Congress Highlights: Schizophrenia International Research Society

View the publications here:

• Oral Presentation on Phase 2 Study of LB-102 in Adults With Acute Exacerbation of Schizophrenia

• Poster on Brexpiprazole Vs Placebo With Active Reference of Aripiprazole in Adolescents With Schizophrenia

• Oral Presentation, Keefe R: Iclepertin for Cognitive Impairment Associated With Schizophrenia

 

Transcript:

Dr Mattingly: Thank you for everyone for joining us for this ACCUMIN talk about recent updates from the SIRS International Schizophrenia Research findings. Our conference champion today is Professor Christoph Correll, coming to us from Germany, a good colleague, a good friend. And he brought what he thought were some of the top highlights from the Schizophrenia Research Society. Joining us today are my good friends, Jelena Kunovac, Andrew Cutler, Rakesh Jain, and myself, truly coming to you from all across the world with the exciting news about what's happening in the field of schizophrenia. 

Dr Correll: The selection here includes LB-102, which is the methylated version of amisulpride, a drug known for 40 years in Europe, always comes up high on meta-analysis, like 0.72 effect size compared to 0.56 with olanzapine. But old data, often head-to-head, so you don't have placebo in there. So, less expectation it won't work. But some recent studies also showed it works. But the problem with amisulpride is that it's not very brain penetrant. So, LB-102 is a methylated version to get it into the brain. So, instead of 600 to 800 milligrams, you need 50 to 100. And with that, you have less buildup peripherally. So, the QT prolongation, which was the highest with amisulpride in the meta-analysis is basically not an issue anymore, and prolactin is also better. So, these are the phase 2 data where 3 doses, 50 and 75 based on PET data, were selected and should go into the 60 to 80% post-synaptic dopamine blockade. A hundred was exploratory because the worry was that it would cause too much dopamine blockade and, therefore, it was underrepresented. It didn't have a 1:1:1 randomization. It had a smaller group. What had the highest effect size despite being smaller was the 100 milligrams.  

So, maybe we actually selected the wrong doses and the next—a number of companies obviously worried to go above 100, but they will go after 100 in the phase 3. So, they're just—they’re raising money for phase 3 now. And this confirmed that the methylated low dose actually works and had effect sizes that were pretty good in the 0.6 to 0.8 even range for 100 milligrams. But they calculated it in certain ways like Karuna did. So, I think we can say this works in an acute setting, 4-week study. And even though it's an older drug, it's exciting because at low doses you might even have negative symptom effects because amisulpride has this 5-HT7 blockade in the right turning stereoisomer, and left, it's D2 D3 antagonism. So, that's exciting because there will be a phase 3 program, and this could be, like, in the quadrant. Like, Cobenfy is being very efficacious and having relatively little side effects because it doesn't have, except for prolactin elevation, not much weight gain, not much sedation or metabolic effects.  

Dr Cutler: But some drug-induced movement disorders. Amisulpride was—  

Dr Correll: At higher doses, yes. But not so much at 50 and 70. Yeah, so it is a D2 blocker. Yeah. 

Dr Kunovac: So, how about QTC?  

Dr Correll: No problem. 

Dr Kunovac: Because the QTC was when I was in Europe, that was kind of an issue past 400 milligrams. 

Dr Correll: As I mentioned, so this is because most of it stays outside of the brain. So, that's why you need to go so high and you have the peripheral side effects. Like, paliperidone basically stays outside the brain. That's why you need 3 times the dose for pali than for risperidone. And you go 3 to 12 instead one to 4 because the 9-hydroxy doesn't penetrate the blood-brain barrier very well. And you have even higher prolactin elevation with paliperidone than with Haldol because, again, it stays outside. So now, with the methylated version, very little stays outside and QT is not an issue. 

Dr Cutler: Interesting. 

Dr Correll: Or at least at those doses. 

Dr Cutler: You know what I found Christoph too, there was a literature of this drug for depression that it actually looked very good for depression.  

Dr Kunovac: Well, we use it for an antidepressant in the lower doses in Europe because it actually dopamine 2 agonist in the traditional formulation up to 300 milligrams, it's considered to be more of a dopamine 2 agonist, not the antagonist. 

Dr Cutler: Agonist, huh. 

Dr Correll: If anything, partial. But I think it's more the 5-HT7. Because what they did, what Otsuka did, was a racemic mixture, nonracemic mixture of 85%, right turning. That's 5-HT7. And 15% left turning. So, that almost made it as an antidepressant. So, it's most likely a lot of that. But as Jelena is saying, it's approved for dysthymia actually in Europe.  

Dr Cutler: That's right. Well it actually has appreciable affinity for D3 as well. 

Dr Correll: Yes. It's same affinity, D2 and D3. That may help the negative symptoms.  

Dr Mattingly: I have a question for you. So, we batted this around. So, how much does methylation of a molecule—is that a common way to increase blood-brain barrier penetration? 

Dr Cutler: Yeah, I hadn't heard that before. 

Dr Correll: It's one way. I don't know whether other drugs have been heaved into the brain that way. But it makes it just—yeah, it makes it more blood-brain penetrant. I can't think of another example. 

Dr Jain: There is one, and that's L methyl folate versus folate. The methylation is the key to— 

Dr Cutler: That makes sense. 

Dr Jain: —dramatically improving not just brain penetrance, but reducing the variability between people. 

Dr Cutler: Yeah, that's good.  

Dr Jain: I looked into the naturalistic use of the drug outside of Europe. So, Asia has this drug too. Not a particularly popular drug there, despite the fact that it's generic. Olanzapine is generic, Risperidone is generic.

Dr Correll: Never been marketed. The French company didn't do anything with it. So, in Germany, I just did a recent study where we looked at drug utilization. It has basically 11% without any marketing, amisulpride.

Dr Cutler: To be honest, to me, the most interesting thing here is the methylation, is the technology because the molecule itself— 

Dr Correll: Well and getting it into the US because of that. It's the only benzamide antipsychotic we have. And it may have some effect on negative symptoms. So, we have another player. 

Dr Cutler: Okay. 

Dr Mattingly: Andy, I was like you. I was taken back by the technology play. 

Dr Cutler: Yeah, I think that's the most interesting. 

Dr Mattingly: This is the path to increased blood-brain barrier penetration and Rakesh, I like your example.  

Dr Cutler: Yeah, that is good. 

Dr Mattingly: Makes it very interesting. 

Dr Kunovac: Yeah, it is. But just one question, Chris, is so when we use that in Europe, we use lower doses for negative symptoms like 800 milligrams. We use higher doses, 400 to 800 milligrams for the positive symptoms. Now, the study that they reported uses these significantly lower doses due to methylation was in positive symptoms. How would you then expect that we're going to see improvement in negative symptoms if we are having such an improvement in positive symptoms? 

Dr Correll: Well, we'll go down the study that we're designing to 10 or 20 milligrams, which is the same as going from 800 to 50 or 200. We're just looking at where the PET study—again, where the cutoff would be. But the company doesn't have the money right now for negative symptom studies. They need to first do the phase 3 study. 

Dr Cutler: Well, you know what clinicians are going to do then. They're going to add this for negative symptoms. They'll add it to other drugs. 

Dr Correll: Yeah, but that doesn't work because at higher doses, the reason why it's not working for negative symptoms anymore is because you are dampening negative symptom effects by too much open blockade. When you add it, you already have the dampening. 

Dr Cutler: Oh, okay. You're right. So, you add it. See, I kind of feel like Cobenfy makes this drug obsolete personally. And getting this paid for, you know, if the mechanism—it's not going to convince payers that it's that differentiated, I don't think, but I could be wrong. 

Dr Correll: Well, let's see how high the efficacy is because, I mean, Cobenfy only treats 40 to 50% of patients and we need a better—this is a better olanzapine basically. It's like olanzapine, at least in the oomph. But it doesn't have the metabolic side effects. So, it puts Lybalvi out of business in a way. 

Dr Mattingly: And Christoph, you think that the prolactin is significantly decreased by the mechanism? 

Dr Correll: It's somewhat decreased, but it's still there. But it's like risperidone basically, and we still use risperidone. 

Dr Cutler: Well, it's not as high as risperidone. Risperidone's the highest. 

Dr Kunovac: I mean, sulpiride was very high in higher doses. I think it was higher than risperidone and 400 to 800. That was the biggest.  

Dr Mattingly: Christoph, why don't you walk us through how you rated the various levels of importance, both scientifically to the molecule and to the class. And then, we'll each take turns kind of going through it. 

Dr Correll: On the science, I gave it a 9 because it's really novel on making the drug differently. The molecule, I was less excited because that's basically—it's still amisulpride. And the class, it is a D2 antagonist. So yes, it has some other option, but it will not change the class of D2 antagonists, antipsychotics. That was my evaluation. 

Dr Mattingly: I'll go next. So, I gave it, on the science, a 7. I think I was very interested in the methylation as far as increasing blood-brain barrier penetration as a way to potentially increase efficacy and decrease side effects. And Rakesh, it made me think about a variety of molecules that that might be a pathway for. The molecule, I was more optimistic. You know, amisulpride has always had high efficacy, but it was limited by side effects. So, if this truly pans out as a way to improve the tolerability, I gave it as a 9. And then, finally, did the class of effect. I gave it a 7. I came back down there. Is this going to knock everybody else out of the water? No. But I thought it was very important to the class as far as ways to maybe increase, once again, CNS penetration through methylation. 

Dr Cutler: Yeah. Okay. Well, I'll go next. And first of all, I'm very glad we had this discussion, Christoph. You've changed my thinking on a couple things. First of all, for the science, I probably now—I scored a 7—I would probably go a little higher because to me that methylation could be—you know, for instance, if it's like deuteration, that's really important. That has made a big difference in certain molecules. So, perhaps I would go a little higher there. For the molecule itself, I gave it a 7. It's important because it's going to support further development of the molecule. And, obviously, this is a very effective drug, as Greg said, may have unique efficacy for negative symptoms, which is a huge unmet need. For the class, I gave it a 6 for some of the same reasons we've heard earlier here. It's—you know, the mechanism's not that novel. I'm very concerned about payers and getting it covered when it's going to be hard to convince them of this being very differentiated. Although if the efficacy pans out, you might have an argument. So, I have always been a little bit down on amisulpride coming to the US. I feel like, to some degree, the horse left the barn here a little bit. That, had it come out 20 years ago, even maybe 10, 15 years ago, I think it would've been a very big deal. But I certainly am willing to be wrong, and I think it would be great to have another option. And essentially, clinicians will sort it out. They'll vote with their feet and they'll figure it out. Yeah, for the science, I'm going to up it to an 8. But I'll leave my other ratings where they are. 

Dr Correll: And then, the other question is—I mean, this has obviously application if it works for negative symptoms or bipolar depression because it could cover from above and still at low doses have enough antidepressant effect. Do we consider this or is that only for schizophrenia here? When we say class, I mean atypical antipsychotics have been used for other indications. What is class? 

Dr Cutler: No, good question.  

Dr Mattingly: I think it crosses across those, Christoph. I think just in the fact that I— 

Dr Correll: Transdiagnostic. 

Dr Mattingly: Yeah, I thought the science was transdiagnostically important, for example. 

Dr Cutler: But I agree, Christoph, that's a bigger unmet need. And if this was a study for bipolar depression, I might be a lot more favorable. I agree with you. That would be a nice niche for this drug. 

Dr Correll: But we will not consider then—this is the data we have, so we don't consider prospect. Okay. Rakesh? 

Dr Jain: Science, I think I'm going to still stay on 6. So, even though methylation is profoundly interesting, many of the side effects that we deal with other than QTC are, in fact, central. So, just because I've got a compound that's methylated and I'm giving them less of a dose at the end of the day to treat schizophrenia—just to stay focused on that—I'm still going to have to use substantial doses. In countries where no atypical is marketed, period—and I'm using India as an example where they've had this compound for many decades now—psychiatrists have learned not to use this drug very much. 

Dr Correll: Oh. 

Dr Jain: Yeah. And there's no marketing there at all because everything is generic, is generic the day it comes in. Everything is branded generic. You know what that means there. So, I'm excited. I'm excited you guys have both, Christoph and Jelena. You actually have experience with it. But I wonder if this was the 18th atypical, which is what it will be in the United States. I think Andy's right. What will it be, its place? So, I worry about it. In terms of molecule, same reason. I didn't give it a 5. I gave it a 6. And in terms of class, my reading was linear, not the bifurcated way that we are looking at side effects and efficacy on different tracks. So, I think I'm going to stay on 6 with all 3. 

Dr Kunovac: And here comes my turn.  

Dr Correll: A pessimist. 

Dr Jain: No, not a pessimist. I think on this one I want to be— 

Dr Correll: No, I meant Jelena. 

Dr Jain: Oh, okay.  

Dr Kunovac: Yeah, I’m the pessimist when it comes to this. 

Dr Correll: Jelena is Dr Doom. 

Dr Kunovac: I am Dr Doom when it comes to this molecule. And importance to science, potentially I can change my rating from 3, let's say to 5. I can say there is some relevance in methylation. But again, my thinking was, well, hyperprolactinemia is centrally mediated. The medication still—  

Dr Correll: It's not. It's not. It's peripherally, it's peripheral.  

Dr Cutler: It's just outside the blood-brain barrier. The pituitary sits just outside.  

Dr Kunovac: It's right there, but I still—I'll give it 5 when it comes to importance of science. Importance to molecule, I didn't learn anything about this molecule I didn't know before, after using. So, I can't give it more than 3. We know it's effective. We know the data. There is a study. I think it was published 2019. First use schizophrenia, where it was the molecule, the medication that the patient stayed the longest. It was the second most efficacious medication after clozapine. So, this doesn't tell me anything. It tells it works. And, at the end of the day, it also makes me a little bit more confused because if you look at the effect size, the effect size in 50 milligram was 0.61. The effect size in 75 milligrams was 0.41. The effect size in the small group of 100 milligrams daily dose was 0.83. When I have the lower end, the higher doses having a higher dose, having the higher effect size at the middle dose, I'm questioning what's happening over there and how is that going to be replicated in a larger study. So, I'm going to stay importance to the molecule, 3. And importance to the therapeutic area, I'm still going to stay as number 3. Because as mentioned, we have 18 atypical antipsychotics that are out there. It's a dopamine 2 antagonist. Yes, it's a different class of a dopamine 2 antagonist, but I'm not sure that the payers would care about that when it comes to the relevance of this molecule to be used in the regular practices. 

Dr Correll: Okay, great. Let's go to the next one then. Okay, so that's the study that actually I'm the last author on. So, this is— 

Dr Mattingly: Highly important. 

Dr Correll: Well, it's a necessary study because brexpiprazole was approved in the United States based on pharmacokinetic bridging. But there was never an RCT against placebo. And almost no company—I mean, in terms of the atypical studies for kids, not a single company had an act of control. And here it's the first study that actually benched brexpiprazole against aripiprazole, and I think that's very gutsy. It didn't pan out as nicely as wanted. Because on the efficacy, aripiprazole looked a little better on everything. But on safety, brexpiprazole looked better because there was less akathisia, less restlessness. 

Dr Kunovac: But just a question. That was numerically. That was not statistically, is that correct? 

Dr Correll: Yes, yes. But, again, it is what it is. I think that brexpiprazole is underdosed anyway because it should have—2 barely makes it in adults. You go for depression until 3. And so, the dose for psychosis should have been 4 or 6. But, be it as it may, here we go. And I think it's an important study because this will lend itself for—and has already lent itself for—approval in Europe down to the age of 13. There are very few drugs approved because there is a common comparator. And I want to give the company more power for having actually done the 3-arm study. 

Dr Mattingly: How many antipsychotics are approved for adolescents in Europe, Christoph, for schizophrenia? 

Dr Correll: Only paliperidone, aripiprazole, and lurasidone. Even risperidone and olanzapine were not approved. And clozapine for—grandfathered it. So, this is now the fourth one. And the only one that went down to 13 is lurasidone because the other drugs, paliperidone and aripiprazole, didn't have enough patients 13 and 14. They only got the approval 15 to 17, even though overall it's positive. But when they were forced to do the sub-analysis in the 13-, 14-year-olds, it didn't pan out for the other drugs. They had too small a sample. So, for Europe, it makes a big difference. Here in the US, I mean, it was approved before. What do we learn? I understand, but— 

Dr Mattingly: Let's go to our ratings. 

Dr Correll: Alright, so I thought on the science, it's an active control trial. We need that. It's so rare that this is done with placebo in there. The molecule, it makes it now expandable in areas of the world to pediatrics. And we have now real data, not just PK data. So, it's the first proof that brexpiprazole, while it's hard to separate from placebo in adults, even at 2 milligrams here, it worked at a mean of 3 milligrams. But for the class it doesn't really make a difference. 

Dr Kunovac: I'll go second this time, if that's okay. For the science, I actually didn't think along those lines. Yes, the studies are rare where we have a comparator, but this is really not a science. This is the methodology that pharmaceutical companies choose to implement. So, that's why I rated it 2 on science, 7 on importance to the molecule. I think it's great that we have the data that is effective, well tolerated in this patient population and that's what we need. And I gave it 2 to the therapeutic area because it's not going to change much what we do when we treat that population. 

Dr Correll: Even in kids? I mean, for adults it doesn't, but for kids it now opens up whole of Europe, which it was not able to give, brexpiprazole. 

Dr Kunovac: I must say, I'm no longer so familiar how hard it is to prescribe off-label with— 

Dr Correll: It's not available. It's not available. 

Dr Kunovac: It's not available. 

Dr Correll: In Germany at least—that's not true. It's available, but it's not approved for schizophrenia—is it approved for schizophrenia in other countries? It's at least not approved for schizophrenia in Germany. It will now be because of the active comparator. 

Dr Kunovac: If it is going to change that way, then I will adjust my rating importance to therapeutic area to 6, if that's going to be the game changer for that. 

Dr Mattingly: Christoph, you're a good negotiator.  

Dr Correll: Sorry. 

Dr Kunovac: That's great.  

Dr Mattingly: No, that's what it should be. Rakesh, you want to go next? 

Dr Jain: Sure. I don't know what to add beyond what Christoph said. I was struck by a population that's underserved, understudied. And in this population, we not only don't have many studies, we don't have a population with an active reference. That really impressed me. I'm a hard grader just, I think, because I'm from India. Seven, to me, is like a B+, A-. And so, that's the reason why I gave it 7, 7. For the class, I gave it higher because this now offers this class of medications in a legitimate way to a whole group of people who didn't have access to it before. 

Dr Correll: But is it the class that it’s offered or is it the molecule? 

Dr Jain: It's fair. Your point is a fair one. I could have shifted that, but I elevated the class and the molecule. I conflated one with the other. But I also think with the class, having a study with both of them in a double-blind compared for efficacy, tolerability should remind us clinicians that while efficacy is not all that different between our compound, safety can be. And as a child psychiatrist, I'm unusually worried about side effects in this group of patients. It's interesting. Of the 5 us, I think 3 of us are child psychiatrists. No, 4 of us are child psychiatrists. So, that's why I gave it in the 7 to 8 range. 

Dr Mattingly: Andy? 

Dr Cutler: So, I certainly agree with what my colleagues have said above. I think this study is a big deal for a couple of reasons that have been mentioned. And then, one important one that wasn't mentioned yet. I think the choice of the active comparator was inspired because many clinicians kind of feel like brexpiprazole is sort of son of aripiprazole. I still think people think that all these years later. And I had the wonderful experience a year ago. I was in Japan. In Asia, by the way, Christoph, it's only approved for schizophrenia. But I was in Japan helping to launch it for the MDD indication, and I got to meet Dr Kikuchi. And Dr Kikuchi of Otsuka is the man who developed aripiprazole and brexpiprazole, basically discovered them. And I had a great geek-out session talking to him about what was he trying to do with brexpiprazole? 

And, essentially, he increased the affinity for serotonin receptors and for the norepinephrine receptors to do 2 things—to try to improve particularly efficacy for mood disorders, not necessarily schizophrenia, and also to improve tolerability, particularly with respect to akathisia. So, I think this is a big deal. As far as science, maybe I could have given it a higher score. But I felt like we have some other studies that are similarly designed, especially to support European approval. For the molecule, I think it's a very big deal. Again, because it's differentiating from aripiprazole, which is widely used, and because it gives it a broader indication, a broader use. I think that brexpiprazole is kind of tailing off in its use in the US to some degree. And certainly when lumateperone gets the depression indication, I think that hurts them a lot. So, this is important. And for the class, I gave it an 8 simply because, as Christoph said, we just don't have enough medicine studied or approved in this population. As we all know, a very high percentage of psychiatric conditions start before the age of 18. And certainly, schizophrenia is one of them. So, I was actually pretty high on this even though it's an established older molecule. 

Dr Jain: Good.  

Dr Mattingly: Andy, I was similar to you. So, I gave science a 6. Listening to this discussion, I'm tempted to go up to a 7, but I gave it a 6. I'll stick with 6. I was impressed by the fact that it was an active control study. And I was impressed by you, Andy. As you said, it was an active control with another dopamine partial agonist. 

Dr Cutler: That's right. 

Dr Mattingly: I thought was very interesting. And the fact that it came out with less side effects than the other agonists, which is already around most of the world, I thought that was important. As a molecule, I thought it was very important, especially in my European friends and European colleagues. I can imagine, Christoph, being a European child psychiatrist, and now I have this medicine that is likely to be approved and it's got a lower side effect burden than aripiprazole. So, I thought that was important, very important to the molecule. And for the class, I came down one notch. I gave it a 7. I thought it was still significant to the class, especially the child psychiatry class, to have another medicine approved, to have a partial agonist. I think it helps to dispel some of the myths about partial agonists aren't effective. See this control study. And, similar to Andy, we know that our kids tend to be very sensitive to extrapyramidal side effects. So, being able to minimize those EPS side effects I thought was important to it. 

Dr Cutler: Yeah, Greg. So, it's interesting. This validates what Kikuchi was trying to do. He actually showed less side effects with brex. So, I think that is a big deal. 

Dr Jain: Christoph, how significant were the differences in, say, weight gain, akathisia? 

Dr Kunovac: Numerically— 

Dr Correll: Not great, not great.  

Dr Kunovac: Not great. So, we really can't say that there was a difference in side effects. 

Dr Correll: Exactly.  

Dr Cutler: Oh, the summary we read it said— 

Dr Kunovac: Numerically. 

Dr Correll: Lower. It was numerically lower. 

Dr Cutler: Oh, okay. 

Dr Correll: And it was already relatively low with aripiprazole too. But, granted, this is spontaneously reported side effects. If you did ratings, it might be different. And the weight gain was a little higher with brex because Kikuchi also increased the histaminic in order to lessen insomnia. So, there's less insomnia, which we show here. 

Dr Cutler: That's right. 

Dr Correll: But there's some more weight gain. 

Dr Cutler: Good point. There is more weight gain. So, wasn't akathisia clearly less though? 

Dr Correll: It was numerically less. 

Dr Kunovac: Just numerically, nothing statistically. 
Dr Correll: Let me tell you the numbers if you're interested, hang on.  

Dr Jain: Yeah, that would help. Yeah, thank you. 

Dr Cutler: Yeah, I am kind of interested now because the summary we said—just said better tolerated or less side effects. 

Dr Correll: So, the difference was insomnolence 4.5% versus 10.8. So, it cuts it in half. But 90% or 89% didn't have somnolence in aripiprazole. Akathisia 3.6 versus 6.9. Cuts it in half. 

Dr Jain: Are those not big numbers? 

Dr Correll: They're not big numbers. It's 3 out of 100. 

Dr Jain: Okay. I see them as big numbers because what I've learned from clinical studies and from patients is, for some odd reason, when I give these meds to kiddos, studies tend to grossly underreport what I end up seeing clinically. So, if in a study, a controlled study, I'm seeing a 50% difference, to me that's a 50% difference. 

Dr Correll: Yes, but 7% versus 3.5%. So, 93% on aripiprazole have no problem with it, at least in this study.  

Dr Jain: Which is interesting because I see far more than 90%. That's true. That's why I'm conflating that to what I was—I thought I was going to be revising my numbers when you said there was no statistical difference. But I think I'm going to hold strong because that to me is significant, not from a study perspective, but my translation of that. 

Dr Correll: The biggest difference is 400% less fatigue. But, again, in low numbers. It's 1.8% for brex versus 7.8% for aripiprazole, which had more somnolence and more fatigue. So, this is more activating in a way without causing more insomnia. 

Dr Cutler: I think we would all agree. The Achilles heel of aripiprazole though is akathisia. I think we would kind of agree with that. That's certainly the impression our colleagues have. 

Dr Mattingly: And, Christoph, as a parent who's had a kid who's been on atypical antipsychotics because she lives in the spectrum, these numbers are actually really reassuring. Because I have a kid who did get ticky, twitchy on almost all the treatments we've tried. So, they have something that cuts those risks in half. That's an important finding for me as a parent and for me as a clinician. 

Dr Correll: Okay, let's move on to the next one then. Made it into Lancet Psychiatry. Impact factor of over 30. So, not bad. Okay, iclepertin, the disaster. As you know, phase 2B worked with a 0.36 effect size. Not great, but anyway it did on the MCCB. And the dose that worked the best was carried forward, didn't separate on scores. They were able to add not only scores, but also the VRFCAT. And now, in 3 studies over 1200 patients, nothing, nothing, nothing on any of the primary or secondary outcomes. So, that's important knowledge because the DAAO inhibitor luvadaxistat didn't work. This doesn't work. So, maybe we should give up on coagonists. 

Dr Cutler: Didn’t work. Yeah. 

Dr Correll: Alright, let's rate. So, for science, I felt it was really important to know this was very well done. And, for the molecule, it's relevant because it's dead. And for the class, it’s very relevant because maybe we shouldn't pursue any of this for cognition any longer. 

Dr Mattingly: So, I'll go next. Christoph, I was like you. These were very well-designed trials. Many of us had had input and been watching these trials as they kind of moved along. I thought they were as well done as you could do 3 large trials, well powered. So, scientifically, I think it was 9 on the impact for this class of molecule. For the molecule itself, I gave it a 9, maybe even a 10. Probably the end of this molecule at least for cognition and schizophrenia. And then, finally, for the class of molecules as far as these glycine modulators, when it comes to cognition in schizophrenia, it was very disappointing. I think it was very saddening for many of us taking care of patients with schizophrenia. And I think the impact of the class was a 9 as well. 

Dr Jain: Okay, I'll be happy to go next. The science, just like you guys, totally believe in it. Molecule because I think it, well I believe it's dead; therefore, I gave it a one. So— 

Dr Correll: Maybe you want to give it a 9 because it's very important for that it's dead. 

Dr Cutler: Yeah. 

Dr Jain: Yeah, because I confused—that's why this conversation is helpful. I got it. Yeah, and again, for the class, I gave it a 9 in the—and I explained it in my notes—the 9 meaning I think it conclusively tells me that this class we should not be proceeding with. So, that's why I've been very borderline in extremes—9, 1, 9. 

Dr Correll: But now, you may want to reframe the 1 to a 9, correct? As you look at it from the other side. 

Dr Jain: Assuming we're aligning that that's how we're going to look at it going forward, absolutely. 

Dr Cutler: Yeah. You're a 9, 9, 9. I like that. 

Dr Correll: And Andy is an 8, 8, 8 for similar reasons.  

Dr Kunovac: But I'm going to stick with 4 to science, and I will explain to you why. While Chris, your comment says here that it was a sound study design. I'm a little questioning the study design because I don't know which number is the study where we have a positive phase 2 data. And we use the same tool, same metric, same design, and we cannot replicate that in phase 3. So, it's hard for me to rate that as science being 9 because I think we're doing something wrong in terms of methodology. We either need to identify different patients, subpopulations that we can actually evaluate in these clinical trials. Because maybe when we scale up from 200 patients to 1800 patients, we have a much more diverse patient population or we have to have a different better patient stratification. So, that's why I'm going to give it, when it comes to science, 4. When it comes to molecule, definitely I'm revising that after we clarified how we rated it, I'll give it to 9. I will no longer develop that molecule. Molecule is dead for me. And the same thing for the class, 9. We tried. It didn't work. 

Dr Cutler: Yeah, I just want to add one thing because I agree with everything. And the one thing is unfortunately the FDA or whoever did not allow them to limit those to those who had higher levels of baseline cognitive impairment. And I think that in studies like this, and this is kind of what Karuna did, if you remember, they sub-analyzed their data based on one standard deviation or more below the norm. And so, I kind of feel, like you're saying Jelena, it's sort of this heterogeneity. All patients with schizophrenia probably have some degree of cognitive impairment, but some have way more than others. And really, it should have been looked at in the group of patients who probably could have benefited the most. So, that's a concern I have, and I understand. I've talked to them. They're going to be doing a sub-analysis to look at that to see. But otherwise, I do think it’s dead.  

Dr Correll: They did. It's negative.  

Dr Cutler: Oh, they did? They did that subanalysis? 

Dr Correll: Yeah. 

Dr Cutler: I don't think they did yet. They told me not yet. 

Dr Correll: Okay. But the thing is, the FDA doesn't tell them not to do it. It's marketing. Because once you have it in there, then clinicians have to actually rate it and show it. 

Dr Cutler: That may be. 

Dr Correll: Yeah. But the problem is that people who may be in the normal range could still have had a decrease from where they should have been. 

Dr Cutler: Okay, fair enough. Fair enough. 

Dr Correll: Yeah. But anyway, it's dead. Next. 

Dr Cutler: But it's a shame because it's such a huge unmet clinical need, as we know. 

Dr Correll: But you know that they're developing another pro-cognitive agent. If that goes through, it would be 2034 that it gets approved. So, it's a long haul. 

Dr Jain: Oh wow. What's the mechanism for that? 

Dr Correll: They haven't disclosed that yet, to me at least. 

Dr Cutler: Well, there's a company that's developing a pure M1 agonist for cognition specifically. And then, we know Cobenfy may be able to demonstrate something. Because M1, I think, does make sense. That is a pretty valid pro-cognitive mechanism. 

Dr Mattingly: Is the field of cognition in schizophrenia, is that a viable pathway for exploration? Having been a part of a number of those trials, the problem is even when they're positive, the effect size is usually about 0.3. And a 0.3 effect size drifts into the placebo effect just so easily. And as Jelena said, if you have any scatter or heterogeneity in your data in your patients, a 0.3 effect size gets lost in the background noise. Do we think that this is a viable pathway going forward or is this a pathway that concerns us for future research? 

Dr Correll: Well, it concerns us because nothing has worked. It concerns us because cognition is highly multi-determined. It's not just one neurotransmitter and one neurocircuitry. So, I think the drugs that will or have a chance of working need multiple neurotransmitter pathways. So, that's where maybe M1 M4 works, even potentially in concert because M4 also has some activity in the hippocampal area. It's why I think RL-007, the Atai drug, may have a chance because it's a triple agent. It has GABA modulation agonism and has nicotinic receptor agonism and has cholinergic muscarinic agonism. So, we need, I think, multi-approaches in one drug. The problem that I see though is that even when you take the hurdle of a maybe 0.5 effect size, the FDA will not give you approval for that. You need to also show that there is functional improvement. And how are you going to do this in a shorter premier trial in patients who may have checked out and it doesn't matter? They are smarter couch potatoes, so nothing changes. 

Do you then put them into a psychosocial intervention program that increases the placebo effect or do you use first episode in early phase patients that are closer to some of these opportunities to execute their prowess? The problem is the current assessments, the scores, the schizophrenia cognition rating scale, asks people what they did do or think they did. That won't work because they don't have sufficient memory or insight. Even the VRFCAT, it goes at capacity. I want performance. And for that, I think the companies must go with digital phenotyping. There is no way for negative symptoms and for cognition without doing this.  

Dr Correll: A hundred percent agree. 

Dr Kunovac: I cannot concur more than that. And I was about to comment. We really need biomarkers, digital phenotypes, and we need novel endpoints. I'm not an expert in cognition, but I have done numerous trials. We need a more real-world function novel endpoint and enrolling in clinical trials, patients who are younger than 35. Whether they're 33 or 37, I came arbitrary with a number of 35. But somebody who has been diagnosed and treated with schizophrenia for over 10 plus years and has been on the whole gamut of antipsychotic medications and we enter them in cognition clinical trials, it's not going to work. 

Dr Jain: Hey guys, define digital phenotyping for me. 

Dr Correll: Well, it means that people have sensors on their smartphones, and you have 24/7 very granular data. How much they actually—how fast do they type? That's, like, processes—data processing. Whether they—for negative symptoms, it would be also GPS, how much they walk around. You can also look at how close they are to other smartphones. Do they talk with ambient noise? And for cognition, you could have them do some cognitive tests, the DSST or whatever every so often. 

Dr Cutler: Yeah, you can push it out to their phone and have them do something. So, the phones have a wealth of knowledge. Well quickly, there's a company of course that was co-founded by Phil Harvey and others called EMA Wellness that is kind of the leader in this field. And they've had discussions with the FDA, and the FDA is very open to considering some of what they're doing. 

Dr Correll: I think the problem is that the pharmaceutical companies are skittish about it because nothing has been approved based on that. So, they don't want to be the first, but if nobody collects data, they can't be first. 

Dr Cutler: That's right. That's right. Chicken and egg.  

Dr Jain: Jelena, what were you about to say?  

Dr Kunovac: I was about to ask, and really a clarification. When we discuss the scientific design or the science behind the molecule. Maybe I view science as something a little bit more, I wouldn't say sophisticated, but complex than rather having a clinical trial, which has a comparator and placebo or just a comparison. Because if we talk about this brexpiprazole clinical trial, I don't see much science there. The way that I perceive science. I can see science that we have a methylated compound, but what do we really consider under science? So that, I'm aligned with the way that we view science as a group to make sure that my ratings are according to the parameters we all use. 

Dr Cutler: Yeah, I was struggling with that too, Jelena. Does science mean the molecule or the trial design or both, I guess? 

Dr Kunovac: Because this trial is not a novel design. It's been done many times. What does science say? 

Dr Correll: It doesn't have to be novel to be really scientifically accurate and have a lot of prowess. So, for me, it's a scientific approach as well as the scientific molecule and doing it with the highest level. This is the first trial in kids ever done with an active comparator in schizophrenia. Wow. That's scientifically very rigorous and also risky. They could have lost against aripiprazole, for example.  

Dr Cutler: That's right.  

Dr Correll: But again, if you feel it's just the molecule, we need to agree on that. I think it's a scientific approach. So, if that would've been done, for example with digital phenotyping, again, the molecule would've been the same. But wow, now I have a different approach to actually prove that it works. I think that's science. It's applied science. 

Dr Mattingly: I agree, Christoph. So, the first rating is supposed to be how important do we think from a global perspective is it scientifically? The trial design, is it doing something novel? Is it replicating something we haven't had replicated before? In this case, the fact that you have head-to-head 2 partial agonists. 

Dr Correll: Rigorous and never been done. 

Dr Kunovac: This really makes a difference in the way that I think about that because I was really not thinking about clinical trials methodology as being the important part of the rating of science, particularly if something was done, whether that's adolescents or not. If it's done in adults, it's just a different patient population because there are head-to-head studies comparing some of the—yeah. 

Dr Correll: As Greg said, it's the second study ever done with 2 partial agonists, and the first one was underpowered and open label. That's Les Citrome's study of brex versus ari. So, this is the first well-powered, head-to-head, double-blind study of 2 partial agonists ever in the world. That's pretty good. 

Dr Cutler: Well, the cariprazine development program, they had aripiprazole as their positive control. It was not a head-to-head study. 

Dr Correll: Well, but you're right, they did have that. So, I take it back that they did have that. They underdosed aripiprazole in that study. 

Dr Cutler: That's right. That is true. I'm not arguing with that. 

Dr Correll: No, this is the third study then. But it's the first in kids. 

Dr Cutler: You're right. So, again, just to be clear, guys, we're saying science is all of the above to some degree. Because methylation, again, I'm counting that as science. And then, the trial design and execution. Is that fair, Greg? Is that fair to sort of— 

Dr Mattingly: Yep, 100%.

Dr Cutler: As long as we clarify it.

Dr Mattingly: From a global perspective, the molecule is specific to the molecule. And then the class is in that relevant class, how important do we think it is for the competitors’ other molecules

Dr Cutler: Right. Got it.

Dr Mattingly: So, let's take 2 minutes, just talk about where do we think we are in schizophrenia research? Are we moving forward? Are we stuck in the past? Is it still a little bit of both? Where do we think we are right now when it comes to research in schizophrenia? Christoph, why don't you start us? 

Dr Correll: Well, had you asked me basically 4 months ago or 5, I would've said we are at the turning point. We have now muscarinic agonist. And one after the other will work, and it will work for augmentation and monotherapy and M4. But now, we're again seeing all these failures. You've seen the press release of the ARISE program, I assume. 

Dr Cutler: Yes, we have. 

Dr Correll: So, it's tricky. So, yeah, it's a very difficult disease. It's very heterogeneous. And we're lucky when we get new molecules and they work, and we have to find out for which subgroups they work. And Jelena is, I think, very much on the mark that we need to up our precision psychiatry momentum. But it's very hard to do. We need to parse the heterogeneity of the illness to get also at the heterogeneity of treatment response. And we're not there yet at the moment. We're throwing things against the wall, in some companies much faster than others, far too fast. We're bridging insufficiently from animal models to humans. It's really tricky. And we're still in the me-too D2 and repetition kind of cycle. And we don't have anything for negative and cognitive symptoms, so we need more. But I think Cobenfy will have an indication for negative symptoms—for, sorry, cognition. 

Dr Cutler: Cognition, yeah. 

Dr Correll: The question is will they have the functionality and will they do the right study design in terms of functionality to differentiate? 

Dr Mattingly: Jelena, you mentioned subtyping our patients that we look in trials. Where do you think we are as a field? I know you do a lot of research. We've all done a lot of research, all 5 of us here. How do you think we're moving as far as the field? 

Dr Kunovac: I don't think we're moving a lot. I think we are running in circles with occasional attempts to go in a certain direction. Most of the time sends us back into that circle. Schizophrenia is such a heterogeneous illness that treating all the patients and bringing every single patient into the clinical trial—whether that's positive symptoms, negative symptoms, cognition—is not going to work. And it hasn't been working. Here and there, it works. Pharmaceutical companies are dinosaurs. They're pretty aversive to novelty and to change. And they keep doing the same over and over, using the same rating scales, the same assessment. And pretty much—most likely pushed by marketing—want all the comers, all the patients diagnosed with schizophrenia to be the part of the trial because that's the bigger market. We will have to define those subtypes. I'm not going to say that we should go to Timothy Crow and positive and negative subtype of schizophrenia because I believe there are many more subtypes of schizophrenia. But until we develop biomarkers, digital phenotyping—and in addition to that, some potentially novel endpoints—and stop using 30 items PANSS scale as a primary efficacy measure, we're going to be running in circles. 

Dr Mattingly: Andy, as somebody who’s spent a lot of his life as a trialist—you've been my mentor in clinical trials. Jelena brought up the PANSS. What do you think the inherent limitations are about using the PANSS as our primary efficacy measure? 

Dr Cutler: Well, I want to echo very strongly what she said, we have the 2 big problems. The one is not picking the right patient population. We don't have a way to match the neurobiology to the mechanism of the molecule. And the second is our blunt instrument rating scales. And the problem with the PANSS, of course, is you have to be very well trained. It takes about an hour to do the darn thing. And it is a real mishmash of symptoms. And we know that different patients have different fingerprints clinically and neurologically. I like to say, over the years, I don't know that we've had a failure of innovation entirely. Because, over the years, we've all studied very sexy novel mechanisms. I think about the Lilly drug. Is it pomaglumetad, Christoph, the mGlu drug? Yes. And that failed. But then, when they did a sub-analysis, it worked very well in people who were early in the illness, to Jelena's earlier point, and those who had not been treated much with antipsychotics. So, glutamate mechanism at that point in the illness might've been more prominent.  

So, I think that we've had not a failure of innovation. We've had a failure of biomarkers. Other fields of medicine, such as oncology, can do that and pick the right chemotherapy. I'm optimistic in this way though. I think we are on the cusp of perhaps getting there. Not only digital markers, which I wholeheartedly agree with, but also AI I think really has the chance to synthesize a lot of this data and pick up some of these differences clinically, digitally, however. So, I'm somewhat optimistic, but I hear what Jelena is saying. I think part of the problem too though with the rating scales is you're always going to negotiate with the FDA and you're going to use what the FDA will accept. So, I really think the dinosaur is the FDA. And if we can push them to use novel endpoints, then drug companies will follow suit to some degree. 

Dr Correll: Well, but the drug companies will have to develop the endpoints and then present them to the FDA. So, maybe have them in addition to the old ones in order to then bridge over. So, that's an interaction. 

Dr Cutler: They can be convinced. I mean, we used to use the HAM-D and eventually they convinced them to use the MADRS. We used to do LOCF analysis. They convinced them to do MMRM. So, you're right. I think it's a 2 way, probably 2-way street interaction. 

Dr Mattingly: Rakesh, as a child psychiatrist, you see many of these patients very early on. What's your thought about the evolving nature of schizophrenia, catching people early versus late? Jelena brought up her idea of catching people under age 35. I would say even catching them under age 25. That early intervention, Christoph. That first break, psychosis intervention, I think is the ideal time with some of these novel compounds. How do we move the needle to catch people earlier?

Dr Jain: Yeah, I want to say a couple of things. The first is a direct response to your question. Private practice psychiatrists in Austin and Dallas are already using Cobenfy in people who don't have schizophrenia but are at very high risk of developing it. They're literally—yeah, and are reporting. I just had lunch with one of the most forward-thinking child psychiatrists I ever met in my life, has 10 nurse practitioners. The volume is just incredibly large. And they've been using Cobenfy now for the last 4 or 5 months. So, I actually don't think things are as dark as I think I hear you guys say because it often is the darkest before dawn. 

And when I look at a disease state, it doesn't matter which one it is. I try not to look at the results of phase 3. I force myself to look at what's in development phase 2A. So, when I look at phase 2A development of compounds around the world, but particularly here in the United States for schizophrenia, it actually looks really good. Sometimes I think what happens to us, because we are humans, we start looking at trees and we forget the forest is actually much bigger than these individual trees. So, when a few trees fall, let them fall. That's just the nature of research. So, here's my optimism. My optimism comes from Neurocrine. My optimism comes from BMS. My optimism comes from Atai. That's where my optimism is coming. And also, the appetite for—that's why I asked you guys what's the digital marker in your opinion? But the optimism comes from the FDA's very open view about digitization in psychiatry. Look, just for a second, just take our—transport ourselves back 15 years, just 15 years. Just think what in 15 years has happened that we've forgotten today because it's already happened. Look at all the things that we've done in just the world of schizophrenia. I think the rate of ascent in terms of treatment options, in terms of prophylactic use—and I don't mean quite primary prevention, but secondary prevention is going to become reality. 

So, to answer your question very directly, that's where I think we are going to be. Two, I think combinations of treatments will become more popular. Forget about the BMS’ challenging study that just came out. About 80, 85% of use of Cobenfy in Texas is already in combination treatment. And we are getting good results in ways that we couldn't get with others. So, I actually feel things are going to be—are not great yet, but I can clearly see that the dawn is coming, is how I feel.  

Dr Mattingly: So, everyone, let me thank you for joining us, first of all, today. Rakesh, I love your analogy. Sometimes trees will fall. I think the forest right now is alive and healthy. I think neuroscience research has never been more exciting. I think we see more companies coming into the field with truly novel compounds looking at the field in a way that's just different. If I think through the evolution of antipsychotics, I think the dopamine partial agonists were a big step forward. I think the long-acting injectables for many of my patients have been a big step forward. I think the muscarinic agents are going to be a big step forward and already have been a big step forward for a number of my patients. So, I'm excited by the forest. I'm excited by the growth. I'm excited by the investment. And I'll have to say, I'm excited by having colleagues like you where we get to come together and share ideas like this. Let me thank you, all of you, Jelena, Andy, Rakesh, Christoph. Christoph, thank you for bringing us back some of your thoughts and excitement from the SIRS meeting, getting up and waking up with us here as you're over in Europe, and sharing with your colleagues here in the United States. Thank you for joining us. Thank you to the ACCUMIN audience. Once again, neuroscience has never been more important. Brain health has never been more important. And thank you for sharing this time with all of us. 

Dr Cutler: Thank you. 

Dr Kunovac: Thank you.