of hosting the management team from Cerevel Therapeutics. Welcome. Thank you so much for flying down here to be with us. And, please, before we delve into Q&A, maybe just give a brief background of where things stand with the business and what we should be most focused and excited for heading into the new year. Yeah. So thanks for having us, and, especially at a time where we're incredibly focused on the year that's right in front of us. 2024 is going to be the most important and most consequential year I think we've had in the relatively short life that Cerevel's been around. We were spun out of Pfizer back in 2018, and basically with a neuroscience portfolio that we're really was purpose-built and designed, focused on doing three things: really focused on understanding, you know, some of the most intricate neurocircuitry of the brain, and then taking that and really digging down. That was inaccurate. Okay. Wow! That was... All right. We're gonna do that again. Yeah. All right. And then really taking that, and then digging in a little bit more once we understand that neurocircuitry is honing in on receptor subtype selectivity. So really making sure that what we're targeting is the most important place where our pharmacology should be focused on, so that we can maximize the effect that we're going for and minimize the side effects. And so we've really taken that baton from Pfizer, and so what we're gonna do in 2024 is have some significant readouts from our three most advanced programs. Our tavapadon program in Parkinson's disease, we'll have a readout that. The first readout will be from our TEMPO-3 program in the first half of 2024, and then from TEMPO-1 and TEMPO-2 in the second half. And then our darigabat program in focal onset epilepsy will read out. It's a phase II study read out in the middle of the year. And then our EMPOWER program in schizophrenia will read out in the second half of next year. So just a real action-packed year for Cerevel. So, Ron, I... Let me just get this back. Apologies. So I realize, there's a range of readouts coming up. I also realize, 90% investor focus ends up going to the last one you mentioned- Mm-hmm ... which is the schizophrenia program. Let me just start there and maybe clarify a couple of things very quick. Number 1- See? You negative hit. You know, it's Karuna doing that. We'll give it one more time. Okay. So, on the schizophrenia program, I think the first and the most important... The first one, I wanna go step by step. There's still, I've found in a lot of investor conversations, an element of confusion around, "Oh, so these are old recycled drugs." Could you remind us sort of the nature of the molecule you guys have versus the competitor one in the muscarinic space? Because there's a very important difference between the two. Yeah, absolutely. I mean, it couldn't be more of the opposite. Our program, our emraclidine program, is M4 specific. So if you think about what's being worked on... Boy! Okay, Apologies. It's like Congress: "Do I get my time back? Yeah. Definitely. All right. So, work on the muscarinics has been going on for decades. Right. Right? And so there's been a lot of, you know, non-specific muscarinic work, and if you look at, you know, one of the most advanced programs, that's an M1, M4 muscarinic that's been around for probably the better part of the last 25-30 years. The program that we're working on was designed and born inside of Pfizer within the last, you know, 10 or 12 years, and really took the aggregate of all the work. Again, what I talked about, really understanding neurocircuitry, understanding in schizophrenia, where the underlying, you know, some of the underlying causes of the disease exist. So much focus had been around the dopamine theory, around serotonin, and some of the other muscarinics. Pfizer honed in on M4, and we're the beneficiary of that. For the other program, again, they've been around for, you know, for a really, really long time. I think we've learned a lot from those programs, but those also. You know, when you're also focused on, when you go beyond M4, you're also hitting other, you know, other non-CNS targets with non-specific muscarinic receptors. And I think that's really what differentiates us from anybody else in the space. Got it. One more dynamic. I know there's a once daily versus twice daily issue, but could you also speak to the PK profiles of the two different components in the competitor program versus sort of the, compound you guys have? Yeah. I mean, look, I don't wanna speak about the competitor's program. I'll let you ask them about it. But what we really, really like about our program is it is, in fact, a once-daily. It does not need to be titrated. It is not a combination product. It is focused on M4. And so we don't need another agent to counteract the nonspecific or the peripheral effects of hitting non-M4 muscarinic targets. And so, you know, in a patient population where adherence is already a problem, having a once-daily pill- Right ... I think is gonna be beneficial. So, so- But stepping back, I think what's really critical here is there has been just a lack of innovation in the schizophrenia space. And the muscarinic, it's, you know, we're rooting for us all to win because it's really competing against existing standard of care that has a whole host of horrible side effects that the muscarinics Spot on. -don't have. Got it. I know recruitment has been a big question mark on several programs over time. I also remember we were making this sort of graphic, trying to think about number of patients relative to the number of sites or the number of months it took some of those trials to recruit. And when we started making that effort, I was very curious that after some timeline changes on your emraclidine program as well, that maybe whatever that trend should be or the regression line should be, you guys are probably falling way off, until I realized you were smack on that regression line. Could you remind us how some of the early timelines were set? Was there an early bolus that drove it? And where we stand now, sort of now that you've been there for some time as well? Yeah, so it's a really good question, and I think, you know, if we look back, there's probably a couple of different factors that played into some of the adjustments we've had to make to our timelines. But with emraclidine specifically, look, we got off to a great start. The forecast we had there, you know, led us to believe that we were going to enroll on a track that was pretty aggressive, and the momentum we saw out of the gate when that program started only confirmed that. What we, you know, what we probably didn't account for is the competition that's going on in the inpatient units. As you correctly pointed out in your research, you know, the track we were on was pretty aggressive. Especially if you layer on top of that how closely we're managing patient variability to minimize the placebo response that is so prevalent in these schizophrenia trials, you know, we were probably too aggressive with that original forecast. And so even if you look at where we are now with our forecast to read this out in the second half of 2024, this is perfectly in line with the timelines that we've seen, and still is probably on the, you know, the relatively shorter side of enrollment for a trial this size in schizophrenia. Ron, you mentioned that the whole placebo effect, and so when you look at the competitors' evolution, between their Phase II and Phase III trials, the placebo response crept up. Absolutely. So, remind folks, what is your strategy to really minimize and mitigate placebo effect in Phase III? So, you know, it, we can look at the competitor studies and look at, you know, the. As the studies evolved and the programs got bigger, the clinical trials got bigger, and the eligibility criteria becomes a little bit more diverse, you open yourself up for, you know, a, an increase in placebo response. And that's not only with our direct competitors. This has been happening now for the last 20 years- Yeah ... in schizophrenia studies. FDA put out a paper a couple of years ago highlighting that, you know, over the last 20 years, we've seen placebo response in schizophrenia studies creep up almost by double in, in that, in that time frame. And a big part of that is how to manage the patient populations, how to manage the sites for these programs, and so you really want to minimize this patient variability. So the first thing, if you think about how we're, how we're measuring the, the primary endpoints, it's around PANSS score, right? So that means when patients come in, there's got to be somebody who is certified to actually do that rating, right? Positive and negative symptom scores. Mm-hmm. So you want to make sure that when these patients come in, that you know, there's not any... You know, there's a very specific approach to how you rate these patients. You want to eliminate bias. You want to make sure that any of the other things that are being measured at the same time aren't out of sync with what you're seeing with the PANSS scores. You want to make sure you don't have professional patients. You want to make sure that you don't have sites that are just pushing patients through to get paid. There's a whole bunch of things, so really honing in on making sure that you have high-quality sites, certified raters. That means, you know, going in every 6 or 12 months, making sure those raters are doing their jobs, doing it right, and making sure that the sites are adhering to the protocols rigidly as possible. One other thing I would add is that we are not going to, for either EMPOWER 1 or 2, start up more than 25-28 sites. And you saw with the ulotaront data, they had over- Right ... 45 sites, and I think that when you get over 30, that's when you see placebo response increase. Right. No, number of sites, clearly relevant. I think another aspect that could be relevant is the number of ex-U.S. sites. Sure. But, to the extent you do need to go ex-U.S., I guess one thing that did confuse me is, I guess, how and why did the CRO recommend Bulgaria? I mean, if you're going to go ex-U.S., there's a lot of places to go. How Bulgaria is kind of pinned into the list somehow? Yeah, I mean, you know- With multiple sites. So if you looked at schizophrenia study site studies historically, it's scattered all, you know, all throughout Eastern Europe. There are very, very good sites. There are centers that do a really, really good job- Mm ... with these PANSS ratings, and they're very, very focused on making sure that they adhere rigidly to the eligibility criteria as well as the conduct of the trial. And so, you know, yes, we're in Bulgaria, but there are sites in other areas of Eastern Europe- Okay ... that are just as good. Got it. Yeah. But I would say the vast majority of our sites are U.S.-based. Yeah. Ron, I know currently the expectation is, Cerevel's once daily, Karuna's twice daily, and then Cerevel's about a certain amount of time behind. But I think the question that hasn't come up much is: Is there scope for potential efficacy differentiation, perhaps even on things like negative symptoms, et cetera? How are you guys thinking about that? Because there was some efficacy data fading in some of the data as it evolved on, on Karuna's side. Yeah. I wonder if that's left an opening, potentially. So, you know, one of the questions you asked about our enrollment. I've spent some time. I try to spend less time now with investors and more time with investigators, and, it's, you know, it because it really helps understand what's actually going on at the site level, in terms of, you know, our enrollment and the quality of the patients that we're getting. And this question I've asked with every investigator that I've ever met with, any of the site staff, is: when your patients are coming in, how do you think about. I mean, right now, there's a pretty standard protocol of atypicals that patients get on, when they're diagnosed with schizophrenia. But as they think about some of these new things coming on, I've asked them, I've said, "Are you going to sit down and look at PANSS scores? You know, are you going to look at what the reduction is compared to the placebo rate?" The answer is no. They're just... If you hit the primary endpoint, Karuna hit their primary endpoints, that's going to be a great product in the hands of prescribing physicians who take care of patients with schizophrenia. If we hit our primary endpoints as we expect we will, we expect that we will have, you know, success in the doctor's office. You know, to the extent that a sales force is going to spend time talking about PANSS scores- Right. Yeah, of course, they're going to do, you know, they're going to do some of that, but the physicians are going to just want to know that you had a statistically significant result. That's important because we get asked from an investor all the time, "Well, what if the effect size comes in maybe 1-2 point PANSS points lesser than a competitor?" So but in the real world, it probably won't. Yeah. I mean- We're 90% powered to show at least a 7-point difference. Okay. If we hit that, that has been shown in a meta-analysis of all PANSS scores in pivotal schizophrenia studies to have a positive impact on the symptoms of in patients with schizophrenia. Got it. Ron, what have you guys said about market potential, and size in terms of schizophrenia, what have you guys said? And I ask because, it's well understood that several schizophrenia products that were very, very large products, but a lot of their sales were also not in schizophrenia. Mm-hmm. They were in other indications, like bipolar depression- Yep. ... major depressive disorder. Those are not the indications you guys are going for, but I'm curious, how have you guys characterized schizophrenia opportunity, knowing that, knowing the side effect profile is so different? Yeah, so to be honest with you, Umar, we haven't said much at all, and there's probably, right now, there's not too much of a need for Cerevel to be, you know, making big market projections on this. You know, we have a competitor that's going to be out there before us, and so we're going to be paying really close attention to everything they do. We're going to, you know, we're going to watch how they build that sales force, we're going to watch how the launch goes, and, you know, see what we can leverage there. But also, you know, if there are mistakes or there are bumps in the road, we'll learn from those as well. There has not been a new class of compound in this disease in decades, and so there is... The one thing I can say, and I'm super excited for Karuna, is we know there's a lot of excitement, there's a lot of pent-up demand for a new approach to treating these patients. And so I think, you know, we wish nothing but success for them because if it goes good for them, I think it's going to go great for us. I guess, Ron, and I realize this is an impossible question, so this is not a question to put you on the spot, but there have been a couple of prominent instances in the biotech land that ahead of phase III, acquisitions have happened in sort of promising areas. One of the issues that stands out when anytime a complex situation like that presents is whether there's a very large disconnect between the company's understanding of the market potential versus the street's understanding of the market potential. Do you think that's an area that it, it's something you guys could potentially look into street education around? Because there could sometimes be a perception that, oh, it's limited schizophrenia, maybe Alzheimer's psychosis is not talked about, things like that. Yeah, look, I mean, what we're really excited about is this real renewed interest and renewed investment in the neuroscience space. Five years ago, we weren't having too many discussions around- We're talking Hep C. Yeah, I mean... Well, that was a little bit longer ago—and some PTSD around that. Looking at it. But, you know, there was almost an evacuation away from the neuroscience space. And now, you know, we, we've worked through all the oncology, we've worked through, you know, metabolic is still hot, but neuroscience is making a big resurgence here, both on the neurodegenerative side, as well as on the neuropsychiatric side. And I think it's because there is innovation, right? It's not just another atypical, not just another L-DOPA or D2, D3. Right. These are all innovative approaches to diseases where you've got, you know, either low adherence, you've got patients that are refractory. You know, one-third of patients are still refractory to epilepsy medications. There's still not a good product for Alzheimer's disease psychosis. Got it. So I think, you know, there's a little bit of a disconnect, but that'll be there until it's not. Ron, why not run an Alzheimer's psychosis phase 3 right now? Look, we're running our- I ask you—I know I ask you this— Yeah every time, but Yep. We're running our healthy volunteer study that will give us the data that we need to make a decision on what our next study should look like. Believe me, Umar, we're excited about that. Our overall lifecycle management strategy from emraclidine is going to really be. We'll get our data in the second half of next year, and then you can count on us having a very aggressive- Got it -lifecycle management plan. Mike just said to me that you guys have some more pipeline beyond emraclidine. I didn't know that. Yeah, we do. We do, yeah. Just to touch upon tavapadon, investors, I guess in the early PD study, the co-primary endpoint is actually MDS-UPDRS part 2 and 3. Mm-hmm. Folks are just hyper-focused on the motor aspect, part three, and less focused on MDS-UPDRS part two, and I know the agency has given it more and more weight in recent years. How do you see it from a regulatory perspective, like, I mean... Any comments on along those lines? No, I mean, look, we, you know, again, we pay very close attention to how the FDA looks at these programs. Right. And so we don't take a step unless we think we are addressing something that the FDA is going to be concerned with. And so- Mm-hmm. As you correctly point out, in the early Parkinson's studies, UPDRS two and three is going to be important. But, you know, obviously, on time is more important in the later stage, in the TEMPO three study. So, we do believe that this is something the FDA is gonna look at, and that's why we have it as a primary endpoint. Okay, just also on dyskinesias, and in phase 2 is around 16%-23% at the 7-15 milligram dose, compared to others at around 17%. So given the fact that phase 3 is longer duration, do you foresee any higher rates of dyskinesia? Well, I mean, look, the way that the drug is designed is we're trying to minimize. You know, we'd like to- Right. I mean, that's what you would see with the with L-DOPA. That's what you see with the other approaches to treating Parkinson's disease. And so, you know, for us, you know, do we expect to see that? Let's... You know, I don't want to, I don't want to predict what we may or may not see on that- Sure ... but I think we're gonna have a much more favorable profile than- I'll make a plug for our December eleventh- I saw that. Tavapadon. Yeah. Uh- That's right. I just saw that. I saw that, yeah. I guess, in general, I know, there's a lot of pushes and pulls on the prior Phase 2 data. Part 3 scores maybe look stronger than Part 2. The endpoint now is Part 2,3 combined. What happens if Part 3 comes in strong and Part 2 doesn't? Does the overall thing hit? How does that happen? Yeah, so that's a great, great question, and that'll just, you know, what we'll do is we'll take the entire TEMPO program. I mean, TEMPO three is a little bit different because it's an adjunct. But TEMPO one and two, we'll look at the aggregate of the data. We'll see what we have, and we'll make some decisions based on that. We'll go to the regulatory authority. If you hit Part three and not Part two, I guess, does the trial work? I think we have to see the totality of the data. We'd want to see... I mean, look, this is a unique disease where, you know, I think there's some latitude with the regulatory authorities, depending on what the totality of the data shows you. So I don't want to predict what one slide, and, you know, one when you move one slide, what it means for the rest of it. I think we'd want to wait and have that discussion with the FDA first- Excellent ... if that happened. Excellent. Mike, do you have one last one, maybe beyond? I know we were getting interrupted in the middle. Yeah, just on your darigabat, phase 2 and then focal epilepsy. Really, still, on track to for mid- Mid next year. Really, what differentiate this mechanism from maybe an orexin receptor antagonist like J&J's asset in treating, you know, actually panic disorder instead of Yeah, well, even panic. I mean, look, we like the data we saw in our early stage CO2 model that, you know, is designed to, you know, model what panic disorder looks like. But I think having an alpha one sparing GABAA two, three, five, you know, really sets us apart from a lot of these other nonspecific benzos that are out there. You know, eliminating the side effects that you see when you have alpha one involved, I think make this a, you know, again, another promising compound that doesn't have the side effect profile, highly targeted, predictable PK, something that we think will be, you know, again, an innovation for patients. You know, again, one-third of patients are refractory to all those other things that you just talked about. Right. Just in the last one second or so, could you remind us the QT profile of the tavapadon program, as well as whether background L-DOPA levels mattered in the advanced trial in phase 2? I realize that may not be a fair question. Yeah, I don't... At the top of my head, I don't remember what the QT profile is. I suspect that there wasn't much of an issue there, or I would probably recall it. And then on the background, L-DOPA, I don't know if I have that data. 400 mgs. Yeah. Okay, but the efficacy was not variable depending on L-DOPA dose in the prior trial? No. Okay. Okay, excellent. Perfect. That's what he told me last time, too. Yeah ... so that's consistent. Right. Yeah. Thank you, guys. Thanks for being here. Thank you. Thanks for having us. Excellent.