh because you could see that by uh adjusting the dose to a different dose yeah you might be able to get intellectual property by adjusting the formulation you could get intellectual property you might be able to change the molecule slightly and that would give you intellectual property as a new molecule and certainly there's tremendous learning in those trials you learn about biomarkers clinical outcomes new designs all the the things that we need to know to advance the field in general but specifically i think we can advance those repurposed compounds if we're clever about how to manage intellectual property yeah there was good discussion around that and i forgot to mention michaela gallagher who we've been supporting and investing in her company aging bio and she was an example of how she got intellectual property by changing the dose to like one tenth of the normally used dose in a reformulated type of pill for her drug which is from mild cognitive impairment and the clinical trial it's essentially a phase 2b phase 3 study if it works you know she might be able to bring that to market and she's been at this a long time and developed a use patent and a very strong intellectual property but she hasn't been able to get a lot of investors and has really kind of run the company on nih grants and nih of course has a lot of money these days so she's gotten something like upwards of 100 million dollars uh to run the study uh with giacomo we're trying to create new intellectual property by creating a new combination of rotigatine which is his drug along with one of the old existing drugs rivers stigma and they're both patches and so we eventually can envision a day where the new intellectual property would be one patch that had two drugs that had different symptomatic effects for patients and that they were headed additive and of course anna pereira has a really exciting drug in my view really is all which could replace one of the existing drugs on the market nematine which is also one of the drugs that's on the market today for alzheimer's that comes from repurposing because it was originally a drug for another indication and somebody came up with the idea there was it was an antiviral being distributed in europe it was sold in europe in the 1960s as an antiviral and someone came up with the idea that you could use mementine for um for alzheimer's disease and there was a big intellectual property fight the generic companies got involved but today mementine most patients in the united states are on two drugs one is a drug like a receptor or dinapazil a colon esterase inhibitor and mementine and mementine is a repurposed drug on the market today for alzheimer's disease so uh yeah we're very excited about our repurposing uh clinical trial i think the other thing that bears mentioning is that those those drugs are less expensive um and and that's why nih can confund them reasonably addf can can have a major role in them uh and that's important because we we if we can figure out how to get around the tremendous expense of drug development we can have more drugs in development and eventually more drugs on market but just to put that in perspective because we did do an analysis of what it might cost to bring a repurposed drug to market excuse me um you know we're supporting phase two trials maybe um three four five million dollars and it gives us enough shots on goal that if they're interesting data hopefully someone nih or investors can come along and fund the next study because um while the repurposing trials we're funding are in the phase two when we get to the phase three now we're talking 50 or 75 or 100 million dollars the overall cost of developing the drug might be 1.2 billion when you start from scratch right so as you said jeff you can leapfrog that and yeah we can reduce the cost but we're still talking about a lot of money which would require i think investors or maybe some nih you know because again they have 3.5 billion but but it's still not inconsequential the amount of money and effort that's required to actually get that new indication and bring these repurposed drugs to commercialization and market and patient access another another thing that i think came up jeff was i don't know if you want to talk about green valley which is one of the first new drugs approved in china and being developed in the united states and i know you've been very involved in the green valley story maybe you could tell us a little bit about the green valley drug absolutely and i see that there's a chat question about xenolytics uh and that really over overlaps with the green valley story so um the green valley is a company that's developing gv green valley 971 and it acts primarily on the microbiome to reduce inflammation in the gut and we've already been talking in with in terms of somaglitide that systemic inflammation apparently drives brain inflammation and if you can reduce the systemic inflammation you can reduce the brain inflammation because some of those inflammatory cells cross the blood-brain barrier and many of the inflammatory chemicals cross the blood-brain barrier so the the idea of gb 971 is to reduce the inflammation which is present in the gut of many alzheimer's disease patients to reduce systemic inflammation which has been measured and shown and that will reduce neural inflammation so we're hopeful about this as you say this there was a successful phase 3 trial in china it was approved in china and is on the market in china and now it's being studied in a global phase three program that is primarily in north america and western europe and china so a really exciting program with i i think a very interesting biology and then that takes us to the cena lytics because c analytics are a class of compounds uh that uh interfere uh with the senescence of cells and therefore have effects not only on the brain but on many cells in the body so in the xenolytic trials many of them include cognition as an outcome but not the only outcome so there might be cardiovascular benefits there might be arthritis benefits as well as benefits on cognition so there are a few of these analytics that are specifically looking at changes in senescence cells in the brain and i think they're very interesting and they might also have systemic effects as well and to tie this back howard to our earlier discussion it looks like tau in the cell often leads to cellular senescence um so senescence may be a downstream effect of tau and maybe we can interfere in that downstream process with cenolitic compounds so i see that as a really interesting novel and important theme that's evolving in alzheimer's disease therapeutic research yeah and miranda ore from wake forest who we funded to do us analytics trial gave a great talk i thought on on her uh her star her clinical trial where she's repurposing two compounds to cinetap which is a cancer drug and quercetin which is a synolytic drug the thing about senescent cells is when cells get old they refuse to die and when they refuse to die they become very inflammatory and they chronically release inflammatory factors that are killing cells in the brain so it's interesting that centalytics are being used and being investigated for cancer treatment to help these cells die die but and you know you want to kill cancer cells in the brain the question is like do you want those cells to die and you probably do you want to get rid of them um but then you know does that kind of mess up circuitry i think was one of the concerns it's kind of a theoretical concern but we're really interested in in this analytics and it's it really extends directly to our strategy which is uh promoting the biology of aging um i i know we have some questions here so i've been instructed to start addressing some of the questions jeff that we see but i just want to encourage everyone that if you go into the chat you can ask questions and we'll jeff and i will try to answer them um one of the questions is jeff um about um you know if if we remove tau and amyloid could that be a possible pathway to treatment my personal opinion is that the way the way drug development works in combination therapy which is kind of the question and where we're going we think with alzheimer's treatment it's going to be combination therapy based on a per person's biomarker profile and so we have amyloid and cow and all these other biomarkers we'll be able to identify people with those kind of abnormalities and then create a combination of therapy so this question is about combination therapy but according to fda regulations or guidance to to develop a drug that's a combination therapy drug you have to have four arms the placebo one drug alone the other drug alone and the drug in combination so you have to show that each drug works alone and then show that the combination is better so if we're seeing amyloid effects that there's some consensus maybe that we are seeing a marginal effect or maybe something more than marginal depending on the antibody um that's a good thing amyloid will someday i believe go into combination therapy with other drugs but will it be tau well if we don't see tau effects of tau drugs tau monoclonal antibodies um then then it's unlikely that there'll be a combination of amyloid and tau drugs because again according to fda guidance uh we need to see the tau drugs in in by themselves having an effect um jeff i wondered what your thoughts were about this issue i i think we're definitely moving towards combination therapy that's that's been the successful story for tuberculosis hiv many cancers um so i i think we're we're definitely going towards combination therapy and there are many combinations that we could envision and i know addf had actually a beating on combination therapy we've just been talking about inflammation so it may be that a combination of an anti-amyloid plus an anti-inflammatory would be a very useful combination but as you say the fda requires that the benefit of each drug be shown independently before they're used in combination or at the same time in a in a four by in a two by two trial of the type that you're describing uh so these are complex uh developmental pathways to try to get two drugs to work and it's also true that two that companies rarely have two drugs that have complementary biology at the same stage of development so then that requires a collaboration which has sometimes been difficult one of the questions about is about some of the other things that were excited in the pipeline and i thought there were two kind of interesting uh trials that uh were reported um that got a lot of press and uh kind of really out of the ordinary i think the cortex study and the cognito study which both you know the cortex zim study got failed in its primary outcome and so the cortex company which is publicly traded and we looked at it and declined an investment it's based on the idea that if you have periodontitis if you have infection of your gums that that's a risk factor for alzheimer's disease and then it was discovered that the bacteria that causes periodontitis releases a factor called ginger pain which apparently gets into the brain and the company had some good evidence that it does so they created and that this ginger pain is neurotoxic and so the theory was that if you had infection of the gums which is very common in older people uh not so much in younger people who actually are developing alzheimer's pre-clinically so it's a one question i think we have but um that this drug that they developed that neutralize the ginger pain in the brain could be therapeutically effective and what they showed in their in their report which was obviously in a press release as well is they studied the whole population of alzheimer's people and this is an interesting clinical trial model actually it's called enrichment using biomarkers so they studied the entire population and they didn't see an effect but they identified people by saliva who had positive uh studies for the bacteria in their mouth uh indicating that there's p gingivalis which is the bacteria that causes the periodontitis and it releases the ginger pain into the systemic circulation and into the brain that the people who had evidence of p gingivalis and therefore would have ginger pain in their brain they responded pretty well to their drug and at the bottom line at the very end they also saw that their drug improved periodontitis so if nothing else you get a drug for your periodontal disease and your gum disease but i thought that was pretty interesting and the market seemed to really uh slam the company but i i thought there was a little signal there for you know if you could test people for this ginger pain or for the p gingivalis bacteria you could treat them to remove that and they might get cognitively better yeah i think it was a really interesting observation howard um and as you say the the main measures were negative the the the trial did not meet its primary outcome but just as you say um those that had evidence of the peach and javalis seem to respond to treatment i'd want to know two things now one is is there was there anything else special about the group that had peach and javalis that could account for that um so so i think we need to more data on that and the other is that i'm still puzzling over this the time course that is the infection that would drive alzheimer's disease had to have occurred about a decade ago uh in terms of our understanding so what how how confident can we be that finding p gingivalis in the mouth now reflects what was going on a decade ago uh and maybe it's very tight you know that's a possibility uh but uh i think there's still some learnings to to do with with that and and but i think they're doing um essentially the right thing which is okay you've got a biomarker defined population let's see whether they respond i would see that a little bit more as a phase two trial than as a phase three trial but these these numbers are somewhat are arbitrary i i see it's a good illustration of how comorbidities can worsen cognition let's say in old age and be a contributing factor that's treatable as opposed to as you said a cause of the disease because you know we know the disease starts let's say when you're 50 and most people at 50 don't have periodontitis so it's hard to speculate that this is the cause of alzheimer's because we know the amyloid's accumulating which leads us to another question that relates to really prevention so with these biomarkers now with the brain scans and even more importantly the blood tests we clearly know that um alzheimer's starts maybe 20 30 years before people become symptomatic um although the earliest symptoms maybe with really sensitive cognitive measures we could pick up earlier than we are now but there are clinical trials that are trying to remove the amyloid in people that don't have symptoms to see if by removing amyloid and people that don't have symptoms you prevent those people from progressing to have symptoms and this is really an amazing paradigm for prevention which i think could really be very exciting going forward although hard to prove these are have to be by their very nature very large trials and i think the idea of using infusions for prevention is not a great clinical model i think it would be much better if we had a little white pill but um i wondered what your take was in the reports at the meeting on this kind of treatment of patients without symptoms no well wouldn't it be great if we could prevent people from ever having alzheimer's disease or at least the symptoms of alzheimer's disease what we're all looking for is a is a healthy dignified aging right and and that that comes close to it is if we can prevent that deterioration that occurs with alzheimer's disease and as you say there's a the solanaceae trial is just about uh ending there are some other prevention trials like in autosomal dominant families that we're going to see reading out before too long and then there's the the new trial that acai is collaborating with in a public private partnership to produce to introduce their antibody very very early we're going to have data on this and i i think that's another place where we're going to see tau be very important the tau blood biomarkers howard because people can have amyloid in the brain for so long that is if that is your only measure then they might have no change during the course of the of the trial but if they have amyloid and rising cow levels that's likely an indication that that patient is going to become symptomatic within the framework a reasonable framework of a clinical trial so i think we're going to be smarter and smarter about choosing patients in which we can see the effect of the drug because they would change if they weren't getting treatment and i just think it's so important and and i uh you know prevention is always better than treatment right we um we've known that from from other diseases as well we don't want to wait for symptoms to occur if we can possibly avoid it and the adtf has been investing in these blood biomarkers as you know um and we did invest in c2n to bring i mean the blood test is on the market now i've ordered it on several patients and i've seen the results and you know i don't have to order the brain skin anymore because the correlation between the blood cyst and the brain scan is so high so uh the blood test for beta amyloid which is an indication of the presence of alzheimer's disease and people with very minor memory complaints is on the market in 49 states it's not on the market in new york because we have the most restrictive qualifications but a lot of my patients are outside new york or can go outside new york to get the test and the tao test will i think the tao test will be on the market in in a year or two and we're invested in that through the diagnostics accelerator which is this 50 million effort that we have with bill gates and leonard water and david dolby and jeff jeff bezos and others and we're just about excited about being able to announce the 2.0 version of that part of that effort was something else that was discussed at the meeting which is digital biomarkers and when we talk about early detection uh so that we can pick up people in even the pre-clinical stage using things like being able to do cognitive testing on your iphone uh and picking up changes in speech and language we have a big effort at the diagnostics accelerator in detecting very early abnormalities in speech and language vocabulary grammar tone [Music] you know the intensity of speech and language has really early biomarkers for those people on the call and myself included uh with my own father i i remember just kind of suspecting he was talking a little bit funny imagine that we'll be able to quantify that in a very uh a very rigorous way and we're setting up a database now that will have thousands and thousands of people in it that researchers all around the world will be able to use to advance this field of digital biomarkers and we're using digital biomarkers for so many other things i thought there were there wasn't a lot but for the first time there were sessions on digital biomarkers as not only early detection and as non-invasive very sensitive markers are the very earliest stages of clinical alzheimer's disease but also for their use in clinical trials and being able to do cognitive testing online for example and greatly again to the degree that the blood tests are going to reduce the cost and improve the efficiency of clinical trials these digital biomarkers i think will do the same for clinical trials in terms of early detection enrollment and monitoring of the effectiveness of treatment what's your view on the value of digital biomarkers in clinical practice and in clinical trials yeah i think it's another just great theme of innovation that's going on right now in the alzheimer's disease world we're seeing so much one of the companies i'm working with and i don't think they presented is able to measure the strength and accuracy of uh keyboard uh strokes uh by people who are typing and also the strength the the correctness and accuracy of your own use of your of your phone uh and of course you make more errors uh you go slower as you have progressive cognitive impairment so that kind of passive monitoring which of course is done with the person's permission there's no there's there's nothing without informed consent but uh increasingly we're able to use these passive biomarkers digital biomarkers to detect early changes and that's the the population for which the new drugs are approved or patients with very early disease and we know that they go undetected for long periods of time and they may go undetected until they're out of the treatment window so we really need digital biomarkers and other means of early detection in order to take advantage of the therapeutic progress that's being made you know jeff one of the questions that's in the q a is we didn't really get in much to discussion of side effects of these uh monoclonal antibodies they're being infused and i know you and some other colleagues wrote some appropriate use guidelines for how to use these drugs in clinical practice like data cannot for example i wondered if you could comment on the prevalence of side effects like the brain hemorrhages and the edema which affect up to 40 percent of people who are apoe4 positive and how we're going to manage those side effects in clinical practice now really an important consideration howard because the last thing we want to do is to increase the burden of disease that the patient has through through side effects now most of these uh aria events are without any symptoms whatsoever so they are detected on routine monitoring with mri uh which we do now because we're worried about the about these events but only about a third of them or have any symptoms associated with them and the symptoms would be like a headache or confusion or some visual disturbances those are the things that are commonly reported by patients who develop arya but a very few of them have severe symptoms like convulsions and there has been one death actually since the approval of adukane meth so we need to take this seriously the management is pretty clearly defined and as you say we wrote appropriate use recommendations that really emphasize the safe use of etocanamed we're going to have to have similar monitoring for all of the monoclonals although they they probably have different rates of arya i i think it's we don't have quite enough data to conclude that yet and the other question that we had just a really great but unresolved discussion about is just as you said the people who have the apo lipoprotein e4 gene are more likely to have arya than people who do not and that's a gene that about uh 60 or 65 percent of patients with alzheimer's disease have so it's common and it seems particularly uh risky for the patients who have two copies of that gene and they have an even higher rate of aria so i think one of the things that the scientific community has not settled on yet is should we require the gene testing before we give the drug so that people can make a more informed decision now the argument against that is that well we would monitor everybody with the same rigor so we wouldn't actually change our monitoring behavior but we might have different sensitivity to the headache that a patient reports or other symptoms that may be very difficult to ascribe to the aria but if we know that they're an e4 carrier maybe we would go ahead and get the mri to make sure that we're not missing a aria i also think a really interesting area of drug development would be a drug that reduces aria and we do have drugs that affect the integrity of the blood-brain barrier which seems to be interrupted and to be a part of the aria physiology so i'm thinking that we might even see the emergence of small molecules which could be very useful in reducing the rate of arya the monitoring that you're talking about to do serial mris over the course of the year uh raises the price of the drug effectively from about 56 000 a year to closer to a hundred thousand dollars a year and we've already seen recently in the newspapers that the medicare pharmacy budget has already been doubled um there's a huge increase in i don't know if double that's the right word actually i think but i read recently that there's a huge increase in the medicare premiums for the part d plans for the drug plans in anticipation by medicare of the use of these drugs and i think the cost issue is going to be a big barrier to utilization because as part b drugs there is going to be a 20 copay at least on the 56 000 a year so even if people have it's confusing and it's complicated but i think the cost of the drug is is really complicated by not just the cost of the drug but the cost of monitoring the drug i guess what i want to close with is something that you and i participated in which was the value of exploratory phase 2a studies we had a great panel myself you uh doctor from um from merck and uh suzanne hendricks who is a statistician and uh and a consultant to a lot of companies on how to design these trials and basically we kind of talked about the adtf's core strength and what we do in terms of funding exploratory trials we kind of alluded to it a little earlier today these phase two eight trials that costs maybe three four five million dollars that look for signals and try to learn about the drugs but they're not necessarily useful for getting regulatory approval there were the the phase two a trials or phase 2 trials that are useful for getting regulatory approval are called regulatory enabling types of trials that are very very stringently monitored and the data is collected we're talking more about the kind of trials that are conducted in academia and small biotechs just to see for the first time if there's a signal if the drug is working and we had one report of a phase two exploratory trial from one of our uh companies that were very excited about pharma trophies where there was a lot of biomarker data but there wasn't any clinical outcomes and the very difficult question about go no-go decisions and i thought we had a great discussion i know there was a lot of audience interest in response to that trial that uh panel um and i'll let you uh comment on what you thought was that you know all the panelists including myself obviously thought that exploratory trials uh are important to create an innovation in drug development we need to be careful about how we use them uh maybe you could comment on that and then we'll turn it back to mark to close the session absolutely uh well um uh some several people came up and said uh jeff that was the best panel of the ctas so i know that people the same experience and uh of course i'll just point out that it built on a great meeting that addf sponsored a few years ago or two years ago and then this year there was a publication that came out of that of that workshop in neurology very prestigious journal and i know a lot of people who have used that article to help them with decision making so addf did a real service uh to to the field uh with with that and i think we've learned a lot about exploratory trials we want to do them rigorously and we have to train academics to do them rigorously but we also have to be more open to different kinds of outcomes rather than just pre-specifying two outcomes that make the difference we we're going to use biomarkers much more as the outcome uh other and the report for those trials there's a different kind of statistics that goes into them so i think learning how to do those trials well is really important and i think that panel went a long way toward defining how to do good exploratory trials all right well thank you jeff and i want to thank everyone for listening and i wish we had more time but i'll turn it over to mark well howard i may i may first of all excellent uh uh doctors cummings and phillip just excellent um as a lot of the postings on our q a were uh shared with you all um i have one just kind of last thing to leave us on and it dawns on me that uh dr cummings you do this once a year and the adbf does it once a year really scans all the alzheimer's clinical trials that are out there there's about 118 that are out there now and howard addf's clinical trials report came out at the very beginning of this uh of last week of of the conference and i i was struck by of the 118 trials that are out there something like three out of more than three out of four are not so much about the plaques and tangles and the amyloid and the tau as much about this kind of concept of biology of aging and i just more than anything else howard and or dr cummings just your your sense of the whole field right now what's going on in the whole field and we can leave leave folks on that well i think the field's really mature because you know in the old days and i'm talking about even three four five six years ago um it was kind of like amyloid all or nothing and yeah and towel or nothing and and it was was it amyloid was a towel or was emily going to work or wasn't it and you know we've been at this for a long time several decades including two decades at adf to look at other mechanisms other pathways the biology of aging inflammation uh neural protection you know autophagy cellular death and you know it's kind of gratifying i have to say to see this much broader perspective taking hold now and i think you know there really is a i think an acceptance in the field that even if the anti-amyloid antibody and anti-amyloid approach works it's not going to be the cure and it may even just be a marginal or slightly better than marginal effect and we're going to need combination therapy so i think this meeting was really one of the first meetings where you saw a pretty good representation of other approaches where they're actually in phase two and we're actually gonna see data and i think we're gonna see a lot of positive data from these other approaches so again it's a maturing of the field it was a landmark meeting and uh i think the the world has changed in alzheimer's therapeutics yes dr cummings last word yes i would just add to that that this increasing repertoire of targets reflects the growth of the science in just such a great way for example we've we've learned so much in just the last few years about the genetics of inflammation and how that influences the occurrence of alzheimer's disease so the growth of that basic science information is allowing us more insight into the disease and that's what allows us to develop new drugs and the biomarkers i might add are really allowing us to do the clinical trials to ask these questions so inflammation biomarkers you know and all the rest we have a whole panoply of new biomarkers beyond amyloid and tau that are going to enable us to do clinical trials to test these new hypotheses and uh on that my good doctors first of all we have to thank everyone who tuned in today or our donors because you literally are making that happen number one so thank you to all of tune in today and really um doctors cummings and phillip you were excellent today thank you so so much and we look forward to hearing about next year's conference take care good good alright bye

Channel: Alzheimer's Drug Discovery Foundation

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Id: nPftMN3M9WQ

Length: 59min 36sec (3576 seconds)

Published: Fri Nov 19 2021