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Ep. 32 Alzheimer’s Breakthrough? Recall Thinks Restoration Is Possible
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What if an Alzheimer’s therapy did not just slow decline, but restored memory and physical health back to baseline?
In this episode of Spark Time, we sit down with Dan Salain, President and CEO of Recall Therapeutics, and Dr. Atul Chopra, Co-founder and CSO, to unpack one of the boldest ideas in neuroscience today: RTX-100, a gene therapy designed to restore cognition and systemic health in Alzheimer’s disease. Dan and Atul walk us through the science behind targeting memory circuits rather than just clearing amyloid, how a liver-expressed protein naturally crosses the blood–brain barrier, and why their preclinical data show full recovery of associative, recognition, and spatial memory in advanced mouse models.
We also explore the overlooked systemic side of Alzheimer’s cachexia, sarcopenia, frailty, UTIs, pneumonia and how RTX-100 appears to normalize body weight, muscle strength, endurance, and fluid balance alongside cognitive recovery. From serendipity in the lab to regulatory strategy and potential paths to market, this conversation opens up a very different vision for what treating Alzheimer’s and even aging itself could look like.
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Transcript
Introduction to Sparktime Podcast
00:00:00
Speaker
Welcome to Sparktime, where biotech's thought leaders, investors, CEOs, and industry experts break down the evolving story of life sciences. Hosted by Danny Stoltzfus and Will Riedel, two scientists and strategic communicators, we dive deep into how biotech leaders can shape the narrative, win investor confidence, and communicate breakthrough science in ways that truly resonate.
00:00:21
Speaker
From emerging trends and cutting-edge technologies to what investors and partners really want to hear, we go beyond the usual echo chamber, bringing you fresh insights, unexpected perspectives, and the strategies that set biotech's top players apart.
00:00:34
Speaker
If you want to sharpen your corporate messaging, decode industry shifts, hear from voices shaping the future of biotech, and get inspired, then you're in the right place. Let's get into it.
Intersection of Neuroscience and Courage in Alzheimer's Treatment
00:00:45
Speaker
Welcome back sparktimers. And you're going to want to stick around for this whole episode because this is the story of what happens when neuroscience meets courage and when a biotech dares to aim for what we consider the impossible, bringing memory and health back versus just trying to slow the progression of Alzheimer's. So this one touched a nerve for me and I think it will for you too.
00:01:10
Speaker
So enjoy.
Meet Dan Salain and Atul Chopra of Recall Therapeutics
00:01:16
Speaker
Today on Sparktime, we're joined by Dan Salain, President and CEO of Recall Therapeutics, as well as Atul Chopra, co-founder and CSO of Recall Therapeutics, the company leading one of the most ambitious missions in neuroscience, that is restoring memory and health in Alzheimer's disease.
00:01:33
Speaker
A seasoned biotech executive, Dan has spent over two decades bringing advanced therapies from concept to commercialization. Before founding Recall, he served as CEO and co-founder of Arnasi, COO and co-founder of AceraGen, and COO of Greybug Vision, where he oversaw global operations, manufacturing, and supply chain for programs spanning rare disease, ophthalmology, and advanced biologics.
00:01:58
Speaker
Atul is a physician scientist who spent his career exploring how the brain and body stay connected and how that connection can be restored in conditions like Alzheimer's. At University Hospitals and Case Western Reserve University, his lab's discoveries have reshaped how we think about the brain-body connection and its role in overall health.
00:02:17
Speaker
Before co-founding Recall Therapeutics, Atul and Dan co-founded Aserogen, a rare disease company they successfully took public. Together, they're now playing that same focus and experience to one of the toughest challenges in medicine, which is restoring memory and vitality in Alzheimer's disease.
Unique Approach to Alzheimer's: Memory Restoration
00:02:34
Speaker
So while most Alzheimer's drugs focus on amyloid clearance or delaying the decline, recall is pursuing a different mission, which is this true memory restoration. Their proprietary gene therapy, RTX 100, crosses the blood-brain barrier, targets the brain's memory circuits, and has shown compelling preclinical data that may change how we think about neurodegenerative care entirely.
00:02:57
Speaker
Additionally, Alzheimer's is a fatal disease as lethal as cancer, affecting not only the mind, but the body as well. Most Alzheimer's patients actually die within five years after diagnosis from the systemic body functions that shut down with the progression of the disease. Recall's RTX 100 is intended to restore most general health functions such as muscle tissue, strength, and endurance, along with maintaining body weight and fluid balance.
00:03:23
Speaker
So with over 7 million Americans and 55 million people worldwide living with some form of Alzheimer's or dementia, and with most approved treatments delivering only marginal benefit at really an enormous cost, Recall's approach could represent a new frontier in cognitive and systemic recovery. So Atul, Dan, it's really great to have you here. How are you today? Doing well. Yeah, doing well. Thank you. That's fantastic.
00:03:48
Speaker
Well, let's kick it off. you know um You spent years in biotech leadership, both of you, but ah Recall Therapeutics has a particularly bold mission, as I mentioned, that's the memory and health restoration.
00:04:00
Speaker
What was the moment that convinced you this could actually be possible in
Breakthroughs in Memory Restoration
00:04:05
Speaker
Alzheimer's? Yeah, this is an interesting sweet one because Atul and I have known each other for a long time, little over 10 years. And as you mentioned, we took um a company public, Acerogen, which is a rare disease company. But Atul and I always find ourselves tinkering around with molecules and discovery. And Atul does a particularly really well job in his Chopra labs. And so we've been messing with this molecule for about three years, primarily for other indications. And about two years ago, Atul and I were on the phone discussing this and he said, you know, this really has CNS implications and I'm going to try it in the CNS side of it. And so he did the experiments, et cetera, et cetera. About two years ago, we had our first hit on memory receptors or the memory circuits coming back in mice. And so we started...
00:04:52
Speaker
We started just kind of down that path and continue to work on the molecule and the delivery of it, which is genius. The delivery mechanism is what really makes this work and turn those circuit breakers or those memory receptors back on. And so Atul really discovered that in his lab and the ability to turn that receptor on.
00:05:10
Speaker
Yeah. So just piggybacking on that, it was really the data. ah And we've been talking on and off. And we're always, you know, every couple years or three years, we're in, yeah hey, let's start another company. but What's the need to fill now in the in the health space?
00:05:27
Speaker
What diseases are still white space and where can we make an impact? Alzheimer's is as about as white space as you can get. By white space, I mean, there's really nothing. There's a couple of proof therapies, but they don't really work.
00:05:38
Speaker
very well.
Challenges with Current Alzheimer's Therapies
00:05:39
Speaker
ah They don't have much efficacy. People are not really writing scripts on them, physicians, that is. And they have terrible side effects. So it's about as white space as as you can you can imagine. you know It's not a crowded space.
00:05:51
Speaker
um Anyway, um what i what I do is like I run a basic science lab, a university lab, lots of bright you know young people working in the lab.
00:06:02
Speaker
And we're always doing experiments. And And with this particular ah you know direction, serendipitously, we started studying the the central nervous system and memory and the brain and immediately started getting results.
00:06:17
Speaker
um That's kind of when I mentioned to Dan, yeah hey, man, looks like we have something that is affecting memory and we can change it at will. um that's that's kind of where it got started. So really, it it started with the data um and lots and lots of serendipity.
00:06:33
Speaker
And I think that's a very common story in science. Yeah, for sure. And I need to understand how this works for a second here, because my brain is going, how do you get a gene therapy into the brain? That's one one question. And i I know, Dan, you mentioned that that was part of the genius of a tool's discovery, but and we can come back to that. But I mean, my understanding, as you mentioned, is most therapies are focused on like slowing the the progression of the disease and amyloid buildups. So tell me more about how how are you able to impact memory in a different way? like Tell me how that works.
00:07:11
Speaker
How is it different from what's on market? Yeah, so what's on the market today is really drugs or molecules that slow memory loss. And they're really focused on the fluid that circulates in the brain and around the brain called the CNS fluid. And in that fluid, as you age and you have a couple of genetic biomarkers that are predestined for either dementia or Alzheimer's, that fluid can get thick or coagulate together and form these little kind of clots. And and what those do is they they just...
00:07:42
Speaker
generally kind of clog up the memory receptors. And so as you age, that gets worse and worse if you're predetermined for dementia or Alzheimer's. And so the discovery that we made was, listen, you don't really have to go after the CNS fluid because those molecules are aggregating on the circuits and receptors of the brain. And if we could actually move them off and or out-compete them for their memory receptors, we would have something. And so part of the genius of the molecule that we have is if you express it at the same level that those CNS fluids are starting to coagulate, our molecule actually outcompetes at the receptor level, and then that's what kicks off the amyloid and then brings back that memory restoration.
00:08:25
Speaker
Just to add on to that, so basically I guess what Dana's saying is that amyloid clogs up everything in the brain um yeah and known it's probably the most well-known molecule uh the well most well-known protein in alzheimer's disease other than tau that's another one and it's been known for a long time uh you know amyloid builds up it uh as dan said kind of clogs together it aggregates together and uh causes all kinds of damage in the brain um So the existing therapies are predicated on removing this molecule from the brain, ah removing this protein from the brain. Yes, yes. And they use antibodies to do that, right? So that's, the that's I mean, really, it's not rocket science. So the idea is yeah in Alzheimer's disease, amyloid builds up in the brain.
00:09:11
Speaker
What will happen was the was the original question asked 20 years ago. What will happen if you take this this aggregating protein down by removing it forcibly from the brain?
00:09:22
Speaker
So folks invented these monoclonal antibodies that go in, bind amyloid, and then you know this entire complex then gets removed kind of ah from the brain, goes into the blood vessels. um And I think what we found is that it doesn't really but it doesn't really work all that well.
00:09:39
Speaker
And maybe that's because you can't really get rid of the the critical amount that is still causing damage. It's actually not known. why Why does this therapy not work very well? Why does cognition not come back? Why do why does memory...
00:09:52
Speaker
and not get restored. um But one of the guesses is you you don't get rid of all that much. And this whole idea of sucking amyloid out of the brain is not without its flaws because it, you know, we knew this like 20 years ago. They tried this light first um and found that it causes brain, because this entire thing, entire complex, the antibody plus amyloid is ending up in the blood vessels. It starts causing leaky vessels.
00:10:18
Speaker
and Oh, that's not good. Yeah. You want little bleeds in the brain. And that's essentially what this therapy causes is little bleeds in the brain, swelling in the brain and bleeds in the brain.
00:10:29
Speaker
They call this ARIA, amyloid-related imaging abnormalities. But really, these are little bleeds, tiny little bleeds and swelling. and And, you know, but that can have lethal effects.
00:10:40
Speaker
And that's why the FDA has put black box warnings on on both of those drugs that are approved that do this. Now, so that brings us to a problem. You know, the idea was good.
00:10:51
Speaker
hey, this is this buildup of this toxic protein. Can we remove it? And we've tried it and we find it has kind of middling efficacy and it produces this horrible side effect profile. So what do we do now?
00:11:02
Speaker
That's where we stand. That work that they did really cleared the way for us because they paved a lot of research and ways to do things and the ways to detect things. which So, you know, while the drugs aren't that successful, they did pave a way for us to be able to discover our our molecule and deliver it to the areas that really needed it without having these kind of side effects.
00:11:25
Speaker
Right. So our our thing differs from this traditional approach very simply. we We don't care about removing amyloid from the brain. We simply move it off the the receptors and the cell surface where it's causing damage.
00:11:40
Speaker
Yeah, or cleaning up the area, basically, to restore that memory function. Right. Because amyloid is known to bind all these receptors and other proteins. a very sticky little protein, very sticky. So it sticks to all kinds of things. And if we can just move it out of the way, can you recover memory? And our experiments will suggest that that approach works.
00:11:58
Speaker
Yeah, i remember one of the first experiments a tool did was associative memory. And those memory receptors... In the brain area. And so, you know, we had normal normal mice that we were testing, and then we have aged mice,
Gene Therapy and Potential Human Applications
00:12:11
Speaker
which you can do through different mechanisms to actually give them on Alzheimer's like disease. And so you can see that they don't remember things and they don't remember where they're at in a maze or they don't remember where where they're at in walking. And then after our gene therapy was applied, after about six months, you could start to see, oh, wow, they remember where they are now.
00:12:31
Speaker
And so it was kind of a really light bulb moment for us when the mice actually started to remember where they were in in that maze process. And so we were able to show in those early studies just on associative memory, complete recall back after nine months, which, you know, in a human, that's that's three, four, or five years of having the disease. Right.
00:12:51
Speaker
That's crazy. That makes me think about a different question. So like there's other like associated symptoms of Alzheimer's, which we kind of already touched on. And besides you know the loss of memory, how does your gene therapy work in terms of, let's say, like the aggression that comes with dementia, for example? Yeah, this is one of the really cool things that we found as side effect profiles.
00:13:18
Speaker
So when when you're discovering molecules, you always have the good and the bad, right? And so you're always kind of looking for that. And the the current drugs that are out there obviously still have these either emotional issues or they have really detrimental side effects, which most people don't die from losing their memory. Most people die of all with Alzheimer's and dementia of all the physical attributes to it.
00:13:40
Speaker
not not drinking fluids and having toxin released to your brain, muscle deterioration, falling, not remembering where you're at to be able to eat and drink, all those physical attributes. And so when we were kind of going through classifying the molecule, we discovered that, wow, this thing really is interesting because now we're actually seeing
Systemic Effects of Alzheimer's Disease
00:13:58
Speaker
two different kind of drug interactions here. One one is, yeah, we improved the memory, but the other one is we actually improved the muscle mass, the fat tissue,
00:14:09
Speaker
uh the drinking ability and the we help prevent that weight loss and so we've done a whole series of experiments now just on the physical attributes um you know a lot of people call that cachexia or sarcopenia in in our world but in the real world that's you know i've lost a lot of weight my muscles deteriorating and that's really causing me physical issues where i can't get around and eat and drink like i normally would and that causes death eventually Right. yeah This aspect doesn't really get talked about very much. You know, we generally and right in the mainstream, we consider amyloid a memory disease. It's a lot more than that.
00:14:45
Speaker
I mean, just consider this. It's a lethal disease. So it kills you prematurely. You know, from the time you're diagnosed, you have about five and a half years to live. That rivals most advanced cancers.
00:14:57
Speaker
This isn't talked about enough. you know So Alzheimer's is a fatal disease. let's just you know Let's just underline that and put an exclamation point at the end of that. um okay so And you're not dying because you can't remember stuff, although that's part of it.
00:15:12
Speaker
The reason why Alzheimer's is is such a is such a bad systemic disease is because, um okay, number one, you don't eat anymore. okay so Advanced Alzheimer's, you don't eat anymore and you lose all your fat mass.
00:15:25
Speaker
So that makes you incredibly frail and you have no energy left in your body. So any little thing happens like an infection, you're much more susceptible to to passing on from that compared with somebody who is you know more robust.
00:15:37
Speaker
Okay, so that's one. You also don't drink water, which leads to, or you you know you don't drink water, so that leads to dehydration. And ah you know urinary tract infections, that's one of the leading causes of death in Alzheimer's disease.
00:15:50
Speaker
Infections, uterus. um and you yeah And you can trace the origin of those UTIs from the from the CNS downwards. You don't drink water. So your're your thirst sort of mechanism is kind of lost.
00:16:02
Speaker
So food intake is down, water intake is down, wreaking all kinds of havoc in your body. And then you lose your muscle mass. So basically, your muscles kind of shrink away. The technical term for that is sarcopenia.
00:16:14
Speaker
So you're basically skin and bones. And you have very little strength and you have very little endurance, which means you don't really move around. which means you get bed sores and pressure ulcers.
00:16:26
Speaker
And that that's another leading cause of death in in Alzheimer's disease is is infections from bed sores. It's a bad way to go. That's miserable. And probably the the most leading cause of, of you know, the topmost cause of death in Alzheimer's disease is pneumonia because another muscle that doesn't work well is the diaphragm.
00:16:46
Speaker
Yeah. you're not moving air out of your lungs and it just becomes ah this nidus of infection and pneumonia. So pneumonia is the number one cause of death in Alzheimer's disease. But underlying all these infections, which cause the death, yeah is this body basically not working anymore, shutting down. Muscles don't work. You have no endurance left. You don't drink water, so you get dehydrated. um You don't eat, so you've lost all your fat mass. And your fat is really where your energy is stored, so you don't have any and energy left in your body. That's why Alzheimer's is is a fatal disease. it's extremely debilitating. Right. And this this second aspect of Alzheimer's doesn't really get talked about very much.
00:17:24
Speaker
So no now imagine... You know, you you were talking about like one aspect of of Alzheimer's, which is aggression. Now imagine if there was a ah drug that one could invent for or discover for, you know, just the systemic effect, that alone would be enough.
00:17:40
Speaker
yeah It has no cognitive effect. It has no cognitive improvement. You don't recover memory. But now the patients are robust and they're not frail and they're not dying from all these infections anymore. That alone would be, you know, would be worthwhile.
00:17:55
Speaker
But what we have in our hands, and this is the central reason why we are so excited, is for the first time, I'll go out on a limb and say first time in the history of man, we have a drug that does both.
00:18:08
Speaker
Restores cognition all the way back to the baseline. So the different kinds of memory domains. So associative memory, which is how you remember your family members. Emotions. So that's another reason why Alzheimer's is such a bad disease. you You kind of forget who your family is. So that's associative memory.
00:18:24
Speaker
Then there's recognition memory, which is how you remember you know objects, novel or familiar objects, it doesn't matter, your recognition memory. And then there's a spatial memory, which is how you remember where where you are in space.
00:18:37
Speaker
We have a drug on our hands that brings all of these memories back to baseline in fairly advanced you know preclinical models of Alzheimer's, which was exciting enough in
Promise of Recall's Gene Therapy
00:18:47
Speaker
and of itself. And then in addition, we found that in those in those same mice, same advanced models of Alzheimer's,
00:18:54
Speaker
All of the physical attributes that make patients pass on from Alzheimer's and become you know but and and cause to the fatality yeah aspect of Alzheimer's, they all come back to normal as well. We're not talking about a little tiny reversal. It all came back to baseline, like health, like ah um a mouse without Alzheimer's, that level.
00:19:16
Speaker
So, That's why we're excited. I don't even to quite know where to go with that because it's just it's just not something you ever hear about a drug development. You hear about fixing one tiny piece of the problem. You never hear about restoring health, right? That's just not spoken about in our industry largely because but I think we think it's unattainable. it It feels too complex and too hard. It is interesting, though. I mean, but when we when we mentioned this to our KOLs, key opinion leaders, who happen to be two of the most probably prominent Alzheimer's disease researchers out there, they've done a lot of the studies recently for our two competitors. But when we showed them this data, they were pretty blown away with the memory component of it. But when we showed them the physical attributes that we were bringing back,
00:19:58
Speaker
they were kind of staggered by that. Like they had never seen that before either. So it was a really magic moment for us, you know, and they're super encouraging for us to continue on with RTX 100, which is the molecule that we have for for Alzheimer's disease and the associated physical attributes.
00:20:13
Speaker
And I wish we could just take credit for having thought of all this before, but you know, it's the way. I'll give you credit. just all that Does that count? we had at the beginning of the story was associative memory. And so we were like, hey, this alone is enough and let's go and start a company on that basis. So that's what we did. But the but the lab work continued.
00:20:34
Speaker
And yeah over the course of you know the last two years, we've kept on like, hey, it's not just associative memory. We can also recover recognition memory. Oh, hey, it's not just associative and recognition memory. We can also recover spatial memory. right And then to our our giant surprise, we could recover muscle you know muscle mass and strength and endurance, body weight and fluid balance. but Not all of these things were expected.
00:20:58
Speaker
some Some were expected because we kind of knew some of the biology beforehand. But most of it was unexpected. So we we are as surprised as as anyone would be.
00:21:09
Speaker
And I think that's also probably a pretty common story. One thing that is kind of true in biology is like, it's so complex. It's sort of like sort of like the universe. you You can't really see all the way out.
00:21:21
Speaker
And no one can. It's just too infinite. So, I mean, i guess what I'm saying is serendipity plays a huge role. in just, you know, in the in the basic discovery that happens. And then you run with with what you have.
00:21:33
Speaker
And that's kind of what we're doing here. Yeah. I would say persistence too, also, because Atul and I, we exchange email, text, we're on the phone all the time. And we're always searching for the what if question, you know, what if we did this experiment? What if we did that one? Atul's done such an ah amazing job with his laboratory and kind of findings and asking these really tough questions that really have benefited all of us, you know, as we've gone through this.
00:21:59
Speaker
Hang on. Did you just say this is all happening like the last two years? Did I hear that right? That's like, yeah you must have an army in your lab at all. Oh, no, no. but Like I mentioned, we we've been working on this for a while, but really the findings for Alzheimer's and the CNS aspects and physical attributes all within the last two to three years. Yeah. Wow.
00:22:21
Speaker
and We've been studying the body weight and the fluid balance and other things for a while. ah Okay. Like, like, the Alzheimer's part came together in the last two years. Yeah, and it's it's incredible. And I want to talk even more about the science because it's so interesting, the molecule.
00:22:38
Speaker
How, yeah let's start with the blood brain barrier. um How's the gene therapy cross the blood brain barrier? And, ah you know, what cells is it? What cells is it going to once it passes the blood brain barrier? Essentially, i try to break it down in real simple terms. So we use an existing protein that's in the body and the real magic to this is overexpressing it to meet that level of tau and amyloid in the brain.
00:23:08
Speaker
And so we found a really cool AAV vector and promoter that we work with. And so this is a simple IV infusion. So it's a one-time infusion for about 30 minutes can be done in outpatient.
00:23:20
Speaker
And the gene essentially goes into the liver and starts expressing this protein. The protein actually knows how to find the memory receptors in the brain and crosses blood-brain barrier naturally. We've been able to show that it existed there previously, just not at the levels that we needed. So that whole magic of finding the right promoter, the right gene, and the right protein to get it to the brain was the the magic to to get it across there to really attack the receptor level.
00:23:49
Speaker
Yeah, so that's basically it. um We're using nature. So nature has designed this protein ah to cross the blood. and It's doing it in all of us right now as we speak. So this protein is crossing our blood-brain barriers and knows how to do it because it was designed by nature to do it.
00:24:05
Speaker
So what we are doing is not really getting our drug into the brain because we don't need to. We are expressing this drug, the gene therapy, in the liver. And all we are doing is increasing the levels of this protein in the blood as a result of that.
00:24:18
Speaker
So that part is easy. That's not a problem, right? Getting across the blood-brain barrier for drugs. So small molecules, really, you have a problem with crossing the blood-brain barrier. Biologics, forget about it. It's it's really hard.
00:24:29
Speaker
In this case, we don't really, we're bypassing that entire problem because we don't have to get our drug into the into the CNS, into the brain. Our drug releases a protein whose levels go up in the blood, and then this protein knows how to cross the blood-brain barrier by itself.
00:24:44
Speaker
It's designed by nature to do so. And that's it. So that's how it works. So it sounds like this is sort of either replacement or overexpression of ah of a protein that that is normally expressed, but is it defective in some way in Alzheimer's patients?
00:25:02
Speaker
Yeah. So the protein itself is not defective. It works with its ah partner protein in the brain, which is defective in Alzheimer's. So amyloid sits on the partner protein, suppresses its activity,
00:25:16
Speaker
And when the protein that we are expressing with our gene therapy um can go in, knock every molecule of amyloid off this, let's call it protein A and protein B, okay? So we are expressing protein A whose levels go up in the blood. Its normal partner is protein B, which is sitting around in the brain, in the neurons, on top of the memory circuits, right? Various memory circuits.
00:25:38
Speaker
And amyloid is gumming up those works. So amyloid is gumming up the activity of protein B. And the whole idea here and the whole discovery is that by using, by increasing the levels of protein A a little bit, not even all that much, you know, just twofold or so, we can knock off the molecules of amyloid that are gumming off protein B. And protein A already knows how to cross the blood-brain barrier, so we don't have to do that ourselves with our drug.
00:26:06
Speaker
Is that clear? Yeah, absolutely. So tell me more about the mouse experiments. I mean, what preclinical data have you seen that's that's giving you confidence that you're seeing real memory recovery because it's so incredible?
00:26:21
Speaker
um You've been talking a lot about associative recognition, spatial memory. I mean, what's happening to these mice? Yeah. So we use very well-established models of Alzheimer's disease. um By the way, ah you know going back to the the origin of this conversation, these are the same models of Alzheimer's disease that were tested 20 years ago for the anti-amyloid ah drugs.
00:26:45
Speaker
And 20 years ago, so 2002, 2003 or so, they showed kind of middling efficacy, just like what we're seeing in humans right now, in in patients right now with those drugs. And 20 years ago, they showed Aurea.
00:26:59
Speaker
They showed the blood, you know, the the the the leaky blood vessels, brain swelling and bleeding. So these, and and obviously that's exactly what we're seeing in the patients. I guess where I'm going with this is these models are really good.
00:27:11
Speaker
one of the One of the sort of, ah I don't know if it's a misconception, but one of the prevailing attitudes in the field is, ah hey, you know, mice don't get Alzheimer's, patients do. So how do you know?
00:27:23
Speaker
How do you know that what you're finding in mice will actually translate to humans? Well, the answer is because there is historic precedent for it. Everything that we are seeing in humans with donanumab and lakenumab, the two two treatments that are on the market and approved right now, was seen 20 years ago in these exact same mouse models. These mouse models actually pretty good.
00:27:42
Speaker
Not only the do they they show the same kind of symptoms of human Alzheimer's, so they cannot remember various things, and we'll get into that in a second, um they also showed the side effect profile 20 years ago.
00:27:55
Speaker
Right. That's what I was saying. They laid the foundation for a lot of the work that we were able to do to kind of bring this to fruition really quickly, because a lot of that legwork was already done. And, you know, the magic of giving mice Alzheimer's disease is pretty easy because it's it's two models. You know, it's a 5x FAD model or NLGF model. both give amyloid and tau on steroids to mice or animals. So you really project that in a big way into those animals. And as Atul mentioned, it's really cool because you get to see the downside effects of any molecule that you're testing. So you can see, are we on the right track or not on the right track? Or or should we go in in a different direction really quickly, which helps the direct discovery discoveryy mechanism? Yeah. So we were like we were super sort of optimistic about using these mice because they've shown us already that they work.
00:28:42
Speaker
They translate to humans. Stuff that you find in these models translates to humans. So we start off with that baseline. So Atul and I were discussing these these mouse models and and what we got. And so when we got the first associative memory, which I described to you guys earlier, um where we fully restored the the memory in these mice, the tool was like, well, we should really challenge this and and use a different model and maybe a different lab. So we made a gene vector and sent it to an independent researcher in a different lab using his own mice, using their own experiments.
00:29:14
Speaker
And so we were we were waiting and waiting and kind of on the sea for the data to come back. And so I got the phone call from a tool and he's like, you won't believe it, exactly the same. So we were able to restore memory again in a different independent study in an independent lab.
00:29:29
Speaker
Yeah, so we have the 5XF80 model in our lab, um and this person, um who we sent the vector to, um the the drug to, has the NLGF model in their lab. We don't have that one, right? So two different models of Alzheimer's, slightly different genetics of how they cause Alzheimer's, but they both basically show the, you know, the the one is a little more um sort of virulent. It's a little faster and more aggressive. The other one is a little slower. Yeah.
00:29:55
Speaker
But nevertheless, both reflect Alzheimer's disease. They both show you know memory loss and and all the systemic features of Alzheimer's disease. ah One has amyloid only, the other one has amyloid and tau, but let's not get into the nitty-gritty of that, right?
00:30:08
Speaker
Both are very well-established models. So, So the first sort of hint that we were on onto something was, so we give these mice, the 5XF80 mice in our lab, ah this therapy, and we give it to them at six months of age, at which time they already have full-blown Alzheimer's.
00:30:26
Speaker
And the therapy takes about, um you know, every AAV is a little bit different, but this one takes about two months to express in a mouse, to fully express. Okay. So we measure the memory at nine months. So we give those mice 90 days after this one-time injection.
00:30:40
Speaker
and There were six months of age when they got it. At nine months, we're starting to assess memory. And to our surprise, associative memory. So how this assay works is it's ah it's a fear conditioning apparatus. So you basically give the mouse a little tiny electric shock. okay It's a little painful stimulus.
00:30:57
Speaker
um don't worry this is approved by the iacook this is a standard technique right we're not portraying mice in the lab or anything like that and you play a sound cue when you're doing it the next day or how much ever time later you come back and you just play the sound cue and you look for the mouse to freeze because it remembers that electric shock associated with the cue is that clear that's that's the memory here so You come back, you play the cue, and you're like, ah the mouse freezes to the same to the amount that a healthy mouse would freeze. and and
00:31:30
Speaker
And you're determining that, okay, this mouse remembers that cue. That's associative memory. And it's associative memory that you're testing because it's an emotional association. It's an emotional it's ah it's an association with fear.
00:31:42
Speaker
Fear of that little tiny pain, Right. Just stop me if but if I'm getting too jargony. and yeah Keep going. Okay, good. So there's gene therapy at six months.
00:31:54
Speaker
We tested this memory at nine months. And the mice, the Alzheimer's mice that could not remember that cue, when we came back and played that sound cue, could not remember to freeze, suddenly started freezing all the way back to like how they like healthy mice that do not have Alzheimer's.
00:32:11
Speaker
So that was 100% restoration of memory. And i I use the word restoration here because the mice already have full-blown Alzheimer's. They already cannot remember. So we we're taking you're not preventing memory loss.
00:32:23
Speaker
we're We're treating mice that already have memory loss, and we're taking them back in time to a profile of a healthy mouse. Yeah, that's I mean, that's obviously the the astounding part. That's incredible.
00:32:34
Speaker
So that's that's associative memory. um We tested recognition memory. So there's ah this apparatus where you know yeah you a mouse spends some time with a novel object. And they're curious creatures. So they they're mammals, right? So we all like novel things.
00:32:49
Speaker
So do mice. So they spend a lot of time with a novel object compared with a familiar object. that's That's healthy mice. That's healthy mouse behavior. And Alzheimer's mouse does not remember what's a novel object and what's a familiar object.
00:33:02
Speaker
It does not remember that one is a novel object. So it it spends basically an equal amount of time with both objects. um So that's an Alzheimer's mouse. So we found the same exactly the same thing as we found with associative memory, that when they got this gene therapy, they spent a lot more time with a novel object.
00:33:20
Speaker
And does the does the timing of recovery coincide? It was exactly the same as the associative memory part. Yeah. um And the same thing for spatial memory.
00:33:31
Speaker
So we are measuring, you know, if there's this various, you know, machines and apparatus. ah One is called ah a Barnes maze assay. Another one is a Morris water maze assay where mice have to find like a hidden chamber, not a hidden platform that is, you know, hidden under the water and they have to remember where it is.
00:33:49
Speaker
And Alzheimer's mice just keep swimming and can't remember where that platform is. ah Whereas once the same Alzheimer's mice have gotten this gene therapy, they can remember as well as the mice that don't have Alzheimer's to begin with.
00:34:01
Speaker
So that's restoration. um We sent over this this drug to ah this lab ah because we wanted independent corroboration of our results using a different experimenter.
00:34:12
Speaker
a novel environment, a different institution, and a different model of Alzheimer's than the 5XFAD that we had in our lab. So they had NLGF. And they found exactly the same things.
00:34:24
Speaker
They tested the mice, ah you know, or gave them the the the treatment at six months, tested the memory at nine months, same recovery. Okay, so that's kind of where we stand when it comes to memory assays.
00:34:37
Speaker
In both of these mice, the first thing we noticed was their body weight also came back. So we're like, in fact, that's kind of how we tracked that this this this treatment was working because one of the functions of this protein we kind of knew was was body weight, you know um but you know, modulation of body weight.
00:34:53
Speaker
So body weight came back in both of these mice, the these two models in two independent locations using two sets of experimenters, two different models of Alzheimer's disease. We're like, this has got to be right.
00:35:05
Speaker
At this point, it's it's not chance anymore, right? So we're starting to get more and more confident that we are onto something um and that this is reproducible, that you know others can take our drug and produce the same kind of effects or see the same kind of effects in a different model with Alzheimer's.
00:35:23
Speaker
And then we noticed, we did the thirst assay, their water intake came back to normal. So that is also reduced in both of these models, like all the way down in the gutter. These mice do not like to drink water the way healthy mice do.
00:35:37
Speaker
Same as as human Alzheimer's. uh their plasma you know mineral levels so plasma osmolality which is a way of measuring salt concentration of the plasma of the blood went back to normal um okay so that's the dehydration part then we were like okay if food intake comes back and body weight comes back does their fat mass also come back their amount of adipose tissue fat mass what stores energy it's all the way back to normal 100 recovery And then we're like, okay, let's just continue and measure all of ah all of the things that make Alzheimer's Alzheimer's. Because the only thing that was kind of left was ah was was muscle.
00:36:16
Speaker
So the first thing we did was um was measure muscle strength all the way back ah restored. Then we put the mice on a treadmill and measured their running ability to exhaustion, which is a standard assay. And that's how you measure the amount of endurance a mouse has.
00:36:33
Speaker
All the way recovered back to normal. So like, this is astounding. that That part was completely unexpected. We had never studied the muscle before. And then um the final thing that we did was was look at the amount of muscle, you know, the the girth of different muscle groups, the mass of different muscle groups, all the way back to normal also. So one of the scariest things I think you can search for on the internet is what does a brain look like when you have Alzheimer's disease? It's this like little shrunk up thing that's kind of scary, to be honest. like
00:37:03
Speaker
What about these brains? like Do they look normal? Do they look healthy? are they all like atrophied like those scary brain pictures on the internet? That's such an amazing question. And I'm glad you're doing the podcast now because I'll be able to answer your question. We'll be able to answer your question. Give us a another a month or so and we'll be able to answer your question. Come on. It's a really good question, though, because if you look at the muscle tissue or the adipose tissue or even some of these brains, you do see it's a very distinct...
00:37:34
Speaker
visual for someone who has the disease versus a normal healthy person. And you know the i think one of the most miraculous things is that this this particular drug, RTX 100, has been able to bring back not only that associative memory and the other memories, but that physical attribute is just huge. And Atul mentioned UTIs, and this is a bit of a passion project for me as well because my mom passed away of Alzheimer's disease. And one thing that she got all the time was UTIs.
00:38:03
Speaker
And so when we saw this thirst profile come back and the ability to potentially eliminate UTI infections, that's just huge. Yeah. Let's let's follow that thread for a second. So...
00:38:15
Speaker
I'm imagining, and I haven't personally dealt with a loved one with Alzheimer's disease, but the cost of caring for that person and is horrendous. I can only imagine the cost to the family, the healthcare system, everyone involved. And then if you add in the cost of the drugs that aren't very effective, I mean, it's not very appealing or attractive, right? So tell me a little more about what what is this going to do for like I don't want to just say saving money, but like saving people's time and energy and just improving the lives of everyone involved.
Cost-Effective Solutions for Alzheimer's Care
00:38:51
Speaker
No, it's a good part of the story actually, because a lot of people associate gene therapies, very expensive, ultra-radivision. And in our case, it's just not that way. We're using a very well-known AV vector. um We know the molecule itself is pretty safe and effective. And so...
00:39:10
Speaker
when you take those combinations into effect we can actually deliver this drug at a very nominal rate so existing therapies run 30 to 35 000 just for the drug for a year you have to go in and get infused either once a month or once every two weeks for that you also have to have mr mri pet scans physical testing transportation which aren't included in that so the total cost is well into the 150 ish thousand dollars per patient per year when you take all the ancillaries.
00:39:40
Speaker
So some of that is covered under medical, but the care with the home care, ah yeah being nursing in homes, memory care, yeah mostly out of pocket. And that's about a $233 billion dollars number that everybody in the U.S. who's associated with the 7 million people who are affected with this disease help cover. And I can share in my personal story. You know, my dad is actually in a memory care unit now. And he's, you know, that's a huge burden on us. It's well over $7,000 a month just to have him in the facility. So the burden is real. We're going to try and deliver this drug in that $100,000 to $150,000 range. So, but the magic to us is it's a one-time treatment.
00:40:24
Speaker
You don't have to go for all of the the follow-on testing like you do with the current drugs, the $150,000 that you're going to spend out of pocket. Now, if you're on these existing therapies, you're going to spend that every single year versus a one-time treatment that takes 30 minutes in an outpatient setting.
00:40:40
Speaker
I mean, who wouldn't choose that, right? Well, if I could get five years of memory back, that would be sign-me-up. I mean, i I just think about like... I can't imagine like forgetting who my children are and how distressing that would be for them. Like that's where my brain goes because I've got three kids, right? So i go like I would rather, that I would do anything to preserve them from experiencing that. and And I guess actually, you know what, I did have a grandparent that went through this and it was really heartbreaking to have them forget who you were. And yeah, I mean, there's just so many like costs that you can't put a number on. Let's put it that way.
00:41:18
Speaker
Yeah, exactly. And so, you know, the average person with Alzheimer's is 65 to 70 years old. They have a five-year life expectancy. And it's it's excruciating if you've ever been through it. You know, i i I have to go through this all the time with my father now. And when you're in a nursing home or you're in a dementia care facility, a memory care facility, you just they just lose themselves. And you just have to continue to remind yourself they're not the same person.
00:41:42
Speaker
And you know unfortunately, that's just the the current state of therapies that we have today. And they virtually just don't work. And so when we found this magic, I think it was really good for us. But it really started us thinking about the whole aging process in general, because not only as RTX 100,
00:41:58
Speaker
really good for bringing back that memory aspect of it, but the physical attributes of your life. And that really is the aging process. And if we can slow that down and give someone five years back or six years back um with longevity to increase their lifespan with full memory or, you know, much better memory, I think that's something that people will be interested in.
00:42:20
Speaker
This last part is actually, you know, just to get away from the economics of the issue for a second. um People die from normal aging, with kind of the same profile. you know Aging associated dementia is one thing, but aging associated cachexia and sarcopenia is is is another thing. So you get the same profile. you know Patients become frail.
00:42:43
Speaker
and they they're ah They become extremely thin. They lose their fat mass. Their muscles shrink away to nothing. They don't have strength and they don't have endurance.
00:42:53
Speaker
And what do what do old people get, you know, um the elderly get ah that leads to mortality? Pneumonias, UTIs, bed sores, the exact same things that we are talking about with Alzheimer's. It's just happening earlier in Alzheimer's, you know, compared pneumonia.
00:43:12
Speaker
And I'm not, you know, I'm not really conflating the two issues. One is a neuro one is ah a CNS disease. The other one is know, but there are similarities, I guess is what I'm saying, between aging, normal aging and Alzheimer's disease. So it hasn't really escaped our attention that we may be onto something.
00:43:31
Speaker
If all this pans out and we get into the clinic and we get approved for Alzheimer's disease, maybe this is something that we can use in the elderly to make more. I don't know if people will live longer as a result of this treatment. We don't know the answer to that because we haven't done the experiment yet.
00:43:47
Speaker
But what we do know and have good confidence for is that perhaps we can increase their health span.
Broader Implications of Recall's Therapy
00:43:55
Speaker
Even if we can increase longevity, which we don't know yet, maybe we can, but we don't know that yet.
00:44:01
Speaker
But we can we feel optimistic and based on on the data that we have, that we can increase the amount of healthy healthy life. that is is currently not there with all the chronic diseases um and normal aging.
00:44:15
Speaker
So we're kind of excited about that part too. um I wouldn't say that's second fiddle to Alzheimer's because it's it's a it would be massive. But I think you're seeing that the entry for our drug is likely to go through a disease like Alzheimer's and then um and then perhaps we can tackle aging as well and health spam and aging.
00:44:35
Speaker
Yeah, our our two KOLs were really excited about the physical attributes of this just for that aging benefit where they said, you know, listen, I would give this to half my patients that walk in the door that don't even have dementia or Alzheimer's yet, that losing that body mass and that weight. And so I i think there are a lot of health implications to 100 and its ability to really solve some of these problems. So I'm i'm i'm curious about other neurodegenerative diseases that have abnormal protein deposits associated with them, um like amyloid plaques. or
00:45:09
Speaker
do Do you see this discovery moving into um and to those diseases at any point? You know, why not? um Cautiously optimistic of that too. If amyloid is the causative factor for any disease, based on the mechanism that we've discovered,
00:45:27
Speaker
that it's knocking amyloid off the memory circuits of protein B. It should be applicable there. We just haven't done the testing yet. So we really don't want to go out on the limb and say that it will work there because we don't know.
00:45:38
Speaker
But... heck I mean, it's it's a great place for us to to do some testing and figure it out. But Alzheimer's itself is such a a formidable challenge that we really want to dot our I's and cross our T's and do all the testing. There's a lot of work to do there, no doubt. yeah yeah In tennis, I like to say one ball at a time. one time at a time It just gets so exciting, though.
00:46:03
Speaker
Definitely. And speaking of exciting, my first obvious thought is, so Wednesday's going to go
Future Steps: Trials and Partnerships
00:46:10
Speaker
into the clinic. tell Tell us about the milestones that are coming. Yeah, so we're working currently with an NHP laboratory in South Florida ah to do our and NHP model experiment. So an NHP experiment is a non-human primate, which you do before you get what's called an IND, an investigational new drug. application with the FDA, which then allows you to go into humans. So we're kind of at that last step now. um We've done our small animal studies and now we need to do our bigger animal study for safety reasons. And so once we pass this negotiation portion of it,
00:46:43
Speaker
I think we'll move directly into that NHPE study, which should be pretty quick. So we're anticipating sometime towards the end of next year to be finished with this animal, this last animal study, and then file our IND.
00:46:55
Speaker
So sometime towards the end of next year. And then we'll be in humans right away. Um, So, ah you know, phase one slash two, we we have got some innovative ideas on that as well in collaboration with our KOLs. We kind of want to do a, you know, phase one study, which is typically done in healthy people because it's a study.
00:47:13
Speaker
We want to do it in a small, so you know, small cohort of Alzheimer's patients. yeah Yes. not only a cell Not only assess safety, but see if we can pick up a little, you know, tiny bit of but efficacy signature, things like body weight, you know, yeah things like Because if that happens, then we are like, you know, everything is about confidence. And at that point, we're like a little more confident than we were, you know, before we received that data.
00:47:39
Speaker
That's kind of what it's it's interesting because i mean, I'm familiar with the phase one, two pathway for like rare disease for sure. I'm interested to hear how the agencies view that approach for something that is so common and not a rare disease. I hope that it's viewed positively and that you're able to do that because I think the faster that this can get into market if it actually works is, I mean, it's critical, right? That's how I see this.
00:48:04
Speaker
Yeah. We're, we're working with one of the leading folks out of FDA, the CEDAR division and biologics that actually she's, she's been involved in like the last five to six gene and cell therapy approvals at the agency. So she's really helped us and guide us to a real clear path for an approval process.
00:48:24
Speaker
And i think that's really invaluable to us to have that kind of feedback from somebody who worked at the agency approving these drugs to kind of help us through that. And our opinion leaders have also done a really good job of saying, you know, maybe you do six patients where you do a rolling study and they prove their safety out over the first six months. And then you um yeah enroll mild patients or early stage patients that are normally healthy, not on previous drugs. And then you can really see what happens because being a gene therapy, you don't really get a placebo effect.
00:48:52
Speaker
Yeah. So you're going to see it work or not work right away. oh, you just made me think of something else. So kind of in one thing that we often hear from clients that we work with is that they they kind of almost fear talking to the FDA. And so the fact that you have been so strongly engaged with someone in order to plan out your regulatory pathway, like, i mean, that's really smart. Like, tell me more about why you chose that approach and what to tell everyone else why they should do it too.
00:49:26
Speaker
I think a lot of people actually in drug discovery make the mistake of waiting too long. and Yeah, exactly. And they're all animal models and they're doing all these tests and then they fix their IND application to send it in only to get one hundred or a thousand questions. And what we found is if you have these pre-IND meetings and you meet with regulatory experts in the field who have already gone through these approval process paths, you can really advance your study. I'm i'm going to quote you on that, Dan. That's going to be all over my LinkedIn channel tomorrow. Yeah.
00:49:57
Speaker
All right, so you've obviously taken multi-billion dollar exits before. do you see that as the vision here for recall or is it you're going to take it all the way or you or you don't know yet?
00:50:10
Speaker
i I think Atul and I are really kicking that around in the background. I don't think there's a clear right or wrong answer here. There are advantages to working with large pharma companies with resources, talent pools, et cetera. We have a very talented team here and could take it all the way with you know maybe a co-partnership or a licensing deal. So I think there are a lot of ways to kind of think about how you exit companies.
00:50:36
Speaker
And obviously Atul and I have done a couple together already. So we're we're not preconditioned in any kind of box. And so, you know, next year, once we get out with all of our data, which we should finish up quite a bit of it towards the end of this year,
00:50:50
Speaker
I think we'll look out there and just start kicking tires to see, you know, maybe who could help us advance this quicker or maybe who may maybe be able to take it on and do it much faster than we can. But the the ultimate goal is to cure patients and improve patient lives. So, you know, whatever the best way we can do that and accomplish that, I think is what we'll do.
00:51:09
Speaker
Exactly. Yeah. Lots of moving pieces to have a definitive answer on that. Yeah, of course. That there is a strategic out there with lots and lots of gene therapy expertise, but not really much of a presence in in the CNS space or in the Alzheimer's.
00:51:23
Speaker
They might make a good partner versus somebody who doesn't have all that much gene therapy experience, but is a leader in in the you know Alzheimer's space. So I guess we'll will probe in all different directions um and try and make a pragmatic choice, a smart choice, with the goal being at the forefront. The goal is... ah How do we get our therapy onto the market ah in the quickest possible fashion?
Redefining Aging and Longevity
00:51:47
Speaker
So for my final question, I want to land on kind of a philosophical note. if If we think about a world where this therapy succeeds and people are able to regain lost memories and and maintain their health, to both of you, what does that change about the way we think of aging itself?
00:52:06
Speaker
That's such a juicy question. Yeah. This is a very good question. There's just so many wealthy people out there who, you know, after they've attained a certain threshold of wealth or success, become really interested longevity. yeah Yes. We can probably rile them off, ah you know. um But longevity is something that has not been cracked.
00:52:31
Speaker
It has, you know, it's it's in it's as white space as it comes, basically. Yeah. We're not thinking of it as a disease, but you know we have been a finite lifespan. And people have adapted over time to thinking about longevity as, hey, maybe we don't need to extend lifespan per se, even though people would like to live longer. ah ah Maybe we just need to make people healthier so that the last five or 10 years of your life, you're not spent you know you're not in palliative care at the end with no muscle and no adeptus tissue and you know suffering all these infections.
00:53:01
Speaker
oh maybe Maybe that future is possible. And just like, you know, with the with the obesity market, just like we, until the GLP-1 receptor agonist came along and we had, you know, nothing that was working for obesity, sometimes things just happen very suddenly.
00:53:15
Speaker
ah Something comes along. Yeah, you've got all this pessimism because for the last 100 years, nothing has worked. And Alzheimer's is, that's where Alzheimer's is right now. But something comes along and it just works.
00:53:28
Speaker
And maybe the reason for that is serendipity or luck and probably a lot of it. well I think the same thing, I can envision the same thing happening for aging, that at some point we just find something that works.
00:53:40
Speaker
And yeah I don't know what kind of world it'll lead to. You know, those questions are above our pay grade, frankly. But but maybe people will live the same amount of time as they live now and the the median lifespans won't change. But people will go out, you know, kind of suddenly at the end, which is like in their sleep or something, instead of having these chronic diseases and lots and lots of infections at the end.
00:54:02
Speaker
yeah I just know speaking for myself, you know, I'd rather not have the knee pain and the ankle pain and the back pain. So anything that helps promote a healthy aging process as you, as you go through life would be great. And you know, that, that pain and suffering, if we can eliminate that and we can bring back memories for families, that's what it's all about at the end of the story.
00:54:21
Speaker
Yeah. yeah I really like that. Well, thanks to both of you for, for joining the podcast today. It's been a real pleasure. Yes. Thank you guys.
Closing Remarks and Future Innovations
00:54:29
Speaker
Thank you. Well, thanks again to our listeners for joining Sparktime. We welcome you to join next time as we continue to explore the ideas, the thinkers and the innovations that drive biotech forward.
00:54:40
Speaker
We hope to see you there.