Episode Transcript
[00:00:00] Speaker A: It's everything I thought it would be. But you have to love, you know, ambiguity and problem solving and all these other kind of really cool, interesting theories and dealing with risk and stuff like that.
[00:00:24] Speaker B: Well, Matt, uh, thank you so much for taking the time to have this conversation. I really appreciate it.
[00:00:29] Speaker A: Sure. Happy to be here. Brandon.
[00:00:31] Speaker B: Yeah. For the audience. Matt is the chief medical officer of a yet undisclosed new 3rd Rock Ventures company. He was also previously the Senior VP of Global Clinical Development over at Sarah Val, famously recent acquired, recently acquired by ABVN.
Had a. A recent hit in Parkinson's as well. So excited today to jump into everything neuroscience and the kind of future of the space.
[00:00:56] Speaker A: Me too.
[00:00:58] Speaker B: Well, Matt, maybe just for me, if you could give me a thumbnail sketch.
[00:01:02] Speaker A: Of your career and how you kind.
[00:01:03] Speaker B: Of ended up doing the work that you do.
[00:01:06] Speaker A: Sure, yeah, absolutely. So I, I pretty much been an industry guy for most of my career. I didn't spend a lot of time in clinical, so I went to med school at Penn UPenn.
Also got a business degree in Philadelphia while I was there, and then was just focusing in pathology and was going to practice, going to be a practicing pathologist and just realized kind of what that life was going to be and just realized I. There was other things I wanted to do. And so I kind of really went right to industry and started out. And since then it's been 17, 18 years since I made that jump. My wife as well, she's also does the same thing I do. She does the clinical development in the oncology space. So we kind of made the jump at the same time. She's also a physician.
Um, yeah. And so it started out the. And I'd been all over the place. I started in derm, got a couple of drugs approved in the dermatology space and that's how I got exposed to kind of immuno. Then I kind of jumped over immuno. Neuro was part of some of the drug development and the approvals in the Ms. Space at Novartis.
I worked on some of their stuff. And then I was. Prior to Cerebell I was at Otsuka and that was really where I got more into Neuropsych and then the neuro side. And that's where I met Ray Sanchez who was at the time, he was the head of the development there. So I was working for him and working across our portfolio, Rick Salty and some of the, some of the newer stuff that's getting approved we worked on before we left. And then Ray went to Saraval, was tapped to lead Saraval, which was the formation of basically Pfizer's Neuro psych pipeline, their Neuro pipeline and a bunch of the industrial financing. So Ray took over CMO asked to ask me he would know, found a way to work together again and to, to come over and, and join him and lead development there. Um, so that was the last five years and a lot of hard work in terms of Parkinson's, space epilepsy, obviously schizophrenia.
Had a bit of a letdown recently in the schizophrenia side with the, with the asset and we can certainly talk about that more and kind of the implications of that. Um, but yeah, we, we were acquired by AVI recently for all those assets and from that I, I took on a new role as you said, as a, as a chief medical officer now myself and kind of going to have the chance to company bringing my own team and stuff. So hopefully that'll be, it'll be disclosed soon maybe hopefully in the new year and stuff like. But I'm, I'm obviously really excited about it but yeah, happy to, to dig in and talk about Neuro and all the happenings of the last couple years, the last couple of months and, and see where it takes us.
[00:03:32] Speaker B: Yeah, absolutely. And just before we dive into Dineura, what's it like at the dinner table? Or are your wife and are you and your wife just talking about clinical development over, over dinner?
[00:03:43] Speaker A: Yeah, and it's, it's like this competition of like I got this approval. I'm doing this well now I'm the chief medical. Well, I'm a chief medical, I'm the head of development and I'm head. But it's, it's been great. She started out in drug safety and just kind of evolved into the oncology space and she's, she's gotten, she's pretty well known. She's got a fair amount of drugs approved as well and she's working at a really nice place also here in Boston. So it's, we keep you out of each other's spaces so it's not like we're not competing and we're not going to the same conferences and stuff like that. But it's nice as somebody who knows drug safety stuff from like hey Mal, if I have a patient that like this is what would you do this kind of stuff and the same thing for us with Neuro. So it's been, it's been a nice collaboration but yeah, it gets a little competitive sometimes. Yeah.
[00:04:24] Speaker B: Well, I know you have kids so maybe they steer into, into the industry or maybe they stay, stay very widely away from it.
[00:04:32] Speaker A: I, I mean, there's different ways to go, definitely ways to, to go in the industry. I mean, getting that MD is med school is brutal and so is residents and stuff. And med medical practice right now is challenging. But that's why I think you see this third pathway, like, so when we did it, it wasn't that common. It was this sort of unspoken third pathway still. But now, you know, there's guys going and getting MDs and, and MBAs and stuff and just going right to McKinsey and going right into the venture side and things like that. And so it's coming much more commonly because it's, it's really a third career trajectory now, which, when, when we did it in, you know, in, you know, the early 2000s, it was still a little, it wasn't the thing they talk about it like in med school and stuff, but here's another trajectory you can go on. But it's, it's absolutely a great career choice for.
You have to break the mode. And my wife and I were the same way, where it's like, you have to like, ambiguity and you have to like, uncertainty and that, like, as physicians, you're trained not to do that. You're trying to, like, put things in a box and classify them. And because you're trying to eliminate medical errors. And obviously people's lives are at stake.
And in the drug development space, we get to work with patients, you know, at more of a distance, but at a larger sort of proportion. But it is much more ambiguous. Things aren't going to work and you always have to be ready to pivot. And every day is slightly different. And so you're, you're, you're trying to innovate and do things differently, which is not necessarily in medicine. There are ways that they're trying to do it, but you also, like your day to day, is trying to keep things in a very circumspect way, controlled.
And so that uncertainty doesn't sort of sit well sometimes with a physician's mode. And so some physicians hate industry and leave because of that. And then some of us love and flourish in it and it just happens to be the thing we like doing.
[00:06:08] Speaker B: So, yeah, you know, this isn't a career podcast, but maybe I'm too curious to ask, like, if, if somebody is a training physician and has an inkling that maybe there's something they can try, like what, what advice do you have for them? And how, how could they think about de.
[00:06:23] Speaker A: Risking it maybe? And Considering it?
Yeah, I mean I think it's you know, if you're in medicine and you, it depends on what your, what your flavor is. It, it like what is what's driving you. If you really like the patient interaction and you really like sort of that day to day sort of engagement with people and the patients and stuff and that's, and that drives a lot of folks to medicine, then you know, it may not be a great career choice because it, it's, it is more far removed and it's more of that sort of larger, the larger doing good at a larger level that you're going to sort of create drugs for unmet needs and, and to help people.
And it does, it is a business, it is a for profit industry and it's all those things that you have to realize that it's not just a scientific experiment that you have to, you have all different stakeholders that are involved that, that aren't involved when you're talking about just patient care. So I mean if you have those instincts that it's, you know, you want to make these sort of larger contributions, you really want to make a dent from a scientific perspective and sort of have large impacts which I think even in academic medicine is very hard to do on a large scale.
And you enjoy sort of changing dynamics and different competing, you know, stakeholders and commercial interest and other things like that that you're sort of balancing all these things and walking a tightrope and, and it's a strategy game as well. It's a, if you like that kind of mindset of so a little bit of game theory and a little bit other things about how you engage with health authorities and how you de risk programs and stuff, always keep it in the back of your mind. And I think the easy way for if you're sort of, if you know that that's what you want to do then I would say don't waste time and just go do it. Find a, find a way in. And there's all different kinds of training programs and they're. They're looking for clinicians are, are always welcome into the industry even, even ones with limited experience. If you're kind of straddling on. I'm not sure if I want to do that. The easy way is, is that I think we see a lot of physicians come from it is get involved in the clin even when you're a resident and or early on in your career and really sort of engage on that and you can really get a feel for what it's like and Running trials and being a part of it and designing in the things that happen. And if you really feel like this is what it will always, you always have that out. Then if you say like, hey, I'm a lot of the clinicians that come to. Come to institute burnt from the grind of the business side of just running sort of the mill of clinical practice and stuff. So um, that would be like my basic career thing is. Is if. If you know in your head like you're not. I look, I was going to be a pathologist. I didn't need the patient contact. I was not. That was not high on my list. I love more of the, the science and the strategy and this seemed like a great way to be able to kind of do that. The big explore the business side as, as well. And it's everything I, I thought it would be. But you have to love, you know, ambiguity and problem solving and all these other kind of really cool, interesting theories and dealing with risk and stuff like that. And if it's feels right to you, start early, you know, get like, get involved even when you're a resident, like with a, with a drug company, do internships and stuff like that with, with drug codes about how do you do clinical development? How do you think about, you know, clinical regulatory strategy and stuff like that and get some exposure early on. Those weren't really options when I was coming up. They really want those opportunities, but there's many more. So now just because I think it is a career pathway for physicians that's very clear.
Even getting in on things like the venture side and the investment side of that, there's more opportunities and just take advantage and explore it, you know.
[00:09:35] Speaker B: Yeah, absolutely. And maybe this is the right jumping off point.
I'd love to hear just like as you think about kind of the clinical development landscape specifically in neuro, maybe paint.
[00:09:47] Speaker A: Us a picture of like how you.
[00:09:48] Speaker B: Think about that landscape today. And then I'd love to kind of jump into what excites you the most.
[00:09:53] Speaker A: Sure.
I mean neuro's always been. And it sounds like a broken record, but like neuro is one of the hardest things to do in terms of drug development in my. And I've done it across the experiment. Maybe going back to the comparison with my wife. Like, I'm not gonna say oncology is easy, but from a true like risk and endpoint perspective, it's. It's very circumspect in how they. And the risks that they deal with and kind of the endpoints that they're dealing with. And, and. And challenges. Neuro is really hard just because, again, it's so subjective. You're talking about how people feel and how they feel kind of on a day. There's not these really good objective measures of a lot of these things, especially in neuropsych, when you're talking about, you know, a clinician's interpretation of what a patient is thinking or how they're acting and stuff, it's just all these things that are subject to variability.
So I think that breeds a certain type of, you know, uncertainty and a certain type of trepidation in terms of, you know, trial failure, the ability for trials to fail and even good drugs kind of failing because, you know, trials aren't executed right or just because of the, the nature of the beast and the variants. And I think it's. That's not as the. That's not as the. That's not the case. And maybe some other therapeutic indications wherein the endpoints and the execution is easier or it's. It. There's just. They don't have to deal with so many uncertainties and unknowns. Um, so I think because of that, there's always this kind of skepticism in neuro about, like, how hard it is to get drugs approved. And it is. And you can look across like it's one of the highest failure rates of all the therapeutic areas. And so it's not for the, for the faint of heart.
And then it's also one of these things because of the subjectiveness of our end points. Placebo response is such an issue for us in terms of these measures and collapsing trials. And we just kind of dealt with that with, you know, the. What happened with imraclitine and some of the other schizophrenia programs. But, you know, major depressive disorder, it's across the board. It's just. It was wake, like incrementally every year. It's getting harder and harder to do these, execute these studies with good data to just to separate from placebo. Because 25 years ago there weren't all these trials that were ongoing. And so it was these. Whether you say the patient populations were fresher or they were cleaner or whatever, whether we've just saturated them or we've recycled too many patients or whatever it is, but like, year over year, it just keeps getting worse. And like, you can look at all the metadata that shows a trajectory of just placebo response and variability and stuff is just getting harder and harder to show drug effects in an experimental design. I mean, it's what drug trials are, an experiment, it's A hypothesis test and it's a controlled environment. And you're trying to show, you know, remove all the, as much of the variables as you can and show that, you know, the drug actually objectively is safe and it's, and it's efficacious and that just keeps getting harder.
And I think the, the degree of difficulty because of just the nature of the beast and competition and how many trials are out there and, and all that kind of stuff.
We're not keeping pace probably with that, with our measures and like, the sensitivity of the measures we're using or the, or the types of measures we can use to get at these endpoints or how we're conducting the trials and accessing different newer patient populations and stuff, and not recycling things and stuff like that. I don't know that we're keeping pace, but I think that's what we have to do. From my perspective, like, the landscape is really, I think it's struggling right now. Like, we sort of had this renaissance in Neuro because we had a couple of big wins and it's always like the right. The pendulum always swings and like then. But that was coming off of like this huge downswing because of all the failures of the beta amyloid drugs. But now one or two of them have kind of worked and now some of the neuropsych stuff hits. But now you see, like, you take a big hit, like, you see you crash back to reality. The Synovian program, the TAR ones, collapsed and then now everybody was into the Muscarinics and now it's like, now they're questioning, yes, bms, Karuna is getting approved, but you know, look, drugs can fail and it brings you back to reality and then it reminds you that these, these are not slam dogs. Just because you have a great molecule does not mean you can get a great outcome.
And I think that's just on all of us that are in the business and in the industry to like, keep reminding ourselves and looking at that, like, you can't get stagnant with sort of innovating in how you're going to conduct trials, how you're going to explore trials and whatever, and you're fighting kind of against that regulatory upswing of what the FDA wants and balancing all these things. So I think it's an evolving landscape. I've been pleased with what we've seen come along in Neuron. I think it'll keep going despite some of the recent hits. But I mean, a couple more failures and then you'll see investors pull back and I think it'll, but like everything else, I think it's cyclical. Um, and we just have to be mindful of and respect sort of the, the drug gods, as I, as it were, as I. We kind of call them the drug gods can be cruel and they will, you know, they, they. You have to remember, you have to have a lot of humility when you're doing this and you have to have a lot of respect for that and, and be very, very cognizant of how you design trials and, and knowing, you know.
Know what you don't know.
Yeah. So, but I think it's, it's certainly encouraging. Again, some of the bigger wins with the bigger investments. I think you're going to see some of that stuff on the neuro side and then on the, on the psychiatric side.
I don't think in, in interest is waning. I think those people are going to keep trying to figure out more stuff. So it's certainly like picking up. But I'm, I'm hopeful that we see a couple of more wins before we see a couple of big, big hits. That it keeps that momentum building. Because I think it's sort of in a tenuous spy right now.
Yeah.
[00:15:24] Speaker B: Oh, you, you, you've painted like a, an interesting landscape as to the challenges in development. Everything from the subjectivity of the scoring to the potential like over saturated, kind of like, like patient landscape.
What, what do you think we should be doing differently in the, in the face of this landscape? Like it's kind of the game on the board now.
[00:15:45] Speaker A: Right.
[00:15:45] Speaker B: So what will he be done about that?
[00:15:49] Speaker A: It's a great qu. I mean it's a great question. Cause it's like if I knew the answer, like I'd, I'd be doing it. Yeah, I'd be doing it. And we would also solve. I mean, I think we saw again and I don't pull punches on this stuff. Like I think you saw, like, there's a lot of, like a lot of consolidation the last few years. A lot of consolidation. Like the, the typical sites that we would use for trials and things like that. Like you're seeing large conglomerates buying up these, these site networks and so you're seeing this sort of rise of large site networks, which is great. I mean it's, it's a thing because it's again, inpatient trials and these things are profitable. Um, but like then you start seeing quality decline and things like that. So I think we just have to start rethinking a little bit about how we're Approaching sort of operationalizing these trials when we need sort of these large patient sample sizes. And I mean that's such a loaded question. You can get into so many different things. Like it means, well, if we're going to, you know, start doing different things outside of these sites or we're going to try to sort of crowdsource trials or any of the kind of the things you think are possible, we have to figure out ways we can control variants and endpoints and stuff. So there's always a cost to something. But I think, I think it starts with continuing to sort of engage with the regulators who say like we want to push on some newer endpoints and some new sensitive measures and we have to get away from sort of the old mindset of like what constitutes a valuable endpoint. It's kind of like dichotomous with the agency wants endpoints that are really patient relevant patient centric drug development, which I totally agree with. But that's completely sort of detached from this notion of all the new advancements in biometric measures and wearables and more objective things and thinking about can your heart rate and your walking pattern, all the things predict your mood or your, you want things that patients say, I feel this, I feel better, it's doing better. And then. But those are the things that are probably the most erratic in the sense of like as a measure that you're trying to study and sort of all over the place and sort of. Because it is, it's, it's so the more subjective you get about how do you feel?
You know, the more, the harder it gets to get like a real signal that a drug works and things like that. So I think we're, we're struggling with that. But I think if we can find alignment there and start there around like let's evolve some new measures that are, you know, that can remove some of this variance that we see that can make them more sensitive but still show us things that are, or at least correlate them to things that are compelling for patients and that are really addressing unmet needs in patients. Like that's the first step because I think there's a lot of like good drugs that we don't have or you just because they die, you never hear about them because they die in sort of the early phases because they can't generate a signal. And it may not be that the drug or the mechanism doesn't work, but, but maybe it's a two week and you could improve on it, but they just never see the light of Day because we don't have the right tools to maybe look at them in the right way. Um, so I think that's gotta be sort of the push for, you know, the industry to keep. To keep working on. And it's hard because a lot of these things take time and they take a lot of patience and they take, you know, lots of different types of studies. But, you know, you. You try a drug out and it doesn't work out, then it's on to the next one, and you have to work on something that's gonna generate interest and value and stuff. There's not a lot of room or time to explore things that aren't working.
[00:19:10] Speaker B: So let me, Let me be difficult, right? Like, whose job is it to develop these measures?
[00:19:17] Speaker A: Well, I mean, this is. It's, it's. It's. You would say it's this.
The sponsors, it. It should be in my purview that we should do that because it will help me develop better drugs. And if I can develop these measures from a proprietary standpoint, it gives me a competitive advantage over my competitors in terms of how I'm going to look at drugs and things like that. But the time and the effort it takes to develop new measures is much harder. And the risk of, like, developing something new and having that working than just going back to what works, what's been used for approval. And again, to the point, you know, like using schizophrenia as a model. And so like that. The PAN scale has been used for now, decades as an endpoint. And not that it's a bad endpoint, it works. And it's been. It's a great measure, but, like, it's got a lot of issues with it, but it's just, it's accepted and it's just like, so if it's almost like, if it ain't broke, don't fix it. So as a, you know, as a drug developer, and I have an asset, and I'm being pushed to develop something fast and. And, you know, make it. Make, you know, get it as efficiently as I can to. To patients. You know, the extra time it takes to, like, just go off the reservation to develop a new measure and all these kinds of things. I'm not incentivized to do that. I'm incentivized to kind of use what works already and sort of be as efficient and not break the mold. But then in doing that, you know, if my drug fails on the pans, was it. Is it cause of the drug or is it because that's showing the flaws in Son of some of these measures. And this is the, the catch 22 is we're not incentivized to go off the reservation when we don't have to. The only time you really get pushed to do it is when you're breaking new ground in a new indication or a new thing where there is no precedent and there is nothing new. So you're forced to do it. And that's where you see some of the, like the most innovation.
But the thing where there's always a ground, there's always everything. Case law already laid down, as it were.
It's very hard to sort of convince, you know, a board or a bunch of others like, yeah, this is all very standard and these guys are doing it fast. But I'm just going to go off and do this at, at the point of time that usually when you figure out that you should have done that, it's too late.
[00:21:18] Speaker B: Too late, too late.
[00:21:19] Speaker A: You know, we should, we could have tried a different measure. We could have tried something different and pushed it to give ourselves a better chance of success. And we didn't.
So a lot of it, a lot of ends, a lot of it ends up happening in academia as opposed to industry. And then you kind of, you have the sponsors kind of pirating what's there and then kind of now maybe modifying it and changing and stuff. But there's not a ton I'd say on that because again, just because of the time it takes and it's just not as congruent with sort of moving efficiently and evaluating a drug and use the tools that you kind of have and try to use the measures you have to mitigate. I mean that's where a lot of the industry has come come from, trying to mitigate placebo response and things like that. It's less about finding new measures, but it's about more like how can we mitigate radar variants and how can we do these things, which is true. And how can we limit placebo response?
And some ways we've been effective there and in other place we aren't, you know, and there's still a lot of limitations and stuff, but that's sort of like developing new tools and new measures.
It's, it's really more ends up being the province of academia or sort of these consortia, you know, spot, you know, the, the industry slash academia consortiums kind of working on stuff that really kind of push these things through. But then, you know, a lot of them never see the light of day and never ever really get traction or new utility for it. Like I said, there's. There's a, A lot of potential interest in things like EEG and, and, and even like facial expression and also like some sleep stuff with respect to like schizophrenia, for example. But to get to a place where you're using that to evaluate your drugs as a PR end point for registration from the pans, like, it'll be decades because just, it'll be so incremental because nobody's willing sort of to paradigm shift it because the pans is accepted and they know it works. And you know, most of the bottleneck, a lot of the bottlenecks to throughput are, you know, getting through with the FDA. Well, we know the FDA accepts the PANs. We know they accept this. And so I gotta just get my drug to work on that and then I work it. So it's your reverse. You're retrofitting your drug into fitt, a regulatory pathway, because, you know, it works that way, you know, so it's challenging.
[00:23:26] Speaker B: It's interesting to hear that like, you might be like, retrofitting your drug for a specific score like, like in the, in a world of neuroscience where it is subjected, like, how is that even possible?
[00:23:39] Speaker A: It's not. I mean, it's like you said, if you're making these assumptions, you say, okay, here's all the historical precedent on what, what is clinically relevant on neve measures or what it is. So that's. I've just set the bar now for my drug, so I have to like, retrof drug into making sure it meets those criteria. And you can say, well, that's good because that sets a bar of, you know, benefit to a patient or things like that, that if your drug is falling beneath it, but, you know, is it really exploring all the things that are relevant to the patient? Is it really exploring and is it really not working? There's lots of different modalities that may be synergistic to helping the patient in terms of other meds that they're on or other things that you just, you're just not able to explore because you can't split those hairs. So it's sort of. You're using this broadsword where you would need a scalpel. But, you know, the broadsword sets a level that it's like, well, I gotta get here, and if I can't get there, and, and it's just. And all these historical drugs have set these precedent of like, you know, but again, like a.
You can put you. And you get, you basically get one shot at it. Right. So you retrofit it, you run these big pivotal trials and if it doesn't work and it's experiment and you don't know exactly what wrong, you rarely have a time, a chance to go back and try again.
But it doesn't mean you know that when you ran that experiment that one time that it didn't work. Like there's all these different nuances that contribute to it. But we just don't ever have a chance to go back and rehash it to see like what really. Like if we had a different tool or we had a different measure, would we have found other ways that the drug was beneficial, that it would have made sense to bring it forward or that it was helping patients in a way? We just weren't detecting what sort of these tools or did something else to benefit their quality of life.
Um, we don't have that opportunity. We just chalk it off as oh, this mechanism doesn't work or wow, you know, we just really fouled these studies or. And then you put it away.
Yeah. And that's a lot, a lot of what happens. And I think you, you see that and that's why I said I think there's, there's lots of drugs, you know, drugs that never saw the light day in the drug development graveyard that probably shouldn't have been there or maybe didn't need to be there and probably could have benefited patient. We just didn't have the right tools to be able to demonstrate what's needed to be demonstrated. So you can obviously meet those, those standards of what is safe and what is effective and what will benefit people.
[00:25:48] Speaker B: Totally. So you know we, we've kind of painted a picture of like the, the challenges in the landscape. I'd love to talk about maybe what you're most excited about looking at the, the kind of current landscape of neuro.
[00:26:02] Speaker A: Yeah, I mean I see the, it goes back and forth. I, I would love, I think we're getting closer and closer now to more definitive disease modifying therapies. Most of my career stuff has been on the symptomatic side. I mean and I, I played around with, with symptomatics but also in disease model. But you know, most of the, the failures in Alzheimer's sort of foul people. But I think we're getting closer now.
[00:26:26] Speaker B: Maybe the definitions around disease modifying symptomatic and why you're so excited about DMTs versus versus the lab.
[00:26:34] Speaker A: Yeah.
So right. A symptomatic therapy meaning like you're going in, you're, you're addressing A receptor or you're, you're bridging something. You found a way to sort of modify something that's happening as part of the disease course.
So a symptom of the disease and you can make those symptoms better, but you're not actually changing the disease, you're not curing the disease, nor are you changing the trajectory of the disease in terms of it's a disease that's neurodegenerative and going to get worse over time.
You're not really interdicting there to slow down that progression. You're treating the symptoms as it progresses. And you know, higher doses could treat the symptoms as they worsen. You know, again, a great example is Parkinson's disease. You know, Parkinson's disease, the standard of care is Levodopa. Levodopa treats the symptoms of losing dopaminergic neurons. It doesn't stop you from losing dopaminergic neurons. And eventually you get to a place where even the highest levels of Levitova can't help you.
So that's versus disease modifying where, you know, with beta amyloid drugs and things like that, where you're actually interdicting now in the, in the true sense of disease modifying, you'd say curative, right? You're, you're talking about cures or things like that. And there's some cases in the oncology space in metabolics where you could talk about that. But in the neurospace we, we generally think about it as changing the trajectory or the progression. So if, you know, if normal, normally a patient would digress over a 10 year period, maybe it's, you're giving them an extra 10 years on their progression so they have better quality of life over that entire time course and slowing it. That's how we look at something that's modifying the actual underlying etiology of the disease versus simply treating a symptom that's a manifestation of it.
[00:28:11] Speaker B: And where, where are we to be that like yeah, these disease modifying therapies, like where are you most excited to see them? Where are they coming from?
[00:28:20] Speaker A: I mean again in the neurospace, beta amyloid and stuff has been the top, it's for Alzheimer's and everything.
But I did some of the initial, I did some initial work on beta amyloid before I went to med school and it was more in the head trauma space, but worked with actually in the same cross coordinator with a lab and published with John Chowski who's like sort of the godfather of beta amyloid. And he passed away, but that was in 1999. And it was like, we still don't know a ton about like how it really plays into this pathway and sort of interdicting with it, what it, what is it really doing in terms of what's the clinical benefit of doing that. We've been chasing this dragon for so long, but I think it's just a limitation of, of the neurospace of really understanding the complexity of these pathways. So what's really got me excited is again, when you start looking at sort of the new tools that we have now in the dawn of sort of these, the new decades that are going to be ahead of us and sort of the use of AI and the use of sort of these ways of changing and creating new models and drug development about picking new models and new entities that can do this stuff. But just even how we understand how things work in a downstream upstream process and sort of how like the rapidity which, which you can model these things and happen them.
I think we're going to come and things like, and also like CRISPR technology where we're actually like, we can get to really sort of more precision kind of stuff. I think you're gonna see in the next, you know, 10, 20, 30 years, like a new generation of drugs that will be able to interdict in sort of these disease pathways. Cause we'll understand what's happening, we'll be able to, you know, have large leaps and bounds in our understanding of just the neural networks that are in play in the human brain. And sort of really like, if you do this, what happens here? We still don't, we still don't have a great understanding of, you know, you can put beta amyloid, in addition, it kills neurons. And you're like, well, if I stop that, it's good, right? But it's just there's so many complex things that like, are just our basic research hasn't been able to get our hand around. So I think it's, it's that it's, it's really my hope and my fingers crossed because I'm an, I'm an end of the road guy. Like, I'm a guy that's like at late stage, like you've got something. And so I look to like all of my peers and my colleagues that are really on the discovery side with all the tools that we have in front of us that are so sort of interesting and, and nuanced that we're going to start figuring some of this stuff out on the day where in, you know, in the. More in the immunology space and metabolic space where the pathways and the linkages and the, and the core, the connections, the correlations are much clearer.
And even in, even in oncology, we've gotten a much better understanding of things in terms of pathways and how the immune system interacts with cancer cells and stuff to really sort of evolve that treatment landscape that you saw from. It was sort of that generation of going from I. I liken it to the, the chemotherapeutics and sort of the. The broad sword of. Of thanks to immunotherapy and cancers and kind of where we've evolved. Yeah, cancer's still everywhere. But some of these therapies that have evolved.
I'm looking for that inflection point for us in the neuro space where we get to enough of an understanding of, of the neuropathways and stuff that we can really start producing some targets that can have some real meaningful impact. And again, it's. Because it's not just a, like, you know, is this a viable. This molecule or something? It's. It's understanding its impact across the landscape of that neural network. Because beta amyloid. Yeah. Is in the brain and interdicting. Going to the. But it's just, it's one small piece of a larger puzzle that we haven't figured out that you have to address many more pieces in that puzzle till you get really meaningful effect. I think that what you see with like the, the. Even the approvals for the drugs, this sort of question of like, are they really impacting cognition? If. And it's just a little like we want to see big leaps and bounds like we've seen in the oncology space, like we've seen in the immunology space. And I think we're getting there. I think we'll get there. But I think that that's the last frontier that, that sort of mapping and understanding of not, you know, we know the genome now and our immune systems and the complex metabolic process going, but like really understanding the real depth of the neural network, part of our, of our brains and how like all of that is interacting and how we can really sort of engage maybe even with therapies, multiple targets in a similar therapy in the same therapeutic to sort of create this constellation of effects that gives you sort of a multiplicative factor. Like, I think we're on the verge of that. I hope we're on the verge of that. The stuff I've seen gives me, gives me comfort in terms of just the evolution of the tools we have in terms of AI and what I've seen on the discovery side with colleagues is very encouraging compared to I think the tools that we had. So hopefully that's my hope for, for the industry. And until then, I mean I think we'll make incremental progress on some of these things. You know, we will see some, some things that will look, you know, we'll be in that disease modification space. You know, I think there's some interesting spaces we've made certainly leaps and bounds in sort of the, the, the like in SMA and sort of the gene therapies and stuff like that. And so I think there'll be more evolution on that side of some of the rarer diseases. But sort of these large, more population sort of issues around dementia and sort of these larger diseases and diseases of the mind like that aren't necessarily even neurodegenerative, but like schizophrenia and major depressive or psychiatry where we can get beyond just treating the symptoms of those diseases even though they're not neurodegenerative, they're not necessarily worsening to a place over time. But we just like, we can't crack the code yet. Unlike like it's so complex. Whereas like again even in neuro, in the neuropsych landscape where you've got neuro, like we know what causes Parkinson's, we don't, well we don't know what causes it, but we know like what's happening. We know that like these neurons are degenerating and we know that you don't have dopamine anymore. Like why that starts to happen with our idiopathic whatever. Like there's lots of theories but like in schizophrenia we just don't know like you know, the end result that dopamine is messed up. But like what are all these genetic components and all these things and can you get at. Are there places for us to get to, you know, sort of curative or disease modifying treatments for major depressive disorder, for you know, treatment resistant depression, for schizophrenia, for anxiety. So these things that plague like so many people and all we, all we can really do now is kind of play around with neurotransmitters and get better at how we sort of attack those neurotransmitters to kind of limit side effects. And that's what you're seeing like with you know, finding new receptors that get it the same way without hitting the old ones that cause side effects or you know, adding a couple of different things together if you had a better effect. But at the end of the day we're still just sort of fighting against the tide about whatever your genetics underlying it or whatever else being produced. You're trying to fight against it. And that's sort of the symptomatic world and there's make no mistake, there's ground to be, to be had there. There's lots of unmet need and there's lots of therapies that I think we can continue to evolve. But to really start seeing some of these big changes like on a population level that will make real dents in the impact of patients lives. I think we're on that cusp of that of seeing that and I'm hoping it may not start in neuro again. I think you're seeing, going to see more of it in the oncology space and stuff but, but it will migrate as we start to understand more of these sort of, these neural connections and, and how like all these complexities of how psychiatric illness sort of manifests itself and what its really root cause is and how it's, it's going on and getting places where we're talking about, you know, steering people or really being able to treat them, you know, definitively and things like that. So there's a, I have a lot of, a lot of hope for the landscape.
[00:35:36] Speaker B: Are there condition areas where you are more excited about or like you feel like we're, we're kind of closer to the, the promised land right now?
[00:35:51] Speaker A: I'd love this. I mean again, I think, I think on the neuro side when you look at the neuro landscape, I think just because of the nature of those connections and sort of, when you're looking at sort of these functional impacts, I think we're at a better place for understanding sort of the basis of cognition. I think there's a lot of good data on and kind of how we interdict there and the different mechanisms. So I think, but, but again getting at the, so treating cognitive decline or cognitive symptoms but really getting at the reason of what's causing it and causing these things. So whether it's you're in Parkinson's or you're in the dementia space of, of Alzheimer's or these other things, I think, I think we're probably closer there in terms of understanding these etiologies and getting more sort of directed targeted therapies. Whether it is even better symptomatics for cognitive therapy, which are the ones we have right now are not good at all or really getting disease modifying. I, I, it's unfortunate but I, I think the, the complexities of you know, schizophrenia Bipolar disorder, sort of the. The. The big. The big elements in the psychiatry space. I think there's just still a lot of. We don't really understand, well, the role that neuroinflammation plays.
We don't really understand sort of the role that the genetics are playing because it's so varied and there's so many different external factors and stuff to really get down to. There's no, like, discrete loci we're getting to. Or, you know, there's. Right.
So I think it's. Those are just farther off. Cause I think those are the most complex. I mean, these are diseases of the mind. No, you know, this isn't. We're talking about neuropathies, like psychiatry. It's a disease of the mind, of the mood, of the. Of the thing. And like, this is the most complex of the self, of. So you're getting into the most esoteric, ethereal part of human existence beyond, you know, your circulatory system and your blood cells or whatever. Like, you're getting in terms of how your brain manifests and all these neurons you have manifest in terms of your mood and your emotions and how you experience the world. And, like, deficiencies and pathologies in that, by that definition, are going to be the most complex to understand. You know, we can understand, like, things that are killing cells and things that are making cells die and sort of neurodegenerative diseases or neuroinflammatory diseases like Ms. Like, we know your immune system is acting abnormally and it's attacking myelin. And we do. And we have these things. We know what's kind of there and what's causing. We don't know necessarily why you get it, and I don't. But we know once the person that has it, what's happening. Whereas, like, not only do we can't tell who's going to get schizophrenia and who's not, but, like, even for the people that have it, we still can't really tell you why you have it or why it's doing that. We know your neurotransmitters are messed up, and we know what's happening. But I think, to me, that's the biggest. Going to be the biggest challenge in psychiatry. So that's why I said that I've always a badge. It's always been a badge of honor to like, sort of been doing development in that space because it is. It is the hardest. Not only is it the hardest disease landscapes to understand and sort of map and model and sort of figure out ways to get at the underlying etiology, finding ways to treat it symptomatically and find a new receptor that will sort of bring dopamine back into balance and things like that. Like that's we've been able to do that, but really get at these core things and then studying it just as a, as a disease state and trying to study it and put it into experiments and look at endpoints and try to do things from a pure.
It's just challenging. It's not for the faint of heart. So anybody that goes into it is obviously gets my, my, my props.
[00:39:13] Speaker B: Well, certainly I'd be curious to get your, your take here. Certainly a lot of excitement recently around developments in these mood disorders, depression, anxiety, with the, with the psychedelic development.
Curious how you're, how you're thinking about the, the kind of latest suite of, of candidates here.
[00:39:32] Speaker A: Yeah.
In the, the depression side I think is, is interesting. I think there's so the two things that have me interested at least in depression. I mean the psychedelics are interesting. I think for me the challenge there is just that the separation of the psychedelics stuff you saw they, they ran into, they're going to run into the FDA a bunch. But some of the other. I think the, the, the psychoplastogen companies that have sort of removed that and I'm thinking, you know, I have colleagues that, that companies like Delics and some other ones that like. I think there's something really, we're talking about neuro remodeling where you're starting to burgeon on this concept of disease modification, right? You're remodeling neurons. You're not just interdicting in, in a, in a receptor or blocking out the endogenous ligand to stop one thing from happening. Like you're talking about remodeling neurocircuitry and it sounds cool, right? It sounds awesome and it sounds great. But if it actually starts to prove that they're getting sort of these real big clinical upsides, I think that's going to be sort of the real first big use case of you know, disease modification or as close as you can get to it in the psychiatry space.
But I think there's a ton going on there and I think again their challenge is going to be one, you know, that separation from all the other side effect psychedelic stuff that we saw lycos run into and stuff like that that I think will be challenging and sort of where the true, the, the psychedelics are going to run into where I think the psychoplastogens, if they can really deliver on, you know, the psychedelic horsepower without the psychedelic part. Like, that's where you have a real. I think, a real. A real. A real potential upside. And then I think there's. There's other places we see in depression, there are some other, you know, newer targets that I think are just going to be more incremental in terms of just getting you to places where maybe lower side effects or something you can add to get better effect out of an ssri. And so, you know, we had some. We worked on some of those receptors and others are working on them. And I thinking about, you know, C cord and others that have some cool, interesting technologies on drug delivery that are trying to get better. But to me, these are, you know, incremental changes that we have to keep doing, because in the absence of having truly groundbreaking stuff, we have to keep doing the incremental until we find something that blows it up. And we. And we really sort of get these big. You know, you never get. It's never Darwinian that you have these mass explosions. It's always sort of these little tiny changes. But then we hopefully get to sort of a breakdown point and something break changes. So you keep pushing it that way. So I think on the, you know, on the depression side and things like that, the Muscarinics were obviously really interesting for us. And I do think there's a lot there. I think it's just still. There's a lot to figure out in terms of, you know, potency and kind of what. What's the best type of an approach there? And agonist and Pam. And still, again, all of these indications are going to be plagued with. What we talked about in the beginning was, is. Is as good as they are, you know, to really overcome a lot of these challenges around patient patient access and patient or at least access to new patients and access to, you know, better tools and better measures. Unless you have this massive effect, which you rarely ever get, you know, which I rarely ever get, it's going to be challenging to be showing, you know, and convincing of a. Of a drug. And that could be the. That's. To me, that's what scares me with the psychoplastogens, is that they. They could be really impactful. But if the effect isn't like.
Like, you know, they're going to deal with the same issues that the SSRs with these sort of small effect sizes, and then if they just get chalked up to, well, they don't really work all that well. They're not better than ssri. So nobody's gonna pay for em, so we're not gonna really deal with them. But like you're really talking about a really novel mechanism that if you can show the effect, is it, you know, is it just that we're just not able to really sort of capture all the benefit in sort of these rudimentary tools that we're still using, but that we have to use. So I think that's the, to me the challenge, but I think that's really for me, the, like any of the, any of these new candidates that we can get sort of into more. And I'm thinking about too, like in the depression space and also right in the psych, in the schizophrenia space, the work that's happening now to understand the neuroinflammatory component, I think that will start to change the landscape. I think we've, we've sussed out a lot on sort of the, the basics of sort of the normal receptors that are working there and sort of just the, how you symptomatically treat these diseases. And you said, well, the Muscarinics are basically a new approach to an old problem of just like, let's find a different receptor that was cool and like, we still can reduce dopamine and we don't get all these dopamine side effects. So, you know, these. Getting the same effects with fewer side effects is a great approach to sort of address the unmet need of side effects at burdening these patients. But sort of really getting the groundbreaking therapy of changing the courses of these diseases and things like that, I think it takes, it's going to take a bit more.
And that's where I want, I want to see things like, you know, better understanding, better mapping of how neuroinflammation plays a role and we can kind of cross linking that in with the genetics of some of these disorders. And I think you might getting, start getting into some real interesting therapies. But I don't think that's, that's not going to happen next year. Right. I think there's some interesting stuff that's kind of brewing around the edges that'll come along. And I think for now you're going to see still a lot of sort of these things that could make impactful changes for people that, you know, maybe have recalcitrant diseases and give them some additional options.
Um, you know, like some new, some new again, whether it's Parkinson's and sort of the drug that the, the, the formal cereal now AB drug, they hit the, the, the Tavidon which was a target people were trying to get for a long time. They couldn't. We figured out a way to do it. It's going to add to that armamentarium. It's going to give them another option if they're failing on certain drugs. So it certainly will help a lot of people.
But having that big sort of population effect on the disease state when that we're looking for it, sort of these bigger things that I think are always kind of the holy grail for drug developers.
I think, you know, we're going to have to keep plugging away, keep trying to, you know, get better measures, get sensitive measures, keep pushing the boundaries on kind of what we will and push new ideas of what, what makes up this disease. That's why again, I like some of the work that I've seen with sort of bringing back the concept of neuroinflammation and the genetic component into schizophrenia and how can we sort of multimodally attack this disease both on the, you know, the receptor side with dopamine, but also on what's happening in the triggering from neuroinflammation and stuff like that. I think I gotta know we'll get closer.
[00:45:41] Speaker B: I gotta, I gotta, I gotta ask.
Which three programs are you most closely watching right now? Are you most excited about?
[00:45:51] Speaker A: You gonna put me on the spot, huh?
With three programs, am I most closely watching?
I mean just out of. See you're gonna get biased like, just out of interest, like I'm. I'm watching the Muscarinic space just because I came from it and because I came off of a failure.
And it wasn't a failure of. I think of execute again. I think it's. And so I want to. I'm really interested to see because I do think there's a lot of value there incrementally of where we're going.
So I'm watching, I think across those different programs where you're looking at Numora, you're looking at Neurocrine, looking to see what Abbie can do and where others. I think there's plenty of interest in the space, but can, can they evolve that? So I think in the near term I'm looking to see because I think that will have a lot of benefit to patients.
And then in the, like on the other side of it, I'm kind of. I'm. I'm more interested in, I think on the pizar, the Parkinson's disease modification stuff. I'm still sort of hopeful around alpha synuclein when I'm looking at some of the, some of the programs that are a little, a little get more isoteric and looking at the inflammasome. And so there's a couple of different programs that are out there that are focusing in on the inflammatory components that are, they're mixing everything with like GLP1 now and stuff like that. But there's I think a couple of different companies that I'm, I'm kind of like Saravance and some other ones that have some interesting stuff that I think are really looking at targets that are getting again a bit closer into the, in the, the mode of more disease modifying or changing sort of the way the disease is processed as opposed to just interdicting at the receptor level. So I think that's probably where I'm most, most interested right now is kind of making.
See what happens with, with the, the Muscarinics, et cetera because I think they, there's still a lot of ground to cover there.
Some of the other stuff, I mean I'm not as like, I think it's, it's kind of like interesting but it's not, it's just kind of like old kind of rehashing of things and they think in like the depression space and stuff like that. So I think, I think that's probably at least in the, in the neuro, the neural space right now that's kind of what I'm. Kind of what I'm watching.
[00:47:55] Speaker B: Gotcha. So. And I've already mapped that to kind.
[00:47:57] Speaker A: Of like condition areas.
[00:47:58] Speaker B: It's like, like the work currently being done in schizophrenia.
Some of the interesting work potentially over in Parkinson's and then a lot of the rest of the field you're like, you're not as closely watching or.
[00:48:13] Speaker A: It'S fine. I mean look in neuro there's, there's tons and tons of rare things to be looking at on the, I mean both on the, on the, on the gene therapy side, the disease modifying side that, that like you couldn't watch all of them if you wanted to. And I'm not an expert in the rare disorder. So I mean I think there's a ton of things for specific people that if they have something in their family or they have something that there's plenty of places to be hopeful in terms of these very small disorders that lend themselves to a very specific therapy like a gene modification or something like spinal muscular atrophy and places where some of those companies have made a lot of ground and I think you still see a lot of people attacking that. You Know you still see where a lot of the, the, the plasma AAV based therapies that are, they're, they're working on like they're going to make, they're going to make up ground and they're going to get better and better technologies and stuff like that. I think again for these, the, the stuff I like to watch is the, the larger, these larger sort of the large big disease burdens of like psychiatric illness and the big neurodegenerative case like Parkinson's and Alzheimer's and stuff like that that I'm kind of watching and hoping to see like in Alzheimer's I'm just seeing like how can we better improve on beta amyloid or what got approved. It's kind of chasing that, they're still chasing that dragon.
So I'm hoping to see, I'm kind of watching and I'm hopeful for some of these companies that are maybe sort of going at it in a new way and we can get better in terms of like you know, genetic targets and more. But I'm seeing a lot of the interest, rightly so a lot of the investor interest goes towards well okay, they finally figured out a way to get some of these drones approved and so let's, let's now innovate on that and incrementally make them better and keep going. Like that's generally what happens in the industry. It's like you find something at work and then you like everybody incrementally improves on it because it's sort of a known thing you can keep doing which is easier to do than kind of forging a new pathway.
But again I think there's, there's a closer, we're probably closer to something meaningful, you know, either genetic based or others in Parkinson's and movement disorders than we are in the dementia space. So I, I tend to watch that pretty closely in terms of, and all, and all the things, you know, even in the smaller rare stuff but just in the larger, you know, sort of like what, what they're looking at. So one of the like for example in the parking space I'm looking at like the, the GBA mutant mutation drugs.
So those are really interesting. So like GBA Parkinson's disease, it's not idiopathic Parkinson's but it is, it's cause we, you know, it's been identified as the GBA mutation causes a Parkinson's like syndrome. And so there's, they're targeting that and so it's, you're getting into sort of disease modification at that level the Lark 2 programs were the same way. It's not treating everybody. But Parkinson's is such a sort of a heterodymer of a disease state where there's lots of different groups in there and like if we can come at them and sort of start piecing them apart and taking them down, I think that's where a lot of the interest will be. See, I, I watch Parkinson's pretty closely.
[00:51:05] Speaker B: Yeah, fascinating. Okay, so I know that we're, we're getting close to the, the end of our time here. Matt, if you had magic wand to change anything about how drug development is, is done today in Neuro, what would you change? Why?
[00:51:20] Speaker A: Oh man, that's a great question.
I mean I always like as a drug developer you're always complaining about the speed at which you can't, you know, the slowness and from a regulatory perspective. But I don't rail against it too much because it's there for a reason. It's there to make sure that you know, we're, we're meeting a burden of proof.
So I, I, I wouldn't wave a wave to say like it'd be great if we didn't have all these regulations and we could just like really kind of because I think that's a way for like people to get hurt. So I don't think it's a way but I think it's, it's a, there's a lot of limitations in sort of what we can explore just the way the sort of like the investment in the financial system is set up for us and what you can, what you can and can't do. And again that all the incentive is around like what we just talked about like Chase, what works Chase, what you know is, has a high probability success so it will return profit because it's a for profit industry.
And that's, I think the, if I could wave sort of this wand, it's sort of to change that notion of you've got academia and academic research which is really for the science of it and then you've got pharma and we make some great innovations and there's lots of cross between that or whatever. But at the end of the day pharma is about, you know, returning investment for, you know, helping patients, but also returning investment share. You have shareholders, you have all these things and you have financial constraints. And so because of those limitations, you know, we're not doing stuff based on grants and we can afford to fail at a lot of things.
I think it just restricts us in our thinking and restrict us and it, and it forces you into a mindset of, you know, being more conservative, more following, following the path that's been set for you. Following the path of like least resistance. Following the path of like.
Well, we, you know, like again what we said around something that's known and it works like I want to make sure it's successful and I want to make. So this is the easy way to do it. But that may be not the best way. And this is, that's not what breeds the most innovation and the most change. And I think, I think we. It would be if I could wave it and just make it a whole different dynamic. And I couldn't because this is the nature of the beast that we're in. And it, and it does, it leads to where the. It's the best environment in the world for drug development. And we make the best because of all those incentives and you know, people that realize the drug industry and stuff for that like the reason we have all these therapies because of the way it's set up. But even then when you see sort of, when you're inside pharma and you see the mentality in drug development and you see how all these different stakeholders that you have to deal with and sort of what we're incentivized or how we're incentivized to behave and think to sort of develop drugs and what we're to do when we're posting versus completely, you know, go the way I think. Like, you know, Steve Jobs was at admin, you know, just like send a whole group off and just think about all new shit and just, you know, like think about everything crazy and do all this kind of stuff.
There's not a ton of incentive. There's maybe the optics of the way we want to do that, but there's really not. And I think that's what I would change because I think that's probably what limits us to more just incre. These incremental benefits over time.
That if we did more of that, you'd see more losses and you'd see more, you know, even more failures and more things like that. But I think it would, it would put us on a pathway to faster sort of large explosions, sort of groundbreaking changes, you know. Yeah, so I wish we had that. I wish we had that luxury, but we don't. We can't make the industry like that. The industry is what it is and it's, and it's, and it works the way it works. And so we make we make incremental changes and we make incremental changes, then hopefully the science catches up at some point in something and the two merge and there's a flashpoint and then we have a big, a big outcome and stuff and we've seen it happen. I just wish it happened faster.
[00:55:05] Speaker B: Yeah, well, and maybe there's some enterprising entrepreneur who's listening to this who thinks, well, maybe there's a different model that I can, I can think through that.
[00:55:13] Speaker A: That maybe I'd love to see it. I, I, I, there's been some, there's, you know, the, the Vant model, you know, like VIVAC is bottled before and like some of these other things about how you approach it was starting to sort of taste that.
But right now the, the landscape that we have of sort of just the large pharma model, you know, looks around for stuff and then the, the startups that I'm in, you know, we, we, we get money, we take the risk, we, we figure something out and we, but we still try to limit all that risk and then we get bought up like that model. I think it's still sort of just driving this kind of incremental stuff that we, if we could think of something different. But yeah, that's for another day.
[00:55:46] Speaker B: Risk, it's risk adjusted. Risk adjusted return is a, the, oh, it's a, it's an important constraint, but it is a constraint on maybe a local maxima.
[00:55:59] Speaker A: Yeah, it is, it is, yeah.
[00:56:01] Speaker B: Well, Matt, this has been a fun conversation. I appreciate you taking the time and taking all the detours with me here.
[00:56:07] Speaker A: Awesome. Yeah, no, it's been, been a lot of fun, Brandon, thanks. Anytime.
[00:56:10] Speaker B: Yeah.
