The Fight Against Alzheimer's: Innovation in Treatment | LSI USA ‘23

Transcription

Henry Peck  0:00  

All right, thank you everybody, again for joining for this panel. Our next panel is titled "The fight against Alzheimer's innovation and treatment." And our moderator is Paula. She's the founder of legacy med search and a member of the Board of Directors for the Central and North Florida chapter of the Alzheimer's Association. So we are super excited to continue featuring innovation in the Alzheimer's space and raising awareness and support for this disease state. And a lot of that is because of the work that Paula and her team have done to help bring that focus to the community and the work of the innovators that are on stage here. So Paula, looking forward to this conversation. Thank you again, over to you.

Paula Rutledge  0:40  

So I'm wearing purple today, which of course is the color of Alzheimer's. And I mentioned it last night I wear hats because of my mom. My mom passed away of Alzheimer's in 2019. And at one point, she had 600 hats. So I started wearing hats is in homage to her and it just kind of turned into a stick, and also is great if I'm having a bad hair day. So I'm very excited about our panel today. And as a member of the Board of Directors of the Alzheimer's Association in the state of Florida, I will tell you off script that I believe that medtech is going to be the thing that solves the Alzheimer's and dementia equation. I'm very excited about our panel today. And so if you can take a quick introduction, I will say that Marc and I have known each other for a while and Mark is also has a family history of Alzheimer's five aunts and a father so if you could introduce yourself and your company.

Marc Giroux  1:32  

Hello everyone. I'm with the CEO of Kurve Therapeutics, we are pioneering nose to brain drug delivery for Alzheimer's among a bunch of other diseases. Alzheimer's is our main focus right now its lowest hanging fruit. But we have figured out how to get the drugs into the brain where an Alzheimer's patient will need it. And we've been running seven clinical trials on mild cognitive impairment since the early or early to the 2010s. So, you know, we've got some really spectacular results. And we're hoping to continue that. So really a pleasure to be on the panel with the other innovators and whatever works works. We have to pursue every avenue.

Peter Schlecht  2:16  

Peter, I'm the CEO and founder of Braingrade and we develop a new form of deep brain stimulator for Alzheimer's.

Paula Rutledge  2:26  

Brent, you've got some exciting news this morning. So you can can reshare that. Oh, sure.

Yeah. Yeah. I'm Brent Vaughn and the CEO of Cognito. Cognito is a optogenetics based disease modifying therapeutic platform for neurodegenerative diseases. We're currently enrolling our our pivotal study in Alzheimer's, go to www.hope for Hope study for eighty.com. We're enrolling across Lilly 400 patients across 50 sites across the US. And so if you know anybody who who would be interested in potentially benefiting from being in a being in a clinical trial, we would love to speak to them. We were lucky enough yesterday to announce that we closed our series B, which was a $73 million Series B which actually equally, equally excited in that we were able to add a new outside director to the board for any of us that are CEOs and are thinking about how to add and people on a board. So you should know it. There's long discussions. But we were fortunate enough to get Dr. Rick Coons, who spent the last 20 years as a CMO and CSO of Medtronic and was instrumental in building and and leading their almost $9 billion neuromodulation business. So when we think about how do we commercialize this, we've got someone on the board now who can give us some well earned advice. 

Rich Macary  3:42  

Rich Macary. I'm the president one of the cofounders of Synaptica Therapeutics. We have a non invasive closed loop neuromodulation approach to treating Alzheimer's disease, I'm sure we're gonna get a chance to explain more about that. I'm here, particularly because we have amazing, unprecedented phase two data in mild to moderate patients. We're working toward a pivotal study. And this is personal for me, I come from the biotech industry, I was co Head of Business Development for Sarepta Therapeutics, which is a RNA based therapeutic platform. But my mom developed Alzheimer's about six years ago. So I took a pivot from being a rare disease focused on neuromuscular disease to neurodegenerative, and had an open mind from other things that I've done to look at things outside of drug. And I've more than done that with the approach that we have within Africa. So looking forward to sharing more on the stage with all you innovators as well. Terrific. So

Paula Rutledge  4:39  

Terrific, so the goal or one of the goals of this panel is you know, we're all here to talk about innovation and we've got some incredible innovators here on the stage. But I also would invite you to think about Alzheimer's and dementia in your personal lives. One in three people one in three seniors will die of some form of dementia. It affects, we Got six and a half million people in the United States alone 50 million worldwide. They're affected by Alzheimer's and dementia. Alzheimer's kills more people than prostate cancer and breast cancer combined. The lifetime risk for a woman over the age of 45 is one in five. For men, it's one in 10. And between 2000-2019 deaths from heart disease decreased 7.3%. And this is a scary statistic. But Alzheimer's and dementia increased 145%. Those are all grim statistics. But I will tell you at the end of this conversation with these innovators here, I am more helpful than more hopeful than ever, that Alzheimer's is going to be solved. So I'm gonna start with a question that seems to be a little bit controversial. What causes dementia? Rich, would you start?

Rich Macary  5:57  

Okay. Yeah, as I said before, this is a loaded question. Certainly the historically the research communities looked at amyloid and tau. They were early suspects in this, they're present. They're part of the pathology of the disease. And there's other players in this microglial activation, neuro inflammation. So there's a whole host of things that I don't know, at this point that the research community has completely figured out. This is definitely a multifactorial complex disease. But one part of it that we think is super important is the electrical side of it. And that's a part that hasn't been fully elucidated, has not been focused on as much from a research perspective, except for some of the people on the stage, and their scientific co founders. So I continue to look at this as a puzzle to be solved, with the electrical side of this disease being a super important part of how we're eventually going to slow and hopefully halt the progression of disease going forward.

Paula Rutledge  6:58  

Peter, you have a little bit different take.

Peter Schlecht  7:03  

Yeah, and I often say, it doesn't matter. What matters now most is that we can do something about it. And that it has an outcome for the patient, or changes their life.

Paula Rutledge  7:16  

And Mark, because you're in all different types of CNS, clinical areas, could you distinguish between what is Alzheimer's? And what is dementia? 

Marc Giroux  7:27  

Well, you know, the best way to, for me to keep it straight in my head is Alzheimer's is just another flavor of dementia. But, you know, the, the idea of, of how we're going to treat these things, you know, Kurve Therapeutics is a technology platform. And we've done 20 to 25, different formulations for CNF, CNS diseases. But we found different results within Alzheimer's with the different drugs. So you know, one drug does a better job on verbal fluency, short term memory and attention span, the other one does a better job of clearing out the tribes in the brain. Rich mentioned the amyloid cascades, which, you know, had been completely resolved, but their cognition didn't improve. So there's a lot of unknowns here. And that's why we want to cast as wide a net as we can, whatever somebody has, as a formulation, they think would have a positive aspect, positive effect on the brain. We want to be the device of choice that delivers it so that we have that opportunity.

Paula Rutledge  8:25  

Brent, anything to add.

Yeah, and I think the question and to Mark's point, I think the question was, was worded, quite interestingly, right, what causes dementia as opposed to what causes Alzheimer's? Right. And I think that I think that I think that we've been, we've been trapped a little bit about the definition of Alzheimer's and the taxonomy here, it makes a difference, right? Alzheimer's is defined by a dimension that is characterized by the accumulation of beta amyloid plaque, right. And so I think if you define the disease that way, it's hard not to focus disproportionately on plaque, which is clearly correlates with disease progression. But now that we've seen from from a sign, I think we will seen from Lily, complete removal of amyloid plaque in the brains of these Alzheimer's patients, and a in an exciting and moderate but not complete ability to slow the disease progression and certainly no rehabilitation or or ability to regain the plasticity of these patients. Right. And so I think, unfortunately, the way that our products get approved and paid for taxonomy matters, if you try to enroll in an all comers dementia, not otherwise specified pivotal study. I just don't see how you get that across the line with the FDA. Right. Are you going after Alzheimer's? Are you going after vascular dementia? Are you going after Parkinson's related dementia? So I think that I think that this is one where we've gotten trapped by the definitions that we arbitrarily created almost 100 years ago. And it's really changed the way we go about this disease. And I think your question about dementia, dementia is a highly heterogeneous population that we don't understand how to deconvolute so the fact that any one thing is going to solve this I think is kind of naive.

I totally agree. I'm going to ask a question that I'd like you to think about. And I asked the gentleman, if I had their permission, and they all gave me the permission, but in your individual life, if you knew that you had you, were you had the propensity to have an Alzheimer's or dementia? Would you want to know? And secondly, would you want to do anything about it? I asked this question, because at the Alzheimer's summit back in late January, the question was, was was posed. And it was interesting to me that the people that are leading Alzheimer's, it was a mixed a mixed bag a bit does someone want to know? So Rich? I'm going to start with you. Do you want to know? And if so, why? And if not, why not?

Rich Macary  10:45  

Sure, I would absolutely want to know. And I could see why people wouldn't want to know, this is a scary disease, the idea that you're going to start to lose your memory. And then eventually yourself piece by piece is something that people might not want to face. But knowing that there's lifestyle interventions, depending upon the age that you find out that you have a propensity, this, you want to know it, you want to start doing things about it. On the more promising note, we're at the beginning, I think of therapy starting to reach the market, after 17-18 years of not being therapies. And when I look at approaches, like the ones on the stage, we might be getting these therapies to market in the next few years. So better to know and better to know everything about it, I'd want to know every aspect that I could, whether it's PET scans, understanding if there's neuro inflammation, because then you start to understand what therapy might work best for you. That's how I think about it.

Paula Rutledge  11:36  

Right? Yeah, another great question. And I think some of us remember when, when there was the first full sequencing of human genomes, the first genome that was fully sequenced with very famous person in the world biology, James Watson, and the one gene allele area that he did not want to know is as equally for status. Right. And that was, I think, I think that's changed a lot. I was at a conference of

for those who don't know, can you explain what the APO II 

Yeah, so if we for status, which is tied into lipid metabolism, which is really interesting, because all of us are talking about amyloid and tau, and none of us here are talking about lipid dysregulation, which is kind of interesting. Someone probably should be. So when people are homozygous for the AP for there are an extremely high risk for developing an early onset, very aggressive form of Alzheimer's. And it's something that we currently have no ability to stem that tide. And tell us one of the things he actually didn't want to know about the only thing you do want No, but I was at a conference just a week or so ago with the CEOs and the head of development from most of the companies that are in late stage clinical development for Alzheimer's. And that same question was asked, Everyone raised their hand, right, everyone wants to know, I think that if anyone's here this morning, got to hear my four minute mile talk with Roger Bannister, post nine till that is that after being the first to run the four minute mile, Roger Bannister became a neurologist, actually. So it's quite topical for us. But I think we're going to see more progress in the next 24 36 months than we've seen in the last 20 years in the space. And so I think that's why when I was in a room with drug developers last week, and I asked everybody raise their hand, because everyone wants to know, because there are increasingly we're starting to see levers we can pull

Peter Schlecht  13:13  

Definitely, I think it's kind of this transition, we are in also kind of on the sickcare to healthcare. And I only don't want to know, when do I get it? I also want to know the progression. And when you talk to patients, what you're doing a lot, they want to know, how is it for me? And how is it turn out? Do I have two more years to have four more years? When will it decline rapidly? And it's about kind of asking here in the room of full of innovators and people who are very knowledgeable in healthcare. But how many biomarkers do you really know about yourself? Kind of in general, and I think it will be very common this transition that we know, way, way more about our body, as we have all the other data. I mean, the typical example is we have more data about the car and or about kind of our stats in the on the phone and we have about our body. I don't know what my cholesterol levels are. I don't know what my blood pressure is. I don't I didn't I not even though kind of maybe how fast my heartbeats right now. But I mean, that's obviously not enough. And I think we'll find kind of way better ways to get granular information, and then kind of adapted kind of to Alzheimer's, and then actually do these positive things for positive outcome for Alzheimer. What we actually also do without getting Alzheimer, so at least then we get a better reason for that.

Paula Rutledge  14:49  

And Marc, I know that you also would want to know, it'd be particularly because you have the genetic predisposition in your in your family.

Marc Giroux  14:56  

That's right. And my father was one of the ones that did not want to know, we had to force him to go. But his five sisters had it and they died of it, he did not. So, you know, I would want to know, and I just kept telling him those same things, right? Knowledge is power, you can't fix something you don't know is broken. But we're actively promoting this through Kurve Therapeutic state tested early, we want people to get tested, late 40s, early 50s. Because if you display a symptom, you've had the disease for as much as a decade, right? So what we want to do is get people who are predisposed or just think that things are maybe a little off to go get tested. But there's a stigma that well, my employer found out find out and, you know, how will I be judged later in life? And will they try to take my, you know, my checkbook away when I get older if people know that I'm predisposed to this. So we want to be able to eliminate that stigma and promote that people want to go and be checked out and get it early. When when we saw that it was running in my family, when I turned 50, I just said I'm never getting this. And I started using our technology as a preventive. And so far, no symptoms, and I'm 10 years in. So I think that knowledge is power, and you should go and you should go and check it out. But I mean, our technology is available to anybody who wants to use it today. So you know, if you're feeling like you have it, or you're a caregiver or you have a loved one, you know, we'd like to talk to you. 

Paula Rutledge  16:30  

So I want to turn to the therapeutic side after the next question. But you know, it is interesting, we all want to know about you know, heart disease and things that we think that we can control and Alzheimer's and dementia, all dimensions are just so much more difficult. Every time I forget my car keys, I go, Oh, is this the start? It's probably not. But it's, it's a scary thought. I want to turn again, before we talk about your individual therapies to some of the pharmacological issues that have really been stymied innovation on the medtech side. So there's been you know, there's there's three drugs that have been approved in the last couple of years. And as Brett said, there's been more done just in the last couple of years and a lot past 30 years, how have the mixed results of some of the drugs approved for Alzheimer's impeded your ability to raise funds? Brent, you're accepted here. So Rich, I know it's been an issue for you with Synaptica.

Rich Macary  17:28  

Well sure, I mean, we're coming out into the space. And I heard Brad talk about this earlier, where the med tech community isn't necessarily educated about Alzheimer's disease. And thinking about this as a progressive, chronic disease, you have to keep treating it, this isn't you're going to put it in remission. So that's been a challenge, really, because you're going through investors, I come from the biotech side, I'm used to walking in there and talking about receptors and mechanisms of action and, you know, analyzing preclinical data up through phase one, etc. And so you're you're walking in explaining a new modality, it's a device, they don't know that's manufacturing, that CDRH very different than cedar and CBRE, different regulatory path different reimbursement path. So we are trying to find, I don't want to say it's a needle in a haystack. But I agree with Brent, there's a group of investors that have enough knowledge about this disease, and enough knowledge about medtech, you know, to play in the space. And yes, it hasn't helped 17 years of failure, big pharmaceutical companies literally getting out of CNS altogether, or certainly out of Alzheimer's dementia. And so yeah, we've paid a price in some ways for showing up with data. And in our case, spectacular data. That is almost hard to believe, because you've had failure for so long. And here's giant drug companies barely squeaking over the line with these amyloid drugs, getting statistical significance, ambulatory expensive employ drugs. And again, we believe we're a cheaper alternative, safer alternative. And so we are going to work and do what we have to do and hopefully go down the same path this brand has gone to raise that capital, we need to get this into a pivotal for for patients.

Paula Rutledge  19:10  

Brent, you're buying drinks tonight, just let you know.

I bought a couple last night, but I'm not that recognizable. The bars. I mean, Steven,

if you could kind of nuance this with you know, Billy Don just just retired from the neuroscience division of the FDA. Which there was a little bit of a cheer, I think from the crowd. So could you talk a little bit about the fact that you know, it has been difficult from both a CMS standpoint, and an FDA standpoint, and how that's really, I guess, not affected you as much but it's affected the industry. 

Brent Vaughan  19:44  

Oh, trust me, it affected us too. Right. Anyone who anyone who raises money in a market like this and tells you it was easy is just not been straight with you? Right, be clear. It's really hard. I think that you know, I think that to To the point I made just a second ago, the most of the expertise about understanding how to de risk likelihood or possibility of approval. And for safety and efficacy and Alzheimer's lies in investors who have invested in on the pharma side. So small molecules for a long time, and then more more lately large molecules, right. And yet, they don't understand how devices get paid for the people that understand how devices get paid for and get approved, don't understand Alzheimer's. And so you need to find the it's not the union of these two groups. I can talk about this point, right, it's the intersection. And so if you're in I think this idea of needles in haystacks is kind of it right. There's lots of investors out there, but there's very few that actually have the expertise on both sides to do this. And so I mean, there's, there's kind of two ways to do it, right? You can build a machine that processes hay, or you can try to find a metal detector and look for haystack needles. Right. And so we decided to look for haystack needles. So I tried to figure out who could actually have the intelligent conversation about both of them. The downside is it's such a huge unmet need. And all of us up here have very disruptive, interesting technologies. There is not an investor who doesn't hear, wow, innovative, non invasive technology that that slows the progression of Alzheimer's three times more than the most recently approved drug. I want to hear more of that. Yeah, I want to hear more about that. But if there's no investment at the end of that discussion, that's time you don't get back. 

Peter Schlecht  21:21  

A lot of time, I don't get back. It's Peter, you've seen the new truck, but a genocide. That's think we don't need any medical device for Alzheimer's. It's like, Yeah, okay. A few months later, if you've seen the outcome, nothing works for Alzheimer's, it's like, and there you are in between, it's like, showing that you have something. And, by the way, cheaper as a medical device, don't mean, it's particularly better for the investor. Because I mean, it's a part, I mean, it's your revenue, what you want to, and then I would look at the overall view of the investor on our space, because I think we all have to care, that kind of for all medical devices, we get from the limited partners down over the VCs more money in the whole system, because we are way too small and way less capitalized for what kind of power all these innovation has and what we can do good for the world. And I hope that it finds way, way, way more capitals, and they're way more good examples for that. Because as many people care about Alzheimer's, I mean, there's a reason why they don't want to invest. Because when you look like in the past, not just into Alzheimer's, you also look kind of what has been the multipliers of medical devices. Yeah. It's like when you take us in an example. And three, four years to market, just add 6 million. And then they think, Okay, what's a typical exit, maybe 400 million. So Medtronic, and Boston Scientific is then going to buy kind of for market expansion. That's nothing What do you want to do kind of for in the risk stacking, you are approaching, and then you have really this very small kind of investors who feel educated enough, who want to do it, because a lot of say, it sounds fascinating, but I'm too afraid to look very dumb, because your brain implant and Alzheimer's and can improve even cognition. Sounds awesome, but maybe I'll show later. So maybe the most hurt phrase of

Paula Rutledge  23:52  

so I mentioned it, there's some grim statistics regarding dementia and Alzheimer's. But I want to turn now to some of the therapeutic focus that these gentlemen have with their very innovative technologies. And Marc, I'm gonna start with you. I want you to explain how the name curve came to be and how you're the name curve. Yeah. And how your inner nasal drug therapy basically is, in your opinion, going to help solve Alzheimer's.

Marc Giroux  24:21  

Well, the name of the company excuse me, I got to touch laryngitis. I'm going to do my best. The name of the company came up when I ran the word sinus. I mean we started out as a chronic sinusitis company nose to brain came to us organically because of our success in the nasal cavity but I ran scientists through a language translator ran through 85 languages that came up sinus and all but German German the German translator got confused with sine and cosine he called it Curve with a K so I said we're taking corners in the nasal cavity, so it seemed appropriate. And VNAs for the product name made sense because we're doing it by way of the nose. All right. So and our, you know, the way the the technology functions is we were just trying at the time to Cure Allergies and chronic sinusitis and, you know, asthma, I tried to keep it under control. And that was my quality of life be so terrible. So I just wanted to get it everywhere. So I need if we wanted to go up to the right to the left, and then take a hairpin turn and get into the maxillary sinus, we figured out how to do that. So when the nose to brain people came to us and said, Can you just put it right here, it was far easier than anything we'd ever done, we did learn to tighten that deposition down so that it was mostly in the olfactory region, which has access to the brain. And that's when the changes really started to happen. And our phase two study with Alzheimer's with intranasal insulin had three out of four patients actually test better coming out and going in. So they had regained some measure of cognitive abilities Dade last, the other 25% did not progress. So while we're separating from placebo, as far out as 18 months, and the trend was still going up, you know, we think that over time, this is gonna, this is actually going to be a very, very effective and the gentleman, right, it's a chronic progressive disease, and so you're gonna have to keep using it. You know, and so, compliance is the next thing behind efficacy, right, so we had to make the patient find a way to use it. So that's gonna be small, fast, quiet, and it doesn't take long, so are intranasal insulin for Alzheimer's takes less than a minute a day. And you can do it standing in front of your refrigerator and just get it done. So we've had really, really good results with insulin, and we're getting far more spectacular results with the polyclonal antibody for Alzheimer's. So you know, the technology platform is very robust in that it can take pretty much any formulation and deliver it into the brain. And we've done stem cells. So if anybody gets that is the biggest thing we've gotten into the brain so far. So small, small molecules are easy, larger, larger, molecules a little tougher. And stem cells were thought to be impossible, but we figured it out. So

Paula Rutledge  27:11  

And Rich, what's your background in the pharma biotech side, you're now working with transcranial magnetic stimulation, would you explain the technology how it works?

Rich Macary  27:23  

Sure, sure. Again, it's a non invasive closed loop approach, when we're looking at neuromodulation, we're looking at a lot of different technologies. Our's specifically is magnetic stimulation, that's a very powerful technology. Essentially, in our therapy, we're using that technology to pulse the brain, we have an EEG on. So when we post the brain, we're looking at the reverberations and the propagation of that signal throughout key networks of the brain, particularly the default mode network. We're reading that with EEG, we're taking that data, we're putting it up in the cloud, where we have our algorithms, a decade of research to understand what we're looking for each brain is unique, each brain is different. It's almost like a fingerprint that we get, starting with healthy brains. And then looking at Alzheimer's brains, we take that we turn it into a personalized therapeutic for that individual patient. We then use neuro navigation and other technology that allows us to precision deliver this, and this is because it's chronic therapy. So we're going to do this over time. And again, I like to look at this therapy from that standpoint, as a electromagnetic drug. Again, going back to my biotech background, instead of an IV and a needle in the arm, it's literally a coil, touching the back of the head, and delivering that therapeutic to exactly where it's needed in the brain. So we've used this in multiple studies, and culminating in a randomized sham controlled, double blinded study a phase two, and just literally got unprecedented stunning results on all the key measures, CDR sama boxes, Adas cog, the stuff that I've been looking at, in drug trials for six years, but also MMSE, ADL, all them going in the right direction, all them backed up by MRI data, fMRI data, electrophysiological biomarkers. So we're excited about what we've created and delivered. We're in the stage of finalizing our system so we can bring it into a pivotal trial. hopefully later this year. The market environment hasn't been as helpful as we would like. So it is hopeful, seeing Brent, bring home a big round of capital, and we want to fall in that in that path.

Paula Rutledge  29:40  

And you know, I think it's interesting, as I mentioned in my opening comments that I do think that med tech is going to be the part of the solution. It might be a combination drug, and medtech solution as well. Have you had any issues in enrolling patients in these studies and what stage are Are you getting are these early stage? Are they MCI? What level? Or what stage? Patient? Are you trying to enroll in your study? Yeah,

Rich Macary  30:07  

so my current scientific co founders were looking at trying to get patients who are already declining. I think we know a lot of the drug development work, they've moved to the MCI, early stage, mild patients, because it's hard to intervene and a process like amyloid that's been building up for 20 years and think you're going to suddenly change things that far along when symptoms have already started when they're already getting impaired. So we kind of feel that we're intervening where there's going to be less and less drug trials, which isn't these patients that are on the decline. So you know, when you're coming at a non invasive approach, that's a technology with a 20 year plus safety track record, you're not necessarily looking for, you know, because we're not targeting amyloid specifically, we're not targeting tau. So you're not necessarily trying to do a lumbar puncture puncture or any other invasive procedure, it becomes easier to recruit patients. And I'm going to say that having great data, unprecedented data, when you're out there looking to recruit maybe 200 250 patients, I think, is a big asset. A lot of these drug trials are going out there. And they're recruiting patients into large phase threes, with signals, with trends with anecdotal stories, or with biomarkers that signal the right direction, and sort of walk in there with this kind of data to do a phase three, even knowing they might be in a placebo arm, the fact that they can convert to the therapy at the end, I think is a big, big motivator.

Paula Rutledge  31:32  

I absolutely agree. And Peter, I've heard you speak, guess at least once or twice. And I remember running up to you and saying, what you're doing is fascinating. Would you explain a little bit about what BrainGrade does, how you came up with the idea. And I know that Peter is a member of Mensa and I'm a member of the postman's a possible group. So that's about the same. So if you could split it up, again, I know that you have a familiar connection with that with your grandmother as well.

Peter Schlecht  32:00  

Yes, and while being a member of Mensa, I have a lot of need for improving my brain. So this BrainGrade upgrade for your brain, this fascinators needed me immensely. Because I believe if we can improve the human brain, this will be one of the key moments for humanity. It's our most important tool. And it's the only one that never got the real upgrade. I mean, makes no sense. So coming from this angle, we thought about kind of how really to sustainable and significantly improve the human brain. And if you want to do it, and you cannot connect with 83 billion neurons at a time, and I don't see a technology out there doing that, then you need to interact in the center of the brain or in the centers. So we thought about, okay, who actually has the biggest need kind of for such a technology. And when you want to do it in the center, it's it's an invasive technology. So how does it look like you often stimulator in the chest, you pull a cable, and then you have four probes with electrodes at the tip. Each has 128 electrodes, that tip very tiny, put it in the brain. So you have four burr holes, and then you record and stimulate in the areas. And our work is based on research of hundreds of people, but mainly on two giants in the field and the one who has done a study stimulating the nucleus Posadas. It's the center of the cholinergic system in the brain. In Alzheimer patients over two years, Professor Kuhn, and he showed an 82% slowdown in disease progression. We call back drug 27% 82%. So a big difference over two years. And it has all these positive impacts on all the biomarkers we already discussed. From glucose metabolism, reduction of amyloid better, it's actually where drugs can try to target kind of to then increase acetylcholine and overall kind of improve then the environment for the electrophysiology. But why only improve the biomarkers to then improve electrophysiology when we can directly improve electrophysiology. And for that, we are building up on the work of 30 years of Professor Hamsun. One co founder of the company and he showed through stimulation the hippocampus in the memory center, that he can improve your memory capabilities and with very basic stimulation, we now just have shown again in six patients based on his work that we can improve by 23%. And like with more sophisticated algorithms and simulations, we're getting up like to 79, or he got up to 79%. And more. What does it mean more sophisticated mean, when you're there, and you have this, I mean, temporal and local resolution kind of listening to the neurons, kind of in milliseconds, you can react to it, and can react to the states of the brain, and you then can fully close the loop, kinda with reacting to the brain. And what I find so fascinating is, while many know deep brain stimulation from Parkinson disease, kind of stopping the tremor, it's suppressing the brain. But what we are doing, we are helping this ultimate patients kind of with the increase of the oscillation of the brainwaves and some synchrony, kind of to enhance the brain and support it. And I think this will be a big breakthrough, because it really opens for us the window and the understanding of the brain. And then we can all kind of from the drugs and all the other therapeutics who have obviously a lot of positive sides kind of not getting forbear holes in the brain has some good sides to it, then it kind of we combine it and we can learn a lot about the brain. So I'm also very excited about the next years to come for us and the development there.

Paula Rutledge  36:24  

And at what stage would you are you recommending the implantation? What is it? Is it MCI? Is it someone that's got more of a cognitive decline? Yeah, it's,

Peter Schlecht  36:34  

as earlier it's better as mothers to protect kinda to slow down, brain atrophy and example. I mean, when you don't have anything to work with anymore. It's bad. But obviously, if I have only very soft symptoms, do I want to get in brain implant? So it's could be a problem, or is a problem of our point. And now we're coming to this whole topic of patient stratification? Who really has Alzheimer's, it's what you started with? And also a question we often get when and how it's scientifically, very difficult and interesting to answer. But when you talk to a patient, who sits in front of you and says, I need it now, I know exactly what my trajectory is. I need it now, then it's somehow irrelevant. And then you'll also understand with all the neurologist we're working with, there is a clear window when patient needs it and ask for more therapies. So I think we all need to get just faster, all the solution we have here to the market, and then we find a good combination.

Paula Rutledge  37:40  

And Brent, your device is also fascinating to me. It's very unique in terms of what it looks like. Could you explain to the audience a little bit about what Cognito has in terms of therapies?

Brent Vaughan  37:53  

Yeah, happy to and and not only am I not as sharply dressed as Peter, but I was specifically uninvited to Mensa meetings. Um, and so, you know, so I think that similar to a couple of folks up here, we we think about we think about the target space, right? So I try to use drug drug language to explain what we do, because that's ultimately where most of our investors are right? And we see, you know, is Alzheimer's A is Alzheimer's disease that's characterized by an accumulation of pathological proteins that promotes neuronal death and and degenerative dysfunctional Yes. Is it A, is it a disease or microglial, dysregulation which start in an anti inflammatory activity, but then ultimately switch over to more of a pro inflammatory leader disease? Well, yes. Alright. Is it a disease of electrical dysregulation across the brain? Well, it actually is, the only reason we care about these pathological proteins is they ultimately disrupt the electrical activity across the brain. Now electricity is the fundamental currency of the brain, right? It determines who we are, what we are, how we are. And so I think that we see this these abnormalities in electro activities as druggable targets. And the way to drug this target is to come in with some degree of of electrical stimulation that changes the brainwave activity. And so our scientific co founders, Dr. Site MIT, she works at looking at novel mechanisms and targets in the world of Alzheimer's. She works with the standard transgenic models and Alzheimer's and Parkinson's. You know, my friends at Genentech like to say we've cured a lot of mice of cancer, right, but it turns out people a little harder, right? Plaques develop in mice over courses of weeks, and they develop in patients over decades. And I think that we're starting to learn even if you look at some of the some of the information from ECI, I think we're starting to think about the heterogeneity in the world of amyloid, and we might decide that that amyloid plaque is the least interesting amyloid target, right? And so I think that there are layers to all this type of story and so, you know, what was what was learned in optogenetics early on was that you can use you can use light to trigger specific Pacific brain frequency and brainwave activities. And there was just a very simple experiment done early on when Dr. Tsai looked at the relative absence of gamma frequency oscillations in the Alzheimer's brains, and this is backed up in the literature of seeing it in patients, you can see in the 80s in the mice, and she reached out to Dr. Boyden, who was our co founder who had co invented optogenetics and decided to use principles optogenetics to see what would happen if you added gamma frequency oscillations back into an Alzheimer's brain. And, and lo and behold, it reversed progression of Alzheimer's that clear the phosphorylated tau as well as the amyloid in the animals and showed improvements. The animal behavior that was published in Nature and widely cited was the basis for our technology. In our face, too, we showed a 75 to 80% slowing in disease progression, with six months of treatment, and uniquely to ours, we showed an almost complete preservation of brain volume. So brain atrophy is quite quickly and we were able to show that we're building neuronal connectivity that you can see an MRI. And if you think about this, you neurologist like to say that, that neurons that fire together, wire together, and as you start getting things to wire together, you're maintaining and we hope, ultimately rebuilding the plasticity that is lost in these in these patients as they as they suffer the onslaught of the progressive degenerative disease

Paula Rutledge  41:22  

Oh, they're excited. We started with some grim statistics of some hope. I've got one quick question. We just have less than a minute left. So I'm just going to go down real quick. When do you think we're going to have a workable solution for Alzheimer's and dementia in terms of just just a swag Guess how many years?

Rich Macary  41:41  

Well, again, when we have FDA breakthrough designation, hopefully we're getting a pivotal trial off the ground by the end of the year. So thinking about a significant slowing of the disease. I believe it's when we and others get to that end game in probably the next two to three years. If we're talking about halting the progression of the disease, I do think that that's going to take a multi modal approach. But hopefully, within the next five to seven years, there's a lot happening to Brent's point, there's a lot happening in the space. So I'm, I'm optimistic,

Paula Rutledge  42:10  

Brent. Yeah, I think that we're on the cusp of what we're going to all look back at and call the beginning of persistent neurology, in the same way that we solve cancer by being able to understand what the specific cancers are, I think that we're going to be able to start looking at like we do, we only enrolled patients that respond to our Gamma frequency stimulation. And so I think we're going to subdivide, and we're going to not solve all the dementia, but we're going to start solving pieces of it in the next decade.

Peter, quick answer.

Peter Schlecht  42:38  

In 15 years, and we have something now, we have all this solution, and it's just about the distribution to the patients and getting through the system. And so the system understands that we have solutions and way way better solutions than anything that is currently available to all of them. 

Marc Giroux  42:56  

in a word. While we're phase three ready, we're going to need 300 of Rich's patients to come over and take some drugs 150 on 150 off, the FDA has already accepted our 300 patient phase three, so it's just a matter of paying for it. So great. That's where we're at.

Paula Rutledge  43:13  

Thanks so much and there is hope for Alzheimer's bucks and I'm happy to pass along any information I have on behalf of the Alzheimer's Association. I thank you for your time and gentlemen, thank you for your technology cube

Panelists  43:23  

Thank you.