TechTalk: Alzheimer’s Breakthrough Therapy Emerges from Seed-Stage Startup

Ken Mariash: 

Thanks, Janina. Happy to be here. 

Janina Teoxon: 

All right. So, to kick it off in two to three sentences, please explain Sinaptica Therapeutics mission for our audience. 

Ken Mariash: 

Yeah. So, Sinaptica is developing a new non-drug way of treating Alzheimer's. We're using noninvasive precision, personalized neuromodulation therapy, targeting a new network in the brain called the Default Mode Network, which is responsible for episodic memory and implicated in Alzheimer's disease progression. And what we do is, we calibrate this brain stimulation therapy for every individual. And by stimulating these key networks, we potentiate their growth, which is called neuroplasticity, which then counters the effects of Alzheimer's. And we've published Phase II trial results, which are absolutely unprecedented, have not seen data this strong in any drug in my 20 years of being in the field. So, I came aboard as CEO about a year ago. We've built a great company and we're marching towards a pivotal trial initiation in 2025. And this is an incredible breakthrough. It's actually an FDA breakthrough product. And as a device-based therapy, it's a little unusual, but after so many failures in the Alzheimer's space, we need to come at this disease from a totally new, fresh perspective. And that is the bold new approach that we're bringing and the results are tremendous. 

Janina Teoxon: 

Wow! The mission is truly ambitious, yet it's so clear as to the solution for the Alzheimer's disease. Yeah. I know a couple of drugs out there gaining FDA approval in this space. However, I think you touched upon this. Sinaptica's approach sounds truly unique and extremely promising. So, how does your approach to treating Alzheimer's differ from the other players in this space? 

Ken Mariash: 

Yeah. It's a completely new approach. So, if you've been watching the news headlines at all for the last 20 years, what you've seen is failure after failure in the Alzheimer's space, with respect to drugs. And we think that's primarily because they're all focused on ... With just a few exceptions, all the drugs in the last 20 years have been focused on amyloid. Amyloid beta is the plaques that accumulate in the Alzheimer's brain. Curious thing about Alzheimer's and amyloid, though, is that amyloid is just loosely correlated with disease progression. It is correlated. There is definitely something to do with Alzheimer's disease progression. But, we think of amyloid as more of a co-variant than the actual cause of the disease. So, there's a lot of patients who have amyloid, but no Alzheimer's. There's a lot of Alzheimer's patients who have no amyloid. So, are we really going after the right thing there by focusing on amyloid? 

Now, after 20 years, the latest drugs do target amyloid and are very good at clearing amyloid from the brain. However, the disease continues relentlessly. So, there's got to be something more to the disease here. So again, we think of amyloid as more like the ashes after the house has burned down. You can clean up the ashes, but we need to focus on the upstream causes that actually burn down the house. We don't pretend to have the silver bullet, but we certainly are a novel approach that focuses on a new target. Our target is different. We're looking at this as an electrophysiological disease. And if you think about Alzheimer's, the Alzheimer's brain has so-called epileptiform activity. There's oscillatory imbalances in the signaling in the brain, particularly in this network that we're targeting. 

So, if there are oscillatory imbalances and excitation inhibition imbalances in the signaling in this big network in the brain, then that suggests that neuromodulation can do two things. It can stabilize the firing patterns in this network. Think about epilepsy and stabilizing the firing patterns in epilepsy, but on a much grander scale. Second thing it can do is induce neuroplasticity. So, strengthening the synapses. It's well known that Alzheimer's is a disease of synaptic dysfunction as much as it is a biochemical disease focused on amyloid and tau. Synaptic dysfunction is what we're targeting. So, we're potentiating those synapses. We're strengthening those synapses across the network. We're not just targeting one little area in the brain, we're targeting the entire network, which again, as I say is the default mode network, which is the network in the brain that's responsible for episodic memory. 

So, it's a network based approach and it capitalizes on two big trends in medicine. One is connectome-level thinking. So we're no longer thinking of the brain as having individual regions, like this region's responsible for auditory processing. And this one is for visual. It's actually more thinking about the brain as distributed functional networks. There's the salience network, there's the dorsal attention network, there's obviously the executive function network in the frontal areas of the brain. And then the default mode network is a large-scale, really backbone of cortical integration, which is where we process our memories. It's actually where we form our internal narratives and our sense of self, which after all, is based on integrating those memories. And so we're taking a connectome-level approach to targeting the default mode network. 

And then secondly, we're doing it in a precise way. So it's a precision medicine approach that's tailored to every individual. It may not surprise you, but every brain responds differently to stimulation. And our tools allow us to probe the brain. We stimulate the brain with single pulses, and then we listen to how the brain is responding. And that tells us a lot about the networks that we're lighting up, where we stimulate. So, we're taking a precision medicine approach that's calibrated for every individual, to make sure we get the right engagement of the right targets. 

We're not firing blindly at the head and hoping that we get the right targets. We're confirming that we're hitting the right targets. And I could go into the technology itself, but suffice it to say, it's like active sonar, like pulsing the brain and verifying that we've hit the right targets, instead of blindly stimulating and hoping we get the right response. So, long-winded way of saying our approach, it's very different and it's focused on connectome-level thinking and precision medicine. 

Janina Teoxon: 

Wow! Thank you. Thanks for that. That's a lot of information, a lot of science in there, but it sounds like it's truly groundbreaking. And you said that the FDA ... I've read this actually online, that the FDA awarded Sinaptica the Breakthrough Device designation, because I can tell, literally, it's a breakthrough therapy for Alzheimer's population, and your approach is really to stimulate the brain and really targeting this specific problem, it sounds like, based on what you just described. You mentioned about technology. Our podcast is about technology. So, how are you leveraging technology to accelerate the solution? 

Ken Mariash: 

Neuromodulation is really now becoming more data driven. So, as we take this connectome-based approach, as we take this personalized approach, we generate a ton of data from every patient. As we probe the brain, again, like single pulses of energy ... It's called TMS technology, if you're not familiar. So, Transcranial Magnetic Stimulation. It electrically induces the brain, and we pair it with EEG, which is a technology everyone's familiar with. So, EEG listens and TMS pulses. And again, it's like active sonar. When you pulse the environment, you learn so much about the environment, but that also generates gigabytes of data, per patient. So, that's the technology piece that I think maybe your listeners might be interested in. 

Those gigabytes of data is highly complex, personalized data that's very messy and hard to interpret. And so, our algorithms are based on cleaning that data. Anyone who's skilled in machine learning understands that your machine learning algorithms are only as good as the data that you have behind them. And so, we first have to clean the data before we can parse it. Once we have clean data from each patient, then we need to do feature extraction, which people who work in technology will appreciate. Feature extraction is looking at the data, knowing which features to look for, which tells you A, the person has Alzheimer's, B, that you're on the right target, and C, over time that the brain is actually responding to therapy. 

So, not only does this technology help us to target, it also tells us that the patient is responding to therapy over time. So, it's really a biomarker over time. So, this is a data-driven approach, no different than a lot of ML-based technologies. We actually have published real machine learning on differentiating Alzheimer's from non-Alzheimer's, using these signals in the brain. So, that's the exciting piece. And we're doing all this in the cloud. It's very intensive computationally. So, we are building our algorithm in the cloud so that we can, again, clean and pulse gigabytes of data within minutes rather than hours, which is what it would take, or even days it would take, if we did this offline. 

Janina Teoxon: 

Wow! That's fascinating. The technology is really incredible and the power of data. And I have guests talk about machine learning and AI, and it's just fascinating how they can aid in the therapy for this particular space. Thanks for sharing that. So, now Ken, can you give me a scenario of what a typical patient treatment would look like? 

Ken Mariash: 

It's like you come in for dialysis, except dialysis is a long process. And remember, Alzheimer's is a terminal illness. And so, when these patients are diagnosed, it's a terminal disease that they're dealing with, just like with kidney failure. So, these patients know that they need to address this. And so, they come in first for a calibration session. When in our calibration session, what we're doing is, we're looking for the right spot on the patient's ... It's called the precuneus, which is in the back of the head. The precuneus is a key hub on the default mode network. That's our target, our window into this network that we're trying to stimulate. And so, it's like finding the mainframe in a house, the main electrical panel. Once you find the main electrical panel, then you can stimulate the entire house. That's what we're trying to do. 

So, they come in for this 45-minute calibration procedure, where they have to wear a 64-channel EEG cap. And then the TMS coil pulses and single pulses repeatedly in different locations, trying to find that sweet spot that tells you that we found the right spot for that particular patient. Now, once we found the right spot, and we've also calibrated the dose to be within a safe dose ... You don't want to overstimulate these patients. You don't want to under stimulate them either. You want to be right in the window that's specific for that individual. Once we calibrate the location and the intensity of the stimulation, now the patient just has therapy sessions that are about 20 minutes each. They don't have to wear the EEG cap anymore. They just come back for weekly stimulation sessions of 20 minutes each. 

It's absolutely painless. They sit back in recliner. They can keep their eyes open, they can even talk to the technician. The only key is they have to keep their heads somewhat motionless, because targetry really matters. And so, they have to keep motionless. But, they don't feel a thing. They hear a clicking sound, which is the sound of the coil pulsing in their brain. And it's about 1,600 pulses that we are delivering in about 20 minutes' time. They absolutely don't feel a thing. And the only side effect from our therapy, which we saw in our Phase II, the only side effect that could happen is a little bit of scalp irritation. That happens in about 16% of patients, or a headache that resolves spontaneously within a few hours, again in about 16% of patients. 

And so, this is the only side effect and if our efficacy is 82% slowing, which is what we've proven or shown in our Phase II randomized sham-controlled study, 82% slowing is an absolute knockout. It is one of the strongest signals I've ever seen. So, not only did we slow the disease by 82% based on the primary endpoint, but we also slowed the disease by over 80% on secondary endpoints that have to do with cognition. And then, on function, this is the ability of the patient to live independently and feed themselves and bathe themselves and clothe themselves. On function, we actually arrested the disease, entirely at six months. So, what that means is these patients have not progressed at all. These are mild-to-moderate patients. They should be progressing. 

In the case of the active arm, they have not progressed at all in six months. Now we don't expect this to continue forever. We do have 12-month data now that shows that these trends do continue to a year. So, they are durable trends to a year. But the disease will continue, relentlessly. It is a freight train. But, at 82 or so per cent slowing, this is a profound result. So, if the patient has to come back for weekly sessions to get that efficacy with so little side effects, I think that's a very small price to pay. After all, we go to the gym, in my case, maybe three or four times a week. I take my mother to get her hair done every few weeks. And the drugs require an infusion of 90 minutes every two weeks. So, we're pretty much on par with that. 

We're a 20-minute session every week. The drugs are a 90-minute infusion every two weeks. So, it's about the same effort level to get the patient in, in either case. Except with the drugs, the side effects are a 17% rate of ARIA, which means that your brain is experiencing potentially micro-bleeds and also hypertension in your brain. This is not good. This requires an MRI to make sure, on a quarterly basis, that you're not experiencing these side effects with the drugs, which could be life-threatening. So, in summary, for a weekly maintenance, we're slowing the disease by 82%. Meanwhile, some of the drugs out there, they are showing some ability to slow, but not even close to 82%. 

Janina Teoxon: 

Oh, that's incredibly detailed and very comprehensive. Thanks for explaining that, Ken. And it's inspiring to know that the treatment has proven to be 80%, or so, effective at slowing the progression. 

Ken Mariash: 

Let's talk about what that really means. What that means is, it's like cancer. Right? The earlier you get to it, the better. You just want to slow it down. You can't stop most cancers. The best you can do is you can slow it down. But 82% slowing, basically means that we're extending these patients' lives potentially by years, whereas the drugs maybe extend your life by months. 

Janina Teoxon: 

What has the reaction been from funders, when you explain to them the premise of Sinaptica? 

Ken Mariash: 

Yeah. It's been a mixture of very strong reactions. And it's a mix of excitement that, "Wow! This is a huge breakthrough and never seen data this strong across so many endpoints," and also a little bit of surprise. It's like, "Wow! We thought that a drug would be doing this," and all eyes have been on drugs for 30 years. We always thought it would be a pill or an infusion or something like that. And so, to see a neuromodulation therapy ... Now for me, it's not that surprising. I come from the world of neuromodulation. It's a huge industry, by some accounts, about seven billion in sales a year in various forms of neuromodulation, treating pain, Parkinson's, epilepsy, you name it. So, for me, it wasn't such a surprise. But, from the investor side, it was a bit of surprise that neuromodulation could be this big breakthrough. And so, there's astonishment, there's excitement, there's hope, and also just surprise that this came out of left field. That's the reaction we're getting. 

Now, in the case of Alzheimer's, there's been so many failures that overcoming skepticism is always going to be a challenge. And so, what I've seen over the last 20 years, though, is hope has been built on very little. Very little. Small animal studies, post-hoc analysis of data that sort of looks like it's trending in the right way. This is a bright-line signal of efficacy across the board, it's non-confounded. Every single relevant endpoint is hitting, not just at some small magnitude, but at a very large magnitude. And, in addition, the clinical endpoints are backed by imaging. So, imaging of the brain, FMRI data and MRI data of the brain, which shows we are literally changing the brain. Literally building new functional connections in the brain, literally preserving gray matter. And so, there's objective evidence that our therapy is literally changing the brain, which corroborates what we're seeing. 

Janina Teoxon: 

It's remarkable. It's remarkable. And I'm encouraged to read that you had so many investors jump in early on, including Time Zero Capital, Sony Innovation Fund, the Daly Family, Wilson Sonsini Ventures, HealthTech Capital and other angel investors. And I thought it's important to understand the perspective of your funders. So, at what stage now of the funding round is Sinaptica currently in? And what do you see as the next step? 

Ken Mariash: 

Yes. When I came aboard a year ago, the Phase II data and everything that came before was entirely based on grants. So, we're extremely grateful for the Italian Ministry of Health and the BrightFocus Foundation and other institutions that have helped us get this amazing data published in a major leading journal, and also help to get FDA Breakthrough designation. So, that was all from grants. Now we've actually raised a proper round of seed capital to build a real team with a real Phase III plan and get a real device built and ready for the Phase III. 

And so, we're so grateful to have investors like Time Zero Capital. The principle there is Dinesh Moorjani who started 17 companies, including Tinder, which you may have heard of and also is an advisor to ... He teaches at UCLA and was an advisor to Warburg Pincus, et cetera. So, we're really grateful to have luminaries such as Dinesh, who's actually on the board. And also, Sony Innovation. They saw the potential of this really early and they got involved really early. So, we're super happy to have them as well. And the Daly family, Bob Daly Sr. worked with Terry Semel to run Time Warner, and unfortunately Terry came down with Alzheimer's. And so, they want to do something big and back this big breakthrough. So, we're super grateful to have their support. 

Now, that we've built a real company, we're moving on to our second round of funding and we're focused on a $9-million convertible note to build our clinical device, which will be used in our Phase III study. And that $9 million note does have a number of commitments and also re-ups from some of our early investors as well. And we're looking to partner with a larger VC's who see the enormous potential of this breakthrough. And so, that note we just opened, we have commitments and it's going forward on a rolling basis. I am also now opening it up to individuals with 100K ticket, up to $1 million to get some individuals in who missed on the seed round and want to be part of this big story. 

Janina Teoxon: 

That's very impressive. And the only way forward is up. And with six million Americans suffering from Alzheimer's, it's a precious gift that you're seeking, the company is seeking to give to these individuals, as you seek to continue this down the road in finding a cure or therapy for the disease. And for my last question, Ken, let's talk about you. And I know you joined Sinaptica a year ago, but you've been in this space for many, many years. So, how have your previous ventures influenced where you are today? And what has been a pivotal moment for you, that you'd like to share with our listeners? 

Ken Mariash: 

Yeah. I've been part of the neuromodulation space for nearly 20 years. And so, I came aboard Boston Scientific to head up the strategy group. Boy, that was 2012, I think, when I came aboard. And so, I've seen neuromodulation really mature over the last 15 years. It's started as a novel, interesting therapy that lacked Level 1 evidence. And now neuromodulation is big. In the pain space, it has lots of Level 1 evidence focusing on many different indications in pain. In Parkinson's disease, deep brain stimulation is well established. In epilepsy, of course, it's well known that vagus nerve stimulation ... And targeted closed loop brain stimulation works for epilepsy. I could go on. There's many, many companies looking at neurostimulation. 

So, it's really matured as an industry with a lot of great data behind it and has become very well established with reimbursement in big companies like Boston Scientific, Medtronic, Abbott, and so forth being a part of it. So, it wasn't such a surprise to me to see that this would work in Alzheimer's. To answer your question about a key "Aha!" moment, for me, it was this recognition that neurostimulation could lead to neuroplasticity. We're not just interrupting a signaling pattern. We're not just covering pain signals and stopping them from reaching the brain in the case of spinal cord stem. The key moment for me was wow! There's network abnormalities in the Alzheimer's brain that we can stimulate and overcome by inducing neuroplasticity in the brain. There's a lot of animal data to suggest that our stimulation does lead to the release of growth factors in the brain that sprout new dendrites, et cetera. 

But that was the key kind of aha moment for me was this is network stimulation, not just neurostimulation of a nerve or two. This is network stimulation across the entire brain. Again, in this case, it's of the default mode network. And so, my experience in neuromodulation, my experience selling capital equipment, in the case of running the Cosman franchise at Boston Scientific, and my experience in Alzheimer's ... I did have experience going all the way back to 2004 when I was a part of a Phase III study looking at intravenous immunoglobulin on the drug side for Alzheimer's. All of this came together and I think made me a perfect fit for Sinaptica. And it just made sense to be a part of this. 

And again, like I said at the outset, I'm super grateful to be a part of being in this amazing breakthrough therapy that our professors Emiliano Santarnecchi at Harvard MGH and Professor Koch over at Santa Lucia Foundation and the University of Ferrara. Their amazing discovery is gift to the world, as you say. And I'm really glad that I get to be a part of it. And I just wanted to put in a little plug for EisnerAmper. You guys have been a great partner. You've been there from the very beginning. The intelligence and the speed with which you act in our finance, accounting and HR processes is really amazing. You're a trusted partner. And if I had any opportunity to recommend EisnerAmper to other startups, believe me, I do so on a regular basis. So, really appreciate the team that backs Sinaptica at EisnerAmper and everything that you do for startups like us. 

Janina Teoxon: 

Great. Thank you for that. I'm really excited for you and for the Sinaptica's team regarding this breakthrough therapy. And I wish everybody all the best as hopefully you'll get this convertible note successful. And Ken, thank you for taking the time to have a conversation with me today. I really enjoyed it. I learned a lot about the neuromodulation space. You talked about a lot of science, very detailed with respect to the patient treatment. So, appreciate your time today. 

Ken Mariash: 

Yeah. Thanks so much for having me. And for folks who want to learn more, just go to www.sinapticatx.com. That's spelled S-I-N, sinapticatx.com and learn about our therapy there or find me on LinkedIn. 

Janina Teoxon: 

Perfect. Thank you. And thanks to our listeners for tuning into TechTalk, the entrepreneurs and innovators who turn to EisnerAmper for audit, tax, advisory and outsourcing solutions to help propel their business forward. Subscribe to the EisnerAmper podcast to listen to more TechTalk episodes, or visit www.eisneramper.com for more tech news you can use.