Excited to have Centessa Management with us. I think this is a very exciting time for the company. I think you're also one of the most sought-after guys right now across buy-side as well as on the pharma side. So I'll let you kick things off, Mario. Thank you. Great to be here today. Thank you for the invitation. Super exciting time for us at Centessa Pharmaceuticals. We are really doubling down on this mechanism, which is orexin biology, orexin agonism, one of the best validated targets we've seen in neurosciences for quite some time. We recently disclosed an update from our first few initial cohorts of our Phase II study of ORX750 in Narcolepsy type 1, type 2, and idiopathic hypersomnia. It was very much the first time a company has shown a robust clinical data set showing clinically meaningful and statistically significant efficacy across the three indications and demonstrated also potential best-in-class profile for Narcolepsy type 1, type 2, and IH. This is just the beginning, Umer, because this is data set from 50, 55 patients, and we're going up in doses. Over 50 patients that, as of today, are being dosed at higher doses, and there are no AEs that we've seen that really limit the therapeutic index of the drug, so we're, as you can imagine, extremely excited to have disclosed this recent release and even more excited about what's coming next, so we really see, I think, the Narcolepsy type 2 as de-risking not only for the idiopathic hypersomnia. As if you recall, Umer, there were a lot of questions on orexin is really going to work for indications where there isn't a loss in orexin tone, and we answered that question, and now we have what we call here at Centessa an Orexin Agonist franchise. We have multiple assets. We have ORX142 in Phase I entering patient studies in Q1 of 2026. That molecule is being directed to these much broader indications, neurodegenerative psychiatric disorders. We are ORX489 entering Phase I in healthy volunteer study in Q1 of 2026. We're really building our Orexin Agonist franchise and really leveraging as much as possible this really exciting biology. Excellent. Fantastic. So there's a lot to go through. I think I want to spend perhaps focus the most on some of the data sets you guys put out recently. But maybe even just ahead of that, the sense I get in a range of conversations I had at World Sleep, where I saw you, was basically that this is a very active category. And these drugs combined, Takeda Alkermes and Centessa, they all combined form the basis of a very large category for patients. And so doctors seem much more focused on orexin as a category than sort of carving out one over the other, perhaps. And is that broadly consistent with how you see it? Because they should make a very meaningful market share into the broader Narcolepsy. Couldn't agree more. So you remember in Singapore, Umer, I think the excitement among PIs was off the charts for this mechanism. And I would even say now even more so, thanks to also part of our disclosure showing the Narcolepsy Type 2 data set with very, very strong efficacy and such an indication with such a high unmet clinical need. So absolutely, I think back then at Singapore, it was still early days. There still wasn't, I think, a lot of data sets to show differentiation among Orexin Agonist class. I think with our recent Phase II update, we've helped, I think, answer some of the questions on differentiation. But obviously, there are still 50 more patients that we're dosing. So we're hoping that the additional 50 patients will help contribute to that even further. Got it. Mario, I want to get into Phase II. We can go through all the data cuts, what was shown, what was not shown. But just ahead of that, higher level, and I often find that this is lost in the broader orexin conversation. Street thinks of this as new drugs for Narcolepsy. We'll see how good they are, if they work in type 1 and type 2 or not. And one of the questions I keep coming back to is, aren't they drugs for far beyond Narcolepsy, perhaps, at least based on some pre-specified and/or post-hoc analysis seen from some of the other orexin players? Cognition, memory, and I don't even know what the indications would look like. Totally. I think the fact that Orexin Agonist can be essentially a functional cure for Narcolepsy Type 1, I think, is what's driving a lot of the excitement among physicians, among PIs. And taking that step further, now demonstrating that the class can work outside of NT1. But you're right, there's a lot of symptoms where, such as cognition, executive function, sustained attention, mood, fatigue. We've seen some of the competitive sets around fatigue. Symptoms that Orexin Agonists have shown that can be addressed and can be extremely beneficial. So the mechanism goes far beyond idiopathic hypersomnia. And I think that's the extremely exciting part. Is that resonating as strongly among clinicians as you guys? It's not your data sets, but some of the other data sets on cognition, et cetera. Is that resonating very well? I would say yes. Of course, it's still not as well validated as idiopathic hypersomnia. But you know what? There's a lot of partial, what I like to call partial clinical validation from wake-promoting agents and stimulants that are still today part of the standard of care in a lot of these indications, like ADHD, major depressive disorder, Parkinson's, just to name a few. And those are mechanisms that are very much focused on a single neurotransmitter most of the time. With orexin, we have such a powerful mechanism because the release of orexin helps the release of all these other, this cascade of neurotransmitters, serotonin, dopamine, histamine in a coordinated fashion, a coordinated effort. And that's essentially how the mechanism could really contribute to addressing symptoms well beyond just the wakefulness needs. OK, got it. OK, great. So as we start to then get into, when is the earliest we see data? And like I said, I'll come back to the Phase II in a second. When is the first we see any clinical data for your new orexin programs, which are presumably meant for these larger indications? So we have ORX142 and ORX489, which are very differentiated PK compared to our lead molecule, ORX750. They are very, very potent molecules, very selective at orexin 2. And ORX142 is currently in Phase I, moving to patient studies in Q1 of 2026. ORX489 moving into healthy volunteer Phase I study in Q1 of 2026. We still haven't. Go ahead, sorry. We still haven't given guidance on the exact indications that we're taking these assets forward. Part of the reason is because, as you appreciate, it's such a competitive space that I think we want to be able to maintain our leadership position on the wider Orexin Agonist franchise at the right time. We'll be commenting more. But there's a lot of indications, Umer, where Orexin Agonists could have a profound impact, whether it's MDD, whether it's Parkinson's, whether it's ADHD. Is one a backup to the other? Because I thought they were both for the large indications. Correct. Not at all. There's actually nothing we really wanted to improve or any key liabilities we could identify in any of the three assets. So they're definitely not backups of one another for that specific reason. They're there to give us an opportunity to go after very, very different markets, very different commercial space, very different commercial dynamics, and obviously carve out certain indications for specific assets. OK, got it. OK, so not reasonable to be expecting some sort of meaningful update on excessive daytime sleepiness on 142 program, perhaps at the World Sleep next year? When it's the right time, we'll be providing an update. We're starting patient studies with 142 in Q1 of 2026. So I think it's too early to comment on which exact meeting. OK, got it. OK, got it. Excellent. So maybe then turning to the main event, then I want to go through the data very carefully. Obviously, you guys put out some data. There was a lot of Street confusion on what was put out versus what was not put out. So let's go through this step by step. Number one, the Phase II trial was originally going to have three arms, three cohorts, not three arms, three cohorts, dose level one, dose level two, dose level three. Clinical trial is now at 96 patients instead of 78. So I think there's a dose level four. So is that true? Is Is there four cohorts? We actually never disclosed how many cohorts we would actually undergo in our Phase II study. The Phase II study is very much designed to answer the fundamental key question, which is, what is the appropriate dose? What is the optimal dose for registrational studies and registrational program, which we are commencing in at least one indication, potentially all three. We'll need to see from the data from the remaining patients in Q1 of 2026. So it can be more than three cohorts. It can be more than four. We want to be in a position where we are no longer doing dose exploration registrational studies. We want to do the dose exploration, dose optimization now in Phase II in order to then really pick that optimal dose for the registrational program in Q1. OK, got it. But so the ratios we saw for the NT1, NT2, IH, those patient numbers are then changing per cohort. Is that right? Because that would be the only way it would make sense. are 10 per fixed dose cohort. There are 10 NT1 patients, 12 NT2s, and 12 IH patients. Now, these are the minimum patient numbers needed to essentially close a cohort. But in reality, we can enroll many more patients per cohort. Could you also enroll less or no? No, those are really the minimum numbers that we need in order to hit all the different statistical analysis. So those are very much the minimum numbers. In reality, we've enrolled more, even in our 23rd of September data cutoff. As you can recall, in the IH, we actually enrolled many, many more patients because there's such a high unmet need. Remind us, how many IH patients is again so far disclosed? Based on our disclosure on Phase II update as of 23rd of September, cutoff at the 2 mg dose, that was our first dose in the cohort. I believe we enrolled 17 patients in that cohort. OK. So 17 there, 10 patients on the four milligram for NT2, and six on the NT1. OK, got it. So these are all the, well, I just want to make sure I get it right. So NT1 had a one milligram, a one and one-half milligram. Presumably, there's a two milligram, and maybe you and I will see. NT2 started with two, then four. Correct. And there's something else. We don't know that. IH, two,, and something else. We don't know that. That's how much we know so far. Did that miss anything or misinterpret? Yes, one and one and one-half in NT1, two and four in NT2, and two milligrams in NT1. You guys were very clear. Saurabh was very clear. There's additional dose levels here. Absolutely. There's 50 patients today, as we speak, that are being dosed at higher doses in multiple cohorts. 50 patients being dosed at higher, and this does not include, so the 50 being dosed today is not inclusive of the 33 that are already reported. These are 50 new patients. So, 50 new patients that are ongoing. OK, got it. I guess the next question then is, as we think about, I'm going to go start with NT1 then. We had six patients' worth of data for MWT, but seven patients' worth of data on ESS, et cetera. So, remind me, what's the deal with that one patient on MWT? There was a technical error in one of the MWT sessions, so that patient was excluded from the MWT analysis, but overall, I think across the six patients, the MWT was very consistent. We achieved a greater than 20 minutes change from baseline. Half of the patients were above 30 in absolute terms of the MWT, and an ESS that went down from 18, placebo adjusted, down to 5. Got it. I remember one of the conversations I had with you was you were referencing back to the 994, the Takeda 994 data in NT1, which was tracking 35 minutes plus on MWT, and I separately remember you guys had said, we'll put out Phase two, and we think we've met a differentiated clinical profile. Is it true that after you saw some of the competitor data, your own expectation on what constitutes differentiated came back in a little bit? Not at all, Umer. I think we saw the data set from the first few cohorts, really very much the initial doses of Phase two study. And we found the data extremely compelling and exciting. I mean, at the 1.5 mg cohort in NT1, we didn't even see, no pun intended, but any visual disturbances. Very, very well tolerated across all dose levels. And an ESS of 5 essentially means that patients are probably doing very well also in the afternoon as there's questions in the ESS around how patients are doing late in the day. Incidence rate ratio, weekly cut-off accuracy rate of 0.13, which is phenomenal based compared to standard of care. And we also showed in NT2 a greater than 10 minute change from baseline on the MWT. As of today, there is no drug approved that has shown a greater than 10-minute change from baseline on the MWT, so you put everything together, including obviously also the IH data set where we saw clinically meaningful and statistical significance there. From the very first few cohorts, there were no AEs that defined the therapeutic index of the drugs. We're like, wow, this is a meaningful update. Shows differentiation so that we have a drug for all three indications. We're cementing our position as potentially best in class, first in class in NT2 and IH. Let's get the data out and now we're just building on that. As I said, we're just going up in dose, so there's a lot of opportunity to even push the dose higher. Not necessarily because we don't think we have a competitive profile today, because we want to cater for 100% of the patient population. As you know, duration of action, in this case, wake promotion, can be very individual. We all have different routines and different schedules in the day, so we want to be able to offer that flexibility by dosing higher. Got it. One of the points everyone was very focused on when the data came out on MWT was whether MWT was on a mean basis more than 30 or not. I think what you guys said was half the patients were above 30. There's six patients total. You can construct your favorite range of distributions, what that would look like. Are you getting any patients with near complete 40 minutes? Because I remember one of the points you guys made was early on, on first dose effect, you're getting to that 40 right away. Maybe on a sustained basis, you're not. So are there any patients that by the end of the time point for measurement, they're in that high 30s? Yeah, we haven't really gone into that level of granularity in terms of analysis and reporting on the individual time points in the MWT. I mean, we did that in our Phase one study once the sleep department study was complete. Or is that even reasonable to expect further out, not a first dose effect, but like two weeks, six weeks out? I think our ORX750 has been designed to have an extended duration of action. We don't have a biphasic PK profile. We have completely linear PK across all doses tested. That's very much the aim is to provide that maximum duration of action. That's part of the ongoing cohorts. I guess I'll tell you why I'm asking. The reason I'm asking is if you told me there are a couple of patients that are in the high 30s, then on the other side, that would mean there are also a couple of patients that are more like low teens, perhaps. So then the spread is wide. I mean, would you argue the spread is more narrow? Or they're kind of like in the 25- 35 range broadly? Yeah, I would love to answer that question, Umer, but I don't think I even remember the data set. But you didn't see the dispersion was too wide, perhaps. I think it was very consistent data. OK, so consistency. Very, very consistent, especially in NT1. The dose response is, I think, very, very reproducible because of that orexin loss. OK, great. In NT2 setting, as we think about sort of the MWT, all you guys said was it's better than 10 minutes. You just kind of left it there. It's hard to interpret that, obviously. But do you think pushing the dose gets you guys to a certain time point? I know the split dosing may possibly be reflected in the ongoing study as well, at 3 plus 2, something along those lines. How are you thinking broadly? It sounds to me almost, if I may, it sounds to me that maybe your first two tests of the day are coming in pretty good. Maybe the third and fourth test of the day, not as hot. So when you have a little more coverage through the day, whatever is 10 minutes today on a split dose is already a meaningful step up. And then you push the dose so that you get additional efficacy. We're very happy with the efficacy we're seeing already at the 4 mg, which is only the second dose of our study, and we're only going up in dose, so we're extremely excited to see the 10 minutes change from baseline. I think in NT2 especially, and we've talked about this before, the baseline can be quite variable, which is why we've really focused the disclosure on that change from baseline, which, by the way, is also the approval endpoint by the agencies. The change from baseline is not the absolute MWT number. Interestingly, in NT2, we. Because above 10 minutes was versus placebo. That was not changed from baseline. It was above 10 minutes changed from baseline placebo adjusted. Absolutely. Correct, correct, correct. So the true within arm is more than that, presumably. Well. Or, where you got to exactly? I think we're saying the same thing. Yeah. And the ESS went down from 15- 8. So we restored actually normative wakefulness also on the ESS. Why didn't you guys show the 4 mg data in IH, by the way? It wasn't ready by then, the 23rd of September. By the way, we didn't. Because I thought if you went from 2- 4, they're all going concurrently. First of all, we didn't disclose the dose for the second IH cohort. We never said it's 4 mg. We only reported on the 2 mg first dose. And the data was, as of 23rd of September, cut off. We basically got all the data of the cohorts that were closed, and data was available at that moment in time. What was the cut off again? 23rd of September. September 23rd. OK, got it. Remind me also from visual disturbances. I think you guys said there's zero from clinically relevant visual disturbances. On non-clinically relevant, I think you guys talked about three cases, if I remember correctly. There were only three visual disturbances that were identified across the entire update. What's the entire 33 patients? 55. OK, so this is what I want to focus on. 33 were shown in what we saw, patients, right? 17 plus 10 plus 7. So it's 34. We reported safety data across 55 patients. And there were three cases of visual disturbances across the 55. We did not see a dose response on these visual disturbances, which is interesting. They were deemed non-clinically meaningful, mild, and transient. Can I say this back to you the way I'm sort of processing it, if I may? We know that in NT1, one and one-half milligram had no cases at all. We had one case in the one milligram, nothing in the 1.5. Oh, OK. One case in one milligram. OK, got it. So that's helpful to know. I guess what I was really getting at was the efficacy population was 34 patients. Separately, you now have an additional 50 patients. So the 55 safety is like halfway between those two. So presumably, those were the higher cohorts. So I was assuming they happened more in those cohorts. But you're saying one happened in one milligram, and there might be an additional somewhere else. Yeah, listen, we didn't see a dose response. So it's difficult to understand what they really are. I mean, I've been spending a lot of time with PIs. I mean, I just came back from a trip in Europe last week visiting PIs. Even though we have a very, very competitive profile on the visual disturbances, I think lower than what others have shown, we really don't think it's an issue. Got it. And this is like light sensitivity for a couple of minutes? The duration is only a couple of minutes? Because I remember Alkermes's had some lasting couple of hours. Yeah, I think they were all resolving, transient in nature. Transient in nature. How did you define what's clinically important? That's up to the PI. That's up to the PI. So presumably, if it lasts an hour, that would fall into clinical relevance. Again, that's up to the PI. I mean, the patients were referred to, they were asked if they wanted to undergo an ophthalmologic exam, and they declined because it wasn't an issue for the patients. OK, got it. So my last question, how should we think about the next major update coming up in the first half of next year? So Q1 update, probably some more granularity on our registrational program, I think would be helpful in Q1 2026. Is there a data update on the Phase two? Plus an update on the Phase two study. OK. Will that be final data, or will that be whatever's ready? It depends. We need to see how these additional 50 patients read out. And the idea will be to provide an update, which could be in one indication in Q1, or it could be in all three. Again, we really need to see the data from these 50 patients. Got it. Fantastic. And you want to get a Phase 3 up and running by, before summer? Q1 2026, we're starting the registrational program. OK. Yeah, that could be in all three indications, or it could be in one. Again, really depends from. OK, the Phase two update will be across all indications. Phase three may or may not be across all indications. Phase two update may or may not be across all three indications. Phase three may or may not. Registrational program starting in Q1 could be, may or may not be across all three indications. OK, fantastic. Anything we missed in the audience? I feel like we can go for another half hour easily right now. All right. OK, fantastic. Mario, always great seeing you. Good to see you, Umer. Thank you. Fantastic. Thank you for making time. Thank you. We'll be in touch.