The Decade of Brain Health: Headwinds, Tailwinds, and Opportunities in Neuromodulation and Neurodegenerative Disease | LSI USA '24

Mike Labbe  0:05  
All right, we're gonna get started. Thanks for coming. As he mentioned, we're going to be talking about neuro stimulation and neurodegenerative, degenerative diseases and some of the trends that are seeing and advancements that are being made in that in that space lately, which has been a really exciting, you know, last five to 10 years or so. So, first off, I'm just I'm Mike lavvy. I work for Valentin, which is a contract development and manufacturing company just outside of Houston, Texas. And our focus is all medical device. But we do mostly neuro stimulation and active implantable development. So this is a field that we work with a lot of companies. So we kind of see a lot of the technology in that space. But obviously now we have four experts that can really dive a little bit deeper. So we don't have a lot of time. So before we get into the meat of it, I'll just give everybody maybe 2030 seconds to introduce themselves. So we know who everybody is, and then we'll drop jump into the to the questions.

Kip Roberts  0:56  
Great, well, good afternoon. Kip Roberts, with Medtronic. I lead strategy, m&a, portfolio management for our neuroscience division. So thanks, LSI, for having us here today.

Ken Mariash  1:09  
Good afternoon, guys. And gals Ken Mariash, Sinaptica therapeutics, been the CEO for the last year previous to that was at Boston Scientific, I had his job, the neuromodulation division had a good time there and having a good run was enough to go

Ana Maiques  1:25  
Hi, everyone. And I'm I guess, CEO of Neuroelectrics and co founder Thanks, Kelly, and Henry for bringing us here. And I'm also known as the lady in the cap. She's got a brand. Thank you. So this is a non invasive neuro modulation brain stimulation device. And I can talk later about our Phase Three registration study in epilepsy, also some data in depression. And we believe in a future where you can send the patient home, stimulate them at home record their EEG signals and with a computational model, personalized treatments in ways it wasn't possible for so I'm looking forward to the panel with all of you.

Brent Vaughan  2:05  
Hard to follow a cap. Hi, I'm Brent Vaughn and the CEO at cognito therapeutics. Cognito Therapeutics is a company with a non invasive neuromodulation solution that is in phase three for disease modification and Alzheimer's disease. We are based on the work of our scientific founders from MIT Ed Boyden from his inventive work in in optogenetics, and applied that with our co founder, Liwei sigh looking at novel models, neurodegeneration, we've been able to show through our phase two studies that we have the ability to not only slow disease progression by showing preservation of both function in both cognition as well as global function, but also quite uniquely to this to this intervention, show that we can slow brain atrophy and preserve structure and, and slow the accelerated atrophy that is seen in Alzheimer's patients and Alzheimer's progression. So we are now in phase three study and we'll be fully enrolled by the summer.

Mike Labbe  3:06  
Thank you. So we'll just get started here. Um, clearly, there's a lot of different areas that this technologies in these technologies can be applied to Alzheimer's is clearly one, we have two on the panel that are working in Alzheimer's. But there's many other conditions as well that we think are great candidates for this therapy. So if the panel could talk a little bit, first of all, why is Alzheimer's a good candidate for this? What makes that an obvious Choice? And then what are some of the other leading conditions to death or degenerative diseases that might also make sense to be targeted with neuromodulation? Sure,

Brent Vaughan  3:35  
I'll go ahead and go first. I think the reason why there's a couple of people here already focused on Alzheimer's helps us think a little bit about the other places it can go. One of the reasons why Alzheimer's makes such sense is that with neuromodulation, we can induce some of the same biological changes that you've seen historically with systemic drugs, but we can target it to the brain. And so if you think about the immune agonists, right, the muscarinic agonist, they've showed that they increase gamma oscillations in the brain, unfortunately, also trigger the misconduct receptors in the GI. And so you have the classic effects of lack of targeting with with our therapy, we drive increased gamma oscillations in the brain, but we can do it without triggering any of the systemic side effects. So I think that that that's one in the same time, being able to have some degree of precision modulation, right. Ketamine is great for increasing gamma oscillations, but it doesn't a very unstructured, asynchronous way. And so it's not therapeutically useful. And so if you think about areas where we're CNS targeting and being able to modulate in effect, I think you start to look at at other areas. We have two phase two studies getting ready to go forward in Parkinson's. And another one in Ms. We've seen through through our mechanism that in the preservation of brain volume we've found with we see that the metabolomics work shows us that we're upgrading lighting up regulating the genes and proteins involved in myelin synthesis and myelin preservation So we then took that into preclinical models of NS and have shown that we have the ability to slow D myelination, accelerate memory myelination. So I think if you look at some of the areas that have been, historically, just undruggable are difficult to drug, right, especially in CNS issues that have struggled with blood brain barrier have struggled with, with, with systemic side effects, I think these are the areas that are are really good, really fruitful areas for for precision modulated approaches like ours, to be able to be able to target.

Mike Labbe  5:37  
Anyone else like to comment on it?

Kip Roberts  5:43  
I mean, I think if the the question is, where else could we go? I mean, look, mood disorders, treatment resistant depression in particular. Addiction, vastly another some external stimulation work going on there. Personally, for me and my family, what we've got some family members that struggle with and maybe for you in the audience migraines, you know, this is the second leading cause of disability in the US. The second, 3 million patients a year suffer from that. And it causes upwards of a $20 billion impact. So if we want to talk about like, Where can we take neuromodulation, beyond the traditional pain areas, the study and Alzheimer's, migraine, nothing for us, as we're looking out over the potential horizon certainly gets us

Brent Vaughan  6:40  
excited. One thing to add, I think, historically, we've taken for granted the idea that, that changing chemistry in the brain will change electrical conductivity. And it is that electrical circuitry that defines mood, memory, really consciousness and who we are. And so I think this this idea of looking at dysregulated networks as druggable targets, and if you were to drug that target, you wouldn't drug it with chemistry, you would drug it with some signal that that resets or modulates that electrical network. And so if you start thinking of you know, electricity is the fundamental currency of the brain, right? So if we can start thinking about depression, start thinking about some of these other things as, as pathologies have dysregulated networks, I think it really changes the way you look at at therapeutic interventions.

Ana Maiques  7:33  
Yeah, and I think that I want to mention that neuroleptics, we're very excited that looking in our co founder is as physicist and mathematician, and we completely look at the brain has this complex network, right. And I think that if there will be a day when we can link depression and the symptoms of depression, whether you have an Adonia, or a mood disorder, with a particular circuitry in the brain, and then you can use technologies like ours with all these electrodes to target those circuits, I think that's going to be a game changer. And that's where other modalities like drugs or maybe very implanted neuro devices cannot get. And I think that's going to be beautiful, especially for patients, right? I mean, our Phase Three in epilepsy is very clear that you have seizures coming from one area or another of the brain. So you need that flexibility. But I hope that can be the case in depression in Alzheimer's, because these are massive indications where I think that there are different circuits that are linked to those symptoms.

Ken Mariash  8:32  
Yeah, I couldn't agree more. I mean, we're, we're on the cusp of, of tectonic trends here that are reshaping the industry and opening up so many new possibilities. I remember the days when we used to talk about how certain regions in the brain were responsible for depression. Remember, it was like Brodmann's 25, like, Oh, if we just hit Brodmann's, 25 we can unlock depression? Well, now our understanding of the brain has evolved. And now it's just seems obvious, we look back, we're thinking of the brain as multiple overlapping functional networks. And so as Brendan Anna, were saying, you know, that view of the brain has itself unlocked possibilities, but also when you marry it with the study of connectomics and personalized medicine, the ability to read the signals coming off the brain and personalize the therapy to the individual that's unlocking so many new personal possibilities, because now we can personalize for every patient's brain. It should not surprise you guys that every brain is unique, at least except in the case of identical twins. And so everyone's brain responds differently. So knowing the signals to personalize based on and the machine learning that sometimes that requires a signal processing can be so intense that it takes days of compute power, but that's now within our grasp. And so it's an applicant therapeutics we are personalizing the therapy by listening to the signals coming off the brain. It's sort of like the sonar for the brain. active sonar we're pulsing the brain and listening for the signals coming back to tell us whether we've got signal in Target The identification or not? And I think of the possibilities in many other disease states are really profound.

Brent Vaughan  10:08  
We could spend the whole time talking about this first question, I think but but I read something a little while ago that just said it so succinctly, right everyone we've always thought about, about how the brain manages and process information. And and that is fundamentally changing, right? There is not a there's not a Lego in there. That is college o chem right, there's not just like, well apart, right? We always used to talk about the ingredients that we use to code information. And I saw this wonderful quote, that the understanding more and more as the ingredient isn't within the cell, it's across the cells. And so you have these networks around the brain. And so what has to happen for you to retrieve a memory or an emotion or a feeling is to connect these these different points. And all of these connections are time stamped. So everything has to happen synchronously. So the tiniest bit of disruption in signal timing or signal transfer, D myelination, or for some reason, the pyramidal or PV inhibitory interneurons, not firing and being potentiate it correctly, suddenly, even though all that protein coding is there, you can't act access that. And so if you start to think about it this way, I mean, keep in mind, this is the only organ system that we don't know how it works, right? We can build artificial hearts, we can build an artificial kidney, we can build artificial thing, we can build an artificial brain, because we fundamentally don't have a basic theory for how it works. But it is evolving quite rapidly. And it's around network theory.

Mike Labbe  11:33  
Yeah. And so we touched a little bit about personalization. And obviously, the big trend in the world today is AI, you can't read a newspaper without hearing. Historically, the, you know, neuromodulation, for pain for overactive bladder, or even for Parkinson's, these were typically open ended one directional stem right? There was no closed loop, there was no feedback. How much do you see that changing? And how much do you think each therapy will now become, you know, kind of a closed loop approach with some big data analysis and AI that will really drive it and personalize it for each patient?

Ana Maiques  12:05  
Yeah, I think that the people that we are involved in, as Brian was saying, the brain has almost 100 billion neurons. And we don't really know how it works right at the fundamental level. So I think that we've been using machine learning and artificial intelligence, so call for years, right? Because it's impossible to understand how the brain works without some help, right? I believe I mean, from the related we have 25 people in the company all only doing brain models. And we call them neuro twin. So it just still crushes me when you go to the doctor, why do they prescribe a pill and treatment and then tell you come back? Right? Why can we do like the flight simulators just build brain simulators in which we can on the computer, do these neuro teams, and then test how the brain will react to a track or in our case to stimulation before we tested on patients, right? So it's because what Brian is saying the brain is the brain is so complex that to build the computational model of the brain is very hard. But teams like ours, and many in the world are now building this computational neuroscience model. So I hope that we can really use artificial intelligence in that way. So we can really personalize and test on the computer before we prescribe treatment to our Alzheimer's or depression or, or epilepsy patients. But

Kip Roberts  13:17  
I think you know, that's, that's why we're excited about what you guys are doing. And that's why we're bullish about medical devices in this space, because it's not just therapeutic. It's also monitoring. So devices can get smarter over time. And they can then begin to personalize their therapy, the simulator, I like that my use that analogy, more

Ana Maiques  13:43  
euro to him, you can call the neuro team or like, the flight simulator is a good analogy. And I think that's where we are so proud to be at LSI. Because we met Tech, we can do these things. Sorry for the truck, guys.

Brent Vaughan  13:59  
I think one of the other things is you think about the idea for for our therapies to be a little more getting towards precision therapy, right. I think we know what type of response we believe we need to see for us to ultimately have a therapeutic effect. And I think one of the other parts about these disease states we're talking about part of the reason why they're so so hard to attack is because there's a whole bunch of underlying heterogeneity in these patient populations. That is not well understood. Right. And so if you can deconvolute some of the heterogeneity, this is what this is what our colleagues did in when oncology went to precision oncology, right. And the last 20 years has been an explosion over there. And so I think that is we start to look at getting more either either engagement note show that you can have target engagement. So when we enroll patients in our phase three, we know that we need to see a threshold level of gamma frequency oscillation. So every patient starts with an EEG. We put the device on them, and we make sure that we have a threshold response or there or we want to Roll them, right? So every one has to be a responder. And as we build up that database, the ability to look at how people respond, there's a, there's a perturbation response, right? As you start to build up that data set, and I think this is types of thing that synaptic is working on as well, right, you can start to understand that even though our brains are have a lot of things that are highly conserved, there is normal variation between enter between and within patients, and being able to show that we can adapt our therapies to that, because the one thing that blank the brain does have is plasticity, and it does adapt. Can

Ken Mariash  15:33  
I just build on that to brand. So you tailor your therapy at the beginning, but then you can also tailor it over time. And you can see if the brain is responding. So in our case, we're pulsing a note of the default mode network in the brain. And we're making sure that the default mode network is responding. And if it's on a stable glide path, we see the patients have responded if the physician had three months or six months or nine months see that that patient's default mode now is declining, when there's something wrong, either therapy is not working, or we need to add a drug. And speaking of that drugs are complementary, I think, to both of our therapies and maybe to yours as well. But on the on the idea of precision medicine, I mean, it's it's not really what the drugs are doing in Alzheimer's today. I would say it's more an enriching strategy. You know, we talked about Donato Mab, which got a surprise delay. Just last week, do not imagine as a high profile monoclonal antibody against amyloid. So same old M amyloids story, although they happen to clear amyloid really well, but they're going after a really narrow patient population that's highly selective to be the Goldilocks patient that will respond. So it remains to be seen whether the broader audience of Alzheimer's sufferers will respond to this drug. And then you have to also consider the side effects that will be very heterogeneous around the patient population as well. So what we're doing is precision stimulation, which we can modify and calibrate over time in order to confirm target engagement, but also to confirm the patient's brain is responding over time and add a complementary therapy if we need to on top of that.

Mike Labbe  17:03  
Excellent. Maybe we'll just touch on this one real quick. But we're talking about you know, so obviously, drugs there have environment has lots of, you know, benefits and safety risks, as we talk about neuro stem and different target areas. And now we're going to be, you know, modifying and personalizing the stem for each patient. Are there concerns or safety concerns when there are safety concerns? Or what are key safety concerns? Or how do we address that versus some of the pharma risks that we saw historically?

Ken Mariash  17:29  
Yeah, I mean, we'll start that I'm sure that Brent will add the, the amyloid drugs do a fabulous job of clearing amyloid, and yet the disease continues relentlessly. So we know that there's more to the story than amyloid. And as Brent was saying earlier, we believe there's an electrophysiological component to the disease, oscillatoria imbalances, excitation inhibition, imbalances can be stabilized with a neuromodulation approach. With the drugs today, you know, just like any drug, you shoot it into your vein, it goes all over the body with all sorts of untoward consequences that are unknown. And the reason why these studies need to be 18 months and 1000s of patients. So fundamentally, you know, it's less of a precise approach, however, is the big however, I do believe that these neuromodulation approaches will be complementary to drugs over time, this is gonna take a multimodal approach. I don't think there's a silver bullet in this disease state. Nor is there one in cancer HIV, it's going to take a multimodal personalized precision device drug combo approach to really knock this disease of Alzheimer's to knock it out completely.

Brent Vaughan  18:37  
Yeah, I just completely agree. And I think that there's been a huge sea change since the accelerated approval of the cambie. That came back at January of last year, they got full approval mid year last year, everyone, including I believe Lilly expected to see approval coming from the FDA. Their their guidance during analyst week in q1 was for q1 approval. So I think that the the ad comm was was a nasty surprise there. I think that if you look at their data, it lines up so well against the Kennedys data. I think most people probably still bet that it ultimately gets across the threshold here. But in the past, and I've I was 20 years ago, I was working with a handful of folks, and we took two small molecules through Phase Two in Alzheimer's, MCI. And for the last two decades, there's really been two camps. You were focusing on amyloid or you were somehow perceived as being against amyloid right? And that all changed because guess what, we can fully remove the amyloid burden from an Alzheimer's patients and then Alzheimer's progresses at greater than 70% less than 30% slowing. When you remove it even faster with banana map you get almost identical 27% Slowing for the can be 29% Slowing for Ferdinand map. And so you know the the the words that make improv work are yes and right. And it used to be either or but now people See what you can clear. You can clear amyloid and once like, Well, yes. And then what are you going to do about the rest. And I think that really opens the door. I see with investors, I see it with partners that they understand and especially if, if, if, like us, and I'm pretty sure with you guys, we are not targeting amyloid. And so we are quite agnostic to amyloid, we've shown that we have therapeutic effect, regardless of the amyloid level, but more importantly, the dose limiting side effect for these anti amyloid antibodies is not off target. It is an on target effect, that antibody removes amyloid. And one of the areas you find amyloid in the brain is in the walls of the vasculature. If you start taking bricks out of the wall, the vasculature you create a leaky wall, and you get cerebral edema, and you get cerebral hemorrhage. So this is not an off target effect. And so I think that really the success of these anti amyloids opens the door for people to now start thinking more broadly in the space.

Ana Maiques  20:52  
And in terms of side effects for our technology in our Phase Three registration. I mean, remember, we are doing these four focal epilepsy patients, so they don't respond to drugs, the alternative is surgery. So we haven't seen in our 190, Pivotal phase three registration study, adverse events, we are not strong current to induce seizures, so maximum and eating or some like eating sensation in the scope. But I think is phenomenal because the side effects of patients that are into two or three meds today for epilepsy, cognitively, especially the children, we are doing nine years to 65. And I think that it's it's a game changer. I mean, I agree that we have to do in combination with drugs, but 30% of the patients with epilepsy today, don't respond to drugs. And the alternative is surgery. So you have 340,000 patients today in the United States, without any treatment and having seizures every day. And you can die from a seizure. Right? So I think that is not only you know, the door, you're opening to all those patients, but I think cognitively, in in epilepsy drugs are very severe to the patient. So I think that a lot of parents are sick and tired of trying, you know, meds and meds and they're like, can you bring something new? So I think neuromodulation can be that something new for some pathologies?

Mike Labbe  22:15  
Okay, so let's switch a little bit, maybe to some of the business concerns. So we have people here on the panel that have worked in LED big companies and a lot of the advancements that are going on there. And then obviously, a lot of startups and I think startups typically do a lot of the innovation, but obviously, at the end of the day, we're there we're kind of at the mercy of the investment companies and the strategics, in terms of what they want to see, you know, for advancements and where they're willing to put their money. So maybe I'll start with Kip, what are some of the key areas that you see is areas that you guys are looking at it the big companies is for investment, and for eventually for acquisition?

Kip Roberts  22:52  
So how I think about this is in the short and the long term, right? So in the short term, we're really focused on advancing what our core capabilities are today. And so I see some of the technology here at this conference, there are people that are working on better sensing capabilities, how can you increase the number of touch points with the brain, we start to talk about BCI, for example, right? workflow, you know, if you think about how traditional devices are implanted today, can we do it better? Or can we do it more seamless, so moving maybe to a cranial implant, as an example, as we think about the long term, look, we've talked about a lot of the areas that as a strategic with Medtronic, but a lot of the other strategics are probably looking at the same markets because they're huge. That we get really excited about, I talked about migraine. You know, we didn't talk about autoimmune disorders. You know, if you look at rheumatoid arthritis, this affects 1% of the nation population, or the world's population, that's 80 million people. And so in 75% of them, by the way, are female. So, you know, what can we do there? Is this a therapy and other there's folks that are out there, they're investing in and looking at what can we do something in that space? Stroke? Look, I think all of us have had family members that were touched by stroke, and strokes doesn't affect the patient. Stroke is incredibly effective or or affecting to the families as well. So if we can do something there, like what we're doing in BCI, but endovascular stimulation as well, to advance the care and to expand the reach of neuro stimulation, those are areas I think you're going to find that not only Medtronic but other strategics are really interested in investing.

Brent Vaughan  24:48  
Yeah, I think I think an area that's that's really interesting. 20 years ago, I was working and we were developing spa molecules and MCI and Alzheimer's. And the problem we have I was with the MCI because the our investors would talk to payers and payers would make it crystal clear there was no financial incentive define and diagnose MCI patients, right? They cost much more to find than they then they cost just to let the progress right. And so there was not a way to develop a therapeutic intervention for MCI, recent studies have shown there's about six and a half million people with Alzheimer's in the US, there's about 10 million within CI about 8 million undiagnosed. And I think you know, what we're starting to see by applying the ICER analysis for, for what a quality adjusted life year would be for our therapy. And I think you'll start to see this with neuromodulation approaches that don't have the safety monitoring costs of things like antibodies, is there's a chance to start to unlock that MCI population. And so if you want to talk about a change in business model, that 10 million MCI patients, if you have a safety profile, and you have a cost profile that allows you to unlock that, and you get a quality down around $100,000, which is about what a payer is, is spending on a 65 year old plan pickleball with no pathology, right, if you get down to that point, that that could double the size of the Alzheimer's MCI market by adding MCI and can fundamentally change the paradigm of actually starting to treat these patients before they ever get to a point where they would need an anti amyloid antibody.

Ana Maiques  26:27  
Yeah, and I think in terms of cycles for startups, I think that you're seeing trends and challenges. I think that the FDA, I mean, has been clear, we have breakthrough designation, you know, our safety profile is really good. So I'm very happy with the regulatory path. But I think reimbursement is a huge challenge, especially with happen with digital health. And, you know, all the, you know, failures we saw there. I think that reimbursement needs a lot of effort. And but I think that at the end, it's about understanding, you know, what this can bring to the patient and the business model of taking technologies home. I mean, the benefit for the payer for the physician to take a lot of these monitoring, and stimulation technologies and personalization technologies. At home, it takes you to a scale point, that it's it's new in neuromodulation. Right. So I think that, that I think that we have to be creative about the codes and the benefits for physicians for you know, payers and for patients. But I think that's where the biggest challenge stands now. Okay,

Ken Mariash  27:26  
well speaking as someone who's had a background in shared with Mike lavvy, here with the non invasive neuromodulation at home device, and also the strategic perspective on the buy side, at Boston Scientific for nearly a decade, I can tell you that there are really big business model challenges that need to be overcome. You know, with TMS, for depression, there were challenges, but they fought through them, they finally got the CPT coding for TMS for depression. So, you know, synaptic is fortunate in that we can sort of leverage the CPT coding that's out there. Ironically, with our therapy, it's more work, we have to calibrate the therapy to the individual. So more work means ironically, higher pain codes. So that's good for us in Africa. But it's a long road to getting those codes. And we're realistic about that. You start with a temporary code, it could take five years or more to get to a cat one code. Now with breakthrough designation and tea set finally becoming almost over the line, we can see a pathway for five count of five, five breakthrough devices a year that might get covered on day one. So you know, it's a laughable amount. But it speaks to the level of resource constraint that CMSs they say that they have and short of congressional action, it seems like they're gonna be resource constrained for a while, but at least there's a pathway to coverage on day one. So there's some hope for some of our therapies that are breakthroughs. And that that's all of us on the stage. The other thing I would say too, is, you know, home use devices are very convenient for patients and represent a new modality that can be personalized to the patient gather, gather a lot of data from the patient. And over time, that can really work well. However, the reimbursement landscape for at home devices, as we will know, needs an overhaul as well. The DME reimbursement pathway is absolutely broken. And I have personal first hand experience on this. And I know Brent, you do too now it needs an overhaul. And so we need to act as a combined medtech lobbying force to try to get some of that reform done at the DME committee at CMS.

Mike Labbe  29:33  
Yeah, that was a interesting experience we had. So following on a little bit on that so these startup, a lot of startups here, and they want to know when to engage with strategic how to engage with strategic should they engage with the strategic or keep everything top secret from both sides of that fence. What do you think are some of the advice you'd give to how that that should be navigated? Kip you want to go first.

Kip Roberts  29:57  
Now that that's when you should be talking to us. That's my perspective. I mean, we're here. There's a reason why our team is here at the emerging med tech conference, we want to meet you. Now look, make sure you got your IP squared away, have your team set up all that, but, but this is the time to start having the conversation with us. I've seen and talked to a number of startups before that they like, No, we're gonna wait. We're gonna wait until we've got everything exactly the way we want it. And then we're gonna have a conversation with a Medtronic or a j&j, etc. Look, these are big companies. There's a lot of people that have opinions in this company. And it takes a while to get everybody on the same page. So that's the first reason. The second reason though, why you should consider engaging with us now is that we do a lot of work with startups. And not all of it is contractual. I mean, you'd be surprised if you call someone at a strategic up. And you say, Hey, I'd like to talk to you about my company. And I have some questions for you. You might be surprised at how much guidance, feedback suggestions that the strategics are willing to give you encouragement, and kind r&d, clinical regulatory support. I mean, there's a lot that we do in our shop, to help the startups out, aside from just traditional investing, and acquisition. So if you're, if you if you haven't reached out, if you're wondering if you should reach out, yes, the position from from my chair is now now's the time for you to do that.

Mike Labbe  31:44  
Anyone from the startup side want to say they agree or have a different opinion?

Ana Maiques  31:48  
I agree, you have to start early, because it takes forever. So I think he's a great advice. I think that to keep them in one. One common is when you find a champion in strategic that is totally in love with the startup and supportive. And then he goes through all these obstacles on committee, and then you make it to the finish line. And then the last day, he's fired and a new team comes. I mean, is that part of the thing we need to I mean, any advice for the startups, just be patient, grow wrinkles, I mean,

Kip Roberts  32:19  
it's, it's, it's a real problem, okay. And and it's something that we, as a large company are cognizant of, I think, if I were in your shoes, as a startup, it's not just about latching on to myself, you know, and saying, Hey, I'm gonna put all the eggs in the basket with Kip. You know, I've got two colleagues right over here, Armando, and DJ, you need to socialize with them as well, you know, and get to know them. So it's about building relationships. But look, I think most of the strategics work in teams, and they work in teams for a reason. So I think it's about cultivating those relationships. And look at this, if the strategics are interested, you got something novel, in something that's differentiated, trust me, they're paying attention, and they will maintain that level of contact with you. But start the conversation now.

Ken Mariash  33:10  
And one bit of advice I can give being 99 years on the buy side is, you know, the obvious stuff, like having a credible thesis for why it's a good fit for a strategic like Boston or Medtronic. That's, that's fairly obvious. But well, I think what a lot of startups will forget is that the BD person, as important as the BD and strategy person is, is not going to be the one that gets your deal over the line, you have to have someone in marketing, and a lot of people miss this, even someone in sales, sometime it can put up their hand and says yes, you put this in my bag, I can sell this, this is an adjacency, I can leverage my time, I'll sign up to a higher quota. If I have this product in my bag, if you have that kind of support from a marketing or a salesperson and strategic, that's what you want to see, to bring together the level of interest that will push a deal forward. That's my experience anyway, being in your shoes.

Mike Labbe  33:59  
You're spilling all the tea today.

I think we're getting close to the end here. But a real quick question. So a lot of neuromodulation historically has been implantable. And invasive. And I've see obviously a couple here today, including a cap down there that is on the non invasive side. Is that a shift in technology? Is that Is there a reason for that? Or is it just kind of a natural evolution? Do you think one is going to become more prevalent the other or is there a need for both in the industry? And we'll start with the cap.

Ana Maiques  34:29  
So as the lady in the cup. Now, I would say that I think there is room for all of us. I think that the pathologies we are going after and the brain diseases that we're going after are so complex I mean I have a cortical stimulation technology is going to be helpful for depression or epilepsy but I don't think for Parkinson's of movement disorder. So I think that every modality has a different impact in different patients. But I think that technology artificial intelligence sensor technology, computing technology, wireless technology, I think that it has helped us, at least in your life to is to scale up to the medical world in ways that was not possible before. So I think it's follows that technology like, you know, evolution of being, you know, more small, you know, more non invasive, you know, higher resolution, and so far so,

Brent Vaughan  35:18  
yeah, I think it's just where the technology takes you right are the Eureka experiment that allowed Cognito coming to fruition was the intersection between between looking at at some of the degeneration seen and in Alzheimer's, along with, along with optogenetics, it was, it was using optogenetics, to do the gene editing to insert the expression of opsins into basket cells, right. So that's pretty darn invasive. What we learned from that were two pretty unique things. Number one, that everyone takes for granted that changing levels of pathological proteins in the brain changes, changes the electrical activity, and in ultimately outcomes, we show that that was bi directional, changing electrical activity can in turn change, change protein expression. And so that opens up the door to disease modification and takes you out of merely symptomatic. The other was that we figured out there's a non invasive way to do this, it turns out, you can leverage the visual and auditory cortex is kind of freeway on ramps to the brain, and it allows you to avoid the whole blood brain barrier issue that most of the systemic therapeutics have. But I think this is this is specific to our technology, I think every technology has kind of their, their window into how they think about they're gonna modulate biology. But if you can figure out how to make it non invasive, that always makes your life so much easier. And we're already

Kip Roberts  36:41  
seeing it, right. I mean, things are gonna get smaller, for sure. But even in addiction, there are companies out there that have external stimulation devices today for addiction, we hear in the pelvic health Arena, that they're going to move into more of external stimulation type devices, potentially. So I think it's going to go in that direction. But also, it's going to the miniaturization of the devices because I want to increase, you want to say, yeah, just

Ken Mariash  37:08  
non invasive is great if you can get the same results. You know, there's clearly some use cases where you just can't get deep enough in the brain. So it's probably going to require an implant. You know, in the case of synaptic is therapy, we were able to publish peer reviewed in the Oxford University Press journal Brain, unprecedented 82% slowing in the primary endpoint, over 80% Slowing on us cognitive secondaries, and 100%, slowing unfunctional endpoints. So if an implant gets a little bit better than 82%, slowing great, but there's probably a 5% of the population that would opt for a wire in the brain. And remember, these are implanted while the patient's awake. This is not something that a lot of people want to opt for, is the convenience worth it? Probably not if you could get a little bit of efficacy out of an implant great. But in the case of our therapy, 82% Slowing is pretty darn good with a non invasive. The most invasive element of our therapy, obviously, is that the patient has to come in once a week for 25 minutes. I drive my mother to get her hair done every three weeks though, so I think I can handle it. 

Mothers are important.

Mine is. 

Alright, I think actually, we're out of time. I want to thank a great panel for all their insights into the fields, all of you for coming and of course LSI for putting this together and listening to have this discussion. Thank you. Thank you