Episode Transcript
[00:00:00] Speaker A: They're calling it the neuroscience renaissance. In a way, that's quite true in terms of people's excitement, not only externally from the investor community, but also from the scientific community looking at the next frontier of challenges.
[00:00:18] Speaker B: Well, Ray, thank you so much for taking the time to have this conversation. I've been so looking forward to it for the folks in the audience. Ray is the former chief medical officer at Cerebell, recently acquired by AbbVie for $8.7 billion. Ray is now over at Bain Capital focusing on the life sciences. I'm really excited to be having this conversation with Ray about everything to do with the future of neuropsych research. So, Ray, thank you so much for taking the time to be on the show. Maybe a good starting point is to give us just a thumbnail sketch of your career and how you got to kind of where you are today.
[00:00:51] Speaker A: You know, I've always been interested, Brandon, in the brain. And even, as I said growing up and remember, conducting experiments and competed in science fairs, all having to do with behavior and psychology and so forth. And not surprisingly, I decided to pursue psychiatry because of its holistic nature, not only looking at the symptoms of the individuals, but also how a person functions and just a more holistic approach to the individual. And so trained in psychiatry at the Yale Medical School, and during that tenure, they were doing trials for risperidone that was being done by jj and one of the things that struck me was how there was a real need for novel medications to treat individuals with psychiatric or even neuropsychiatric disorders and the role that I could play in being able to work with a team of individuals in developing novel therapies. So over time, even though I did enjoy the practice of psychiatry, I decided to pursue the pharmaceutical industry and was very fortunate to join the team that developed Abilify from its inception globally and then lived in Europe to oversee the neuroscience group for Bristol Myers Swibb at the time, and then transitioned to Otsuka, who actually owned Abilify.
And we developed the long acting injectable for Abilify, Abilifam antenna, and also the first combination product of a small molecule with a digital component to monitor ingestion, which was approved in 2018. So that was a terrific feat. But we also then developed the next generation after Abilify of a dopamine partial agonist, Rexulti, Brexitrazole, and were approved with two simultaneous indications in schizophrenia and as adjunctive treatment in major deposition depressive disorder. So really, collectively, that led me to consider the opportunity to build a CNS organization with Bain Capital Life Sciences, who had reached out to me and had a very compelling portfolio of therapies that had been developed by Pfizer. And what really stood out to me was that they were designed with this receptor subtype selectivity that spoke to having potentially better efficacy and better, better side effect profile. So in 2019, you know, we started the Cerebell organization that went from three individuals all the way to about 350 individuals over, over a four and a half, five year period. And to your point, on August 1st, we were acquired by Abbvie, which is terrific for the portfolio and the reach that the portfolio can have over time.
[00:03:44] Speaker B: Yeah, absolutely. And I'm just too curious to hear more. Five years to 350 people, $8.7 billion outcome. What was that journey like? That must have been unbelievable.
[00:03:54] Speaker A: Yeah, so it was a terrific journey. You know, we started, I mean, first of all, I mean, two things really make a company, I think, very solid and exciting. One is, of course, having a very good management team. And we had a terrific, very experienced and seasoned management team. We also had a portfolio that was extremely promising. And then the third component was the balance sheet. We had an initial investment from Bain Capital Life Sciences that then allowed us to continue to raise capital over time. We had a very strong investor syndicate, and that really allowed us to be quite successful in our execution in terms of making sure that all our early, mid and late stage programs continued to move along. And so it was a very prolific journey. We had very exciting data readouts that really spoke to the benefits of these therapies in these populations that still needed novel treatments where there was still great unmet need. And so it was a very exciting, energizing journey. And so now it's in the hands of another, you know, organization. And I'm sure that they will take it to the next level for the various populations who will benefit from these therapies.
[00:05:11] Speaker B: Yeah, absolutely. And I'm sure we'll talk a little bit more about the future of that work later on. But maybe just let's back up a moment. Could you start by giving me maybe just like a landscape, your view on the landscape of neuroscience research today and maybe what excites you most about developments in the field.
[00:05:28] Speaker A: So it's interesting because I think in the last five to 10 years there have been a lot of advancements in terms of looking at novel targets, looking at novel mechanisms, and, you know, you now have the psychedelics, which, you know, many, many years ago were really not in the realm of possibility in terms of understanding their utility and treating disease. You also have these novel targets like the Muscarinics at, you know, CAR XT that recently Copenhaged that just got approved very recently that Bristol Myers Squibb now acquired Karuna as you know, and then other other companies that are looking at a more tailored, personalized approach to precision medicine and psychiatry, which is something that hasn't been really discussed for a very long time, Brandon, as you know. And so looking at digital biomarkers and other forms of biomarkers to ensure that the fit for purpose therapies are targeted to individuals who could really maximally benefit from them is something also that has arisen. But I think they're calling it the neuroscience renaissance.
And in a way that's I think quite true in terms of people's excitement. The not only externally from the investor community, but also from the scientific community. Looking at the next frontier of challenges, of course lie within an organ that we just don't know enough about, which is the brain.
And so I'm excited to see all the endeavors that are are being executed across the landscape by many.
[00:07:10] Speaker B: If I'm a caregiver, what should I be most looking forward to?
[00:07:13] Speaker A: I think that really if you think about the neurodegenerative space in terms of Parkinson's disease and Alzheimer's and think of the recently approved Anatomab and lecanemab in terms of disease modifying therapies, there's work being done in disease modifications in Parkinson's. I think it's. And then of course other therapies that are more symptomatically focused but better options for individuals to treat their symptoms in schizophrenia, in other psychiatric disease states, PTSD and anxiety and so forth. I think what's exciting is the commitment and the passion by which people are pursuing these therapies and looking tirelessly at novel ways to treat these disease states.
As a caregiver, optionality is really important, but giving them optionality in terms of new therapies that potentially will provide a different course of treatment with better outcomes is something that I think everyone should be excited about.
[00:08:17] Speaker B: Yeah, and I'd love to maybe just step through each of these condition areas one by one, because I know that the kind of domain and landscape for each of them is slightly different. Maybe we start with schizophrenia, given the recent success of some of these muscarinics that you've been describing. Maybe walk us through the kind of overview of major treatment approaches in schizophrenia and how it's recently evolving back, back.
[00:08:39] Speaker A: You know, when you had the typical neuroleptics like haloperidol and other therapies, they worked very well. And, you know, and to this day, haloperidol is still being used in emergency rooms. And these were known as dopamine antagonists. And the problem with, with those drugs, of course, was the fact that they had increased extra pyramidal symptoms or Parkinsonian symptoms. They also had issues with prolactin issues as well with, you know, with other symptomatology that was quite debilitating. And so then you had the atypical antipsychotics. Their side effect profile was a bit more enhanced. In other words, lower extrapyramidal side effects, better, better outcomes in terms of their safety and tolerability.
Drugs and therapies like Risperidone and Olanzapine and Abilify, and that really came into play and those really changed the landscape in terms of not just treating schizophrenia effectively, but also a better side effect profile. And then came Abilify, by the way, was the first dopamine partial agonist. So in terms of trying to still block the dopamine receptor, but partially meaning that it would still be efficacious, but because of its partial antagonism, it would allow a potentially better side effect profile, which we did see in those trials and then continuing, continuing those therapies, we had, you know, cariprazine, and we have other therapies that have evolved since then. However, the challenge has always been how are we going to treat the patient holistically. And so, of course, you know, you have negative symptoms, it is still to, in the US to be approved. Imisopride is approved in Europe as the only therapy to treat negative symptoms, but it's not. We don't have any negative symptom approvals here in the U.S.
also, cognition, you know, cognitive impairment associated with schizophrenia is another area that is people have tried to study, but not successfully to date in terms of approved therapies. And now we have this new class, this new target of muscarinics. And the muscarinics work by still lowering dopamine in the striatum, but doing so via acetylcholine. So it's a different mechanism. CAR xt, as you know, or Cobenfi is a pan Muscarinic agent that's M1, M4 preferring. We also have Imraclidine, as you know, that serovel inherited from Pfizer, which is an M4 positive allosteric modulator. You have other companies that have an M4 agonist like neurocrine and so, you know, there's really an excitement to look at novel mechanisms and novel targets. And beyond the muscarinics, there are other. Other targets that are being. That I can't disclose, but that are being looked at currently for future. For future treatments in. For patients with schizophrenia.
[00:11:49] Speaker B: Help me with the kind of naive questions here around. I've heard you say negative symptoms, positive symptoms, and lowering dopamine. What exactly are positive negative symptoms? And why would we want to be lowering dopamine?
[00:12:02] Speaker A: So it's been known, first of all, it's been known that increases in dopamine are hypothesized to be the underlying cause for psychotic symptoms.
And so it's, I think, more. It's multifactorial, but that's kind of the ongoing thesis. And so that's why, you know, when you block dopamine, one of the challenges by doing so directly is that you also lowered the dopamine levels to a point that can cause Parkinsonian symptoms. And that's the issue with Parkinson's disease. You know, you just don't have enough dopamine as you try to increase or replace the lost dopamine. So dopamine, of course, implicated in schizophrenia in terms of positive and negative symptoms, but the negative symptoms a little more complicated because it's not just dopamine. There's also serotonin that's implicated. But positive symptoms are things like hallucinations and delusions, paranoia, patients hearing voices, those types of things. The negative symptoms are things that patients should have but do not. And so if you think about it from that perspective, that's why they're called negative symptoms. So things like affect patients who are basically dysphoric or patients who lack motivation.
And so all of those symptoms that are not necessarily in terms of specific things that you are, you know, hallucinating or that you are basically paranoid about, or things that are as disturbing to you at the moment. These are things that are more lingering in nature. And you can see a lot of patients with schizophrenia that their positive symptoms are, are attenuated via the therapy, but yet they have basically residual negative symptoms, which in some, in some cases mimics very similar symptoms to someone who could be dysphoric or even depressed, but in fact, they're part of the disease state of schizophrenia.
[00:14:11] Speaker B: Walk me through Muscarinics and how they kind of fall into this framework of positive negative symptoms and why. Why they're more appealing than the kind of current treatments that are available.
[00:14:22] Speaker A: Yeah, well, they're more appealing because Brandon they still lower the dopamine levels in the striatum, which have been implicated in hypothesize as being the cause of the symptoms of schizophrenia, but indirectly so. So that by not directly blocking the dopamine receptors, you're still lowering dopamine in the striatum, still seeing the positive outcome of lowering the positive symptoms of patients with schizophrenia, but not seeing the side effect. And that's where the key thing is, that you have an effective therapy that doesn't have the side effect profile that the current therapies, the current neuroleptics do of extrapyramidal symptoms, of increased prolactin, of other, you know, very debilitating symptoms, of target dyskinesia as an example. That's irreversible. So again, treating the symptoms effectively, but doing it in a way that is much more tolerable to the patients who are getting the therapy.
[00:15:22] Speaker B: And if I'm, if I'm following properly the dopamine hypothesis links to the positive components of schizophrenia. What about the negative components?
What are people thinking about there?
[00:15:32] Speaker A: Well, as you know, it's really conflating, right, because it conflates not just dopamine, but also serotonin. And so if you look at, for example, something a drug like abilify, you know, that is 5ht1, a partial agonist, 5ht2 antagonist, but also dopamine, partial agonist, it all conflates in terms of not just treating positive symptoms, but also potentially treating the negative symptoms as well. One of the challenges with developing therapies for negative symptoms is that, you know, finding the right patient with those residual negative symptoms that are still continuing even after you treat positive symptoms is definitely challenging. But I think the also, you know, the, the regulatory path to getting an approved therapy is also a bit of a challenge. And that's something that I think many are looking at and trying to address are negative symptoms something that needs to be addressed separately. And what I mean by that is by a different therapy that there isn't any one therapy that works for, I mean, in treating both positive and negative symptoms, even with residual negative symptoms. But there may be another type of therapy that potentially could be as an adjunctive treatment to treat negative symptoms. And all those potential opportunities are being looked at even as we speak.
[00:16:54] Speaker B: What are you most excited about in that domain?
[00:16:56] Speaker A: Well, what I'm most excited about is, I think, is treating the patient holistically and that these are individuals. Schizophrenia, as you know, affects 1% of the population.
It is quite devastating, if not Treated appropriately. One of the challenges with patients with schizophrenia is really adherence or lack thereof, patients not being adhering to their therapies. And what's interesting about the disease is that with every, every time they relapse, the brain doesn't go back to its original baseline. So with every relapse, you actually decline over time.
So the goal is to obviously keep the patient treated effectively in a way that they're compliant with their medication. So it speaks to, you know, having therapies that are dosed less frequently, that have a less complicated paradigm to reach its dosing goal, or even the long acting injectables that in some patients who cannot be compliant, fulfill that objective of trying to keep them on therapy. And so the challenge, I think, with the population is trying to keep the person stable. And the only way you can keep them stable is to have them stay on their medication. But you know, because of some of the side effects that some of these therapies have, they are prohibitive to some individuals. And so they over time discontinue the medication. And so that's a huge challenge that I think the muscarinic class, because they have a better tolerability profile, will be, is a terrific new option for patients with schizophrenia in terms of the compliance piece, while still being able to treat them in a holistic manner. I think the future needs to also consider therapies, of course, as we talked about, for residual negative symptoms as well as cognitive symptoms as well. And one of the issues that patients with schizophrenia have are these residual cognitive decline issues that occur with the disease. And so enhancing the cognitive piece, enhancing the negative symptoms, not just focusing on the positive symptoms is the ideal outcome with this patient population.
[00:19:14] Speaker B: And in your intro, you also mentioned this idea of precision neuroscience. How are precision techniques being applied to the realm of schizophrenia today?
[00:19:25] Speaker A: Well, I think that schizophrenia, I don't think we're there yet in terms of using precision approaches to schizophrenia. I think that that will potentially come in time, hopefully in looking at biomarkers that are more indicative of individuals who will be potential appropriate or a privacy potential fits for a certain therapy. But I don't think we're there yet, Brandon. And so, but we are looking, you know, the field is looking at that, but they're also looking at the affective disorders like, you know, major depressive disorder and bipolar disorder. And you know, can, can you glean something from different characteristics of these disorders to find the right patients who will respond to the therapies that are, that are being developed? And so I don't think we're there yet. I think it's still in the experimental stage and looking at various, both biomarkers and also disease characteristic markers and using also, by the way, digital biomarkers to understand, you know, the manifestations of the disease states and then being able to collect all that data to understand what's the best approach in treating various patient populations that could be either treatment resistant to what's available currently or having difficulty, you know, achieving, you know, the, the, the outcome that is desired and so forth. So I think it's, you know, that's what's exciting. And you asked that question early on. That's what's exciting about the landscape now that so many different individuals are really taking on that challenge and really taking on those risks in terms of understanding what's going to work, what's going to be potentially more of a challenging or more aspirational approach, but still very critical to the future of treating mental illness holistically and successfully.
[00:21:35] Speaker B: And we're not quite there yet, but if you throw a number out into the air, when do you think we might start seeing some of these techniques make their way into everyday practice?
[00:21:44] Speaker A: So they're currently being evaluated in clinical trials. I would say probably in the next five to 10 years, you know, we'll see some of this work manifests itself into a way that can be used clinically with a bit more precision. We're looking at, you know, genetics, you know, we're looking at different approaches to understanding the biological basis of disease. And then how can we use more objective measures to understand the effectiveness of these therapies over time? And so that's something that I think currently we're learning more. So every year we learn more than the year before. And so now I think we're encouraged with, you know, the progress that is being made. But still, still we're on a very steep trajectory, Brandon, to ensure that that outcome is achieved sooner than later.
[00:22:45] Speaker B: Yeah, absolutely. And I was just having a conversation with Dr. Smoller over at MGH who is saying that, you know, the state of trial and error in neuropsych treatments needs to, we need to evolve past that. So this is certainly in line with some of that thinking as well.
[00:23:00] Speaker A: Absolutely. I mean, I think the thinking is evolving and it's something that we've, we've got it, it's calculated risk, but we've got to take the risk to try to come up with these novel therapies, novel approaches, looking at various different formulations for more vulnerable populations and so forth. So it's just, you know, can really be.
Persevering is really the perseverance is really the word that I'm looking for in terms of how we move forward in the next decade and beyond.
[00:23:34] Speaker B: Absolutely. And now that you're back on the kind of capital deployment or advising on the capital deployment side of the world, what risks are we not taking that we should be?
[00:23:44] Speaker A: Well, I'm not really advising on how to spend capital and what to spend it on, but just really evaluating different therapies and looking across the landscape in various forms, not just with Bain Capital Life Sciences, but with other individuals as well, looking at novel targets, novel therapies, novel formulations and so forth. I think looking at how it's not so much the target because you want to. Obviously you validate those targets preclinically, you move them into human beings and you. You're hoping that they manifest themselves accordingly. But it's really understanding how the. It's in the approach.
So it's how the. The therapies are, you know, designed or developed. And then in. In these clinical trials and the different approaches, the methodology, you know, all the, the moving parts that are really important to put together very mindfully to ensure that you give the therapy the greatest likelihood of success, to show benefit in the population it's intended for.
[00:24:55] Speaker B: Now, Ray, maybe, maybe. Let's talk about the elephant in the room, if you don't mind.
I know you're no longer actively involved with the Cereval or the ABBVIE team, and you don't have access to the underlying data, but we'd love to kind of hear your reflections on the kind of disappointing phase two news that came out of Andracladine.
[00:25:15] Speaker A: Well, you know, I was really, first of all, I'm very encouraged, I think, by the approach to try to come up with novel therapies. I think that imraclidine, being an M4 positive allosteric modulator, is something that shows great promise. We showed when we were Seravel In a Phase 1B trial that was underpowered, 57% powered underpowered, purposely, because we really wanted to do that trial to really understand one, if the drug worked, two, did it need to be dosed twice a day or once a day? So we answered that question. And, you know, what was really the effect size? What was the effect of the therapy before we launched into larger, more broader trials? And what was shown there, as you know, is that we got very robust results with very robust P values that showed that 30 milligrams a day reduced the pan's total score by 19 and a half points, which is very compelling. And the placebo response was quite low. But again, it was. Which is close. It was like a little over six points. But again, it was in five sites and 75 patients. So it was a small trial. The challenge always is, Brandon, and you see this across the board, really, with a lot of psychiatric trials, is that when you're going from a small trial, now you're opening it up to a larger patient population, so you're increasing your sample size, you're increasing the number of sites. What happens is you basically increase variability, and that's just something that just naturally occurs. So you try to minimize the number of sites which was done in the. In that phase two program that you're alluding to. You know, no more than 24 sites were used in each trial. You minimize the number of countries, and you try to really get the best sites possible. And, and part of the challenge with that, of course, is that if there are competing programs across the landscape, then everyone's using similar sites because they're the best sites to go to. So, you know, you want to. You want to achieve all those. All those objectives, but you also want to make sure, you know, you get the right patients, and you also want to make sure you have swift enrollment, because naturally, people want that data sooner than later. They want to get that medicine to patients sooner than later. So I was extremely disappointed, as was the team with the results that we learned about a week ago Monday. A week ago Monday.
And so I'm confident that the ABBVIE team will continue to understand and do the appropriate analyses to understand what could potentially have been done differently or what potentially went wrong in terms of, you know, the variability that, you know, led to the outcome of the trial. But I do think that the mechanism, surely, you know, is robust, that it provides a novel approach to a therapy that will be dosed once a day with no need for titration, will have benefits not just in schizophrenia, but in other populations, as you know, as well. And so, you know, one of the things I've learned over the years, and you see it across the landscape, it's never linear.
The journey is never linear. We have so many therapies that are terrific therapies, but that have had a, you know, rocky and labile journeys to get to the approval stage by the age by the FDA and other agencies. So I think perseverance, as we mentioned earlier, is important, but understanding your therapy is most important. And so to that end, you can't you can't use one therapy, even if it's in the same class as a surrogate for your therapy. You've got to really understand your own therapy and really learn from the data from your own therapy. And that's what Abbvie, I'm sure, will be doing and redirecting the trajectory of Imraclidine. So I'm excited to see that day when Imraclidine does get approved.
[00:29:17] Speaker B: I want a little bit deeper into maybe the kind of unique challenges of running a larger trial and kind of schizophrenia. I know that you mentioned variability is one of the kind of challenges is that particularly different in psychiatric trials versus non psychiatric trials? Help me understand that.
[00:29:34] Speaker A: Well, I think the variability comes in because the endpoint is subjective. So part of the challenge is you have the positive and negative syndrome scale, the PANS total score. And as you know, it's a scale that, it's a 30 item scale that's rated from 1 to 7. And so that rating is done by a rater who's trained and certified. But nevertheless, there's so many potential issues with subjective scales, as you know, and there's, you know, rater expectation, patient expectation. There's so much that can go into that. Unlike, for example, if you look at tumor growth very different from saying, you know, you have the tumor either smaller or it didn't change, or, you know, so you have something that's a bit more objective. And. But that is the impetus underlying the looking at biomarkers and looking at the precision psychiatry approach is how can we use biomarkers and more objective measures to ensure that the therapy that you are evaluating has the greatest likelihood of success to show its potential benefit. And so when you're conducting these trials, whether it be in depression or anxiety or PTSD or, you know, in schizophrenia, you're relying on subjective scales that even though the sponsor, the company trains the individuals, they're well versed because they've historically been able to rate many patients with these diseases, that there's still variability. And so you see that in trials where you go from, let's say 12 sites to 22 sites to 32 sites of the same therapy, you see that effect size really being impacted and you see the placebo adjusted differences continue to be impacted by that variability. So the way around it is you try to minimize the number of countries, you try to minimize the number of sites. You want to ensure that the patient profile, which is critical to the success of the trial is one that is positioned for, for the greatest likelihood of detecting the signal of the therapy and so things like disease severity weigh in and other factors as well. So again, you know, it's what I meant by it's never linear is that many therapies have had this challenge across the landscape for many years.
And so but what we do know, and especially in the US that the placebo response has increased exponentially. And the FDA published several, many years ago this paper that showed this exponential growth of the placebo response in schizophrenia trials. And so that's just something that we continue to try to mitigate as much as we can. But it's all around the methodology and it's around all these other features that I mentioned.
[00:32:32] Speaker B: Absolutely. Is there a world where we move away from the subjective scoring to some more of these objective biomarker based scores in these conditions? How do you think about that?
[00:32:44] Speaker A: I hope so. I mean, I think it's really trying to find, you know, validated biomarkers that are more objective in nature. And I think there's a, there's certainly a great need for that. And the question is, what are those validated biomarkers? What do they look like and what are they? And that's what I think challenges the, the community in general in terms of trying to find. I know the FDA is very eager and willing to be part of that solution. The question is what makes good sense in terms of finding validated biomarkers that can be more objective and less subjective like they are now.
[00:33:27] Speaker B: Now I've never had to propose new biomarkers to the, to the fda. What does that even look like? How does that happen?
[00:33:34] Speaker A: Well, I mean, I think you have to obviously come up with a biomarker that suggests that it really is the, is appropriate as an endpoint to suggest that the therapy is actually treating the disease.
And so you've got to go through, it's a lengthy process of doing validation work, working very closely with the Clinical Outcomes Assessment Group at the agency and the division itself, depending on which division you're, you're working with to try to go through that process. So I, I personally have not gone through that and I think that many have not gone through that because we haven't really found validated, you know, objective endpoints that we can really point to. But there's definitely a need for, and I know that work is being done in that now. As you know, in Alzheimer's they look at amyloid aggregation potentially as, as the biomarker.
Some others consider the tauopathies use tau as a biomarker.
But in schizophrenia, in depression, in anxiety, in PTSD and other disease states. You just don't have those biomarkers as a surrogate for predicting therapeutic success. So that's just something that the field continues to struggle with. I know there's a lot of work that people are contemplating and others are doing to really understand how to basically make these programs a bit more objective in their evaluation than subjective.
[00:35:09] Speaker B: Well, let's categorize that under the kind of neuropsychiatry renaissance that hopefully we're in the midst of today.
[00:35:16] Speaker A: Yeah, I mean, I think that part of the neuroscience renaissance, as we call it, is really the excitement that has been a result of all the therapies that have work, worked well in the last few years. And a lot of the data and a lot of the initiatives that, you know, are ongoing. And so they speak to what the future looks like and the risks that people are taking now and to look at new modalities and novel mechanisms and novel therapies for the future. So adding it to the list, I think is going to be critically important to look at more objective measures to your point.
[00:35:52] Speaker B: Now, I'd love to talk a little bit about Parkinson's. Talk me through maybe the kind of current landscape of Parkinson's kind of treatment and research. How do you think about it?
[00:36:00] Speaker A: Yeah, so for the longest time, you know, as you know that Parkinson's disease has relied on Levodopa, you know, the Carbidopa combination treatment, you know, for it being an effective therapy to treat some of the side effects of Parkinson's disease. You have the D2 D3 agonists such as Primipexol and Ropinirol. But they also have side effects that, such as, you know, hallucinations and impulsivity and hypotension, that somnolence that, you know, make them somewhat prohibitive after a few years, so they get discontinued and people get put on Levodopa earlier than later. And then you've got therapies like Rasagiline, the MAOI inhibitor that's also used. But again, you know, the Parkinson's community needs therapies that are much more effective, not only in treating them symptomatically, but but also in disease modifying. So there are efforts to look at different disease modifying therapies. You know, alpha synuclein, as you know, has been implicated. And so looking at therapies that impact alpha synuclein, I think are ongoing.
And so that's something to stay tuned for because disease modifying therapies and Parkinson's are desperately needed, but also symptomatic control. How do we, you know, have better therapies for treating the symptoms of Parkinson's that currently are not optimal? And so that's something that the therapy, for example, Tobapadon that Cerebel and now Abbvie are pursuing, which is a D15 partial agonist, which works in the direct motor pathway as opposed to the indirect pathway. And by working in the indirect pathway, then you assume all these side effects that I mentioned earlier. Levodopa performs well, but it acts through the direct motor pathway and the indirect motor pathway. So having something that's a bit more focused like a tabapodon, a D15 partial agonist, I think will be quite transformative to the landscape and being in treating the side effects of Parkinson's disease. But I think the ideal scenario would be having disease modifying therapies where you still need effective symptomatic control therapies, but disease modifying therapies obviously will be the ideal goal over time.
[00:38:20] Speaker B: Now, what is the path to better disease modifying therapies?
[00:38:24] Speaker A: I mean, it's really looking at, again, looking at what is at the culprit underlying the disease and understanding how you prevent the culprit in this case, let's say alpha synuclein and how you basically mitigate that risk, you know, in terms of, you know, slowing down the progression of disease.
So it's not a cure, but it's looking at how do you slow down the progression of disease and how do you catch it early enough so that the, the trajectory of that, of the progression of that disease is actually a much longer and a better one than currently exists?
[00:39:10] Speaker B: You know, why has it been so hard in Parkinson's?
[00:39:12] Speaker A: You know, we started off the conversation with saying that we just don't know enough about the brain to know, you know, exactly how to best approach it. And I think that's really true. And I think, you know, we look at, if you look at, you know, amyloid, amyloid and tau and alpha synuclein, if you think about all these disease states, it's really, it's really hypothesized, you know, and you know, they perform well on these, on these endpoints that are used. But at the end of the day, I think it's more of a syndrome than it is one particular something that you can point to. It's more of a syndrome, I think it's, it's a conflation of a lot of different things. And so understanding and breaking that syndrome down in terms of what's the key culprit, but what are the Other contributors to the disease, as I see it, and the complexities of that is something that I just think over time just needs to be better understood. But for now, looking at these therapies and looking at potential contributors to the disease itself is, Is, I think, a good, obviously a good approach. But there's more to it than just a specific, you know, protein or a specific issue. I think it's more about what are the other contributing factors are there that we're potentially not yet learning about or knowing enough about?
[00:40:31] Speaker B: Certainly not monocausal.
[00:40:33] Speaker A: No, no, no, not at all. Not at all.
[00:40:35] Speaker B: I mean, I know it's not well understood, but maybe hypothesize with me a little bit. Where, where do you think we should be exploring more if we think of this more as a syndrome? Where do you think more kind of research needs to be done to understand?
[00:40:50] Speaker A: Well, you know, I think that, you know, I think understanding, you know, even, Even, you know, even post mortem, you know, understanding, you know, the diseased brain and what, what else is contributing to the. The actual kind of constellation of symptoms that the patient is experiencing, you know, we've done that, I think, well, to date, but still more work needs to be done. It's just, I think, break. Brandon's just breaking it down and understanding what else?
Because, you know, for a long time there's been this, let's say, take Alzheimer's as an example, this whole, you know, debate about am, you know, amyloid beta versus, you know, versus tau. And so, and so how, how. How do they. Is it. Is it really about amyloid and tau or is there more to it? And I do think it's a syndrome, and I think there's probably more to it. But the question is, what is also implicated in that? And that's the, the question that needs to be better understood. And the same thing with Parkinson's. You know, alpha synuclein has been implicated. But is it just alpha synuclein in general or is it there? Or is there more to it than that? And there's probably more to it than that, but you have to start somewhere. And so. But I don't. I think it's oversimplified. When you just look at alpha synuclein, when you just look at amyloid, when you just look at tau, you know, I think there's more to it than that.
[00:42:19] Speaker B: It's convenient to hope that things fit into these neat categorical distinctions, but to your point, more complicated than that.
[00:42:27] Speaker A: Yeah. And you've got to, Brandon, you've got to start Somewhere, you know, because I think these are, I mean, look at als, look at ms, look at Huntington's. I mean, you can go on a lot of devastating illnesses that we still aren't very close to at all understanding so that we can come up with better. I mean, we will come up with therapies, but we need to come up with better therapies that are disease modifying, that ultimately potentially even are curative in some way. And that's obviously, that's probably not in, you know, in a lifetime. I think it's fair, far away in terms of the curative piece, but in terms of understanding the disease to a point where you can come up with, you know, better targets. A better understanding is really, really critical. But when you just don't understand the disease well, how can you understand the therapy that is fit for purpose? And so that therein lies the rub. And I think that gap over time needs to be addressed and it's being addressed. And you know, we've made some progress, but there's still, for people or individuals who are suffering from these illnesses, it's, it's just not enough. And so we just need to continue to persevere and invest in the research that needs to be done to understand it better.
[00:43:56] Speaker B: And, you know, I'd love to maybe close on this idea of this renaissance. What are you most excited to see happen over the next 10 years?
[00:44:02] Speaker A: So I'm most excited to see disease modifying therapies. You know, I think those are really, really important and, you know, good for the two companies that have pursued it in Alzheimer's. And I still think more work needs to be done in that area in Parkinson's. I think it's imminent that we'll see disease modifying therapies. They're on the horizon. And so I'm excited about that. I'm also excited about potentially looking at more objective biomarkers, as we spoke about earlier, so that we can give a lot of these therapies that have failed initially, give them a better chance to get to the patients sooner than later. And then looking at new classes of therapies, you know, that are being developed currently and looking at new targets and just the, the, the trust and the confidence and the commitment that I think the external and internal communities have shown in neuroscience. Because I always remind everyone that just because we're in the field we're in, it doesn't make us immune to, you know, the illnesses that are, are, you know, plaguing so many. And so it continues to, it continues to give us the motivation that and, you know, and the passion that is needed to move the field along. But I think that we'll continue to not only look at the therapies, but also look at the patients who suffer from these therapies, Brandon, because I think they do need the psychosocial support and the focus that is needed to give them the support beyond just the medications, but also give them access to clinical trials. And I think having these new platforms of decentralized trials and so forth will give individuals the opportunity to participate in therapies, in trials with therapies that potentially will be beneficial to them and to many. And so access to these clinical trials and access to better therapies is really very critical now more than ever, you know, so looking at those modalities that give them access and will be really critical. And I know that part of your audience is listening are individuals who can benefit from those types of approaches.
[00:46:25] Speaker B: And now you may know my traditional closing question here, but it's the magic wand question. If you got a magic wand and you can change anything about how research is done in this space today, what would you change?
[00:46:35] Speaker A: I think coming up with objective biomarkers, I think the biomarkers is really it because I think that there are a lot of therapies that do work well, but they just don't have the opportunity to show it readily.
And so the burden of cost and work to get them to show their benefit is really monumental in many cases. And so, you know, having objective biomarkers that will allow us to better understand the benefits of these therapies, I think is really important in the neuropsych space for sure. I think some other areas like oncology and so forth have them already, of course. But I think in the neuropsych space and you know, and in other other therapeutic areas, as well as in pain, for example, is in other areas that we didn't touch upon. But it's also think about how many pain medications over time have failed in order to, because of the subjectivity of, of how you assess pain. So, you know, looking again at having objective biomarkers to evaluate the effectiveness which is both the, you know, efficacy and the safety tolerability of a therapy is really important.
[00:47:54] Speaker B: So if anyone listening is excited to kind of pursue a direction there objective biomarkers, Ray wants to hear your thoughts.
[00:48:01] Speaker A: I mean, I think it's so critical, Brandon, and I think, I think so many individuals have the scars, you know, to show that that's a great need. Of course, you know, the magic wand also extends to understanding the brain better, but just being practical in the immediate future, you know.
[00:48:20] Speaker B: Well, Ray, I want to thank you for taking the time and lending us your brilliant brain for this episode. Thank you so much for, for joining us for the show and sharing your thoughts.
[00:48:27] Speaker A: Thank you for the opportunity. I hope that was helpful and I really enjoyed, enjoyed the discussion. Thank you.
