Good morning, everybody. Sorry we're getting started a few minutes late. Just had an issue, one of the elevators is down. It is very much my pleasure to welcome Saurabh Saha, who is the CEO of Centessa, and very much appreciate you being here today. Maybe we could start by just having you talk about the company's orexin program. Specifically, how has Centessa become such a prominent player in the orexin space? Thanks, Dave. Appreciate having me here today. It's a great question, and it all begins with, I would say, a crazy one, and that is Mario Accardi, who came up with this bold idea six years ago to target the orexin receptor, one of the most validated targets in neuroscience in decades. He wanted to do something that was extremely difficult, which is to target this small pocket that's in this orexin receptor with a small molecule, which big pharma companies had tried for decades and were unsuccessful. The key insight came in a partnership with Sosei Heptares, now Nxera, where we had access to a crystal structure, and it wasn't just any crystal structure you can download off the internet. This was a crystal structure which had a single point mutation which altered the conformation of the structure to allow for screening of compounds. That was the very beginning that, and a very talented chemistry team and a team, in general with exquisite biology and experience in the sleep space, that has now allowed Centessa to have a treasure trove of molecules, that are orexin agonists, that we believe are best in class. We feel very well positioned as a company today, being, in a fortunate position to be working on one of the most validated targets in neuroscience, but also having demonstrated now clinically, in our phase I setting in acutely sleep deprived healthy volunteers, that we're able to keep, these, these subjects up in the early hours of the morning with a single dose of ORX750 and do so, in a dose proportional exposure proportional linear, manner, with a very, very good safety and tolerability profile. That in a space that is really desperate for a better redefinition of what standard of care could be. I think others have shown as well as us is that the orexin agonist can very much redefine what is, will be hopefully the new standard of care for treatment for not just rare hypersomnias, but potentially other indications where excessive daytime sleepiness is a comorbidity. Excellent. Obviously, it is a competitive space. Could you just talk about, you know, the specific structure or structures that you're working with and, at a high level, how you see them or how you've demonstrated that they're differentiated from the competition, for example, relative to the Alkermes program, which is slightly ahead timing-wise? Yeah, so we have the fortunate position of coming slightly from behind, in terms of being able to see what those competitors have generated in terms of their data and the safety tolerability profile of their molecules ahead of ours. I think that's actually been a competitive advantage for us. We were many, many years behind, but now we feel that we not only have the potential to be best in class amongst all the orexin agonists across the rare hypersomnias, NT1, NT2, and IH, but also potentially first in class with NT2 and IH as we've promised to have data in all three indications, clinical data from our phase II trial this year. In terms of what differentiates our molecule from the others is that number one, we are not dose -capped. We don't have, and we haven't seen at this point, tolerability or safety issues that would preclude us from exceeding a certain dose. That, I think, gives us a tremendous amount of flexibility to be able to offer these patients a wide dose range so that everyone can benefit. If someone wants to stay awake up till 6:00 P.M. or 10:00 P.M. or depending on their physiology, we would have potentially the opportunity to offer them that ability to stay awake because we have such linear PK and potentially a flexibility in a dose range. Why is that? When Mario and the team went through the screening cascade of all the compounds that were hits and then ultimately leads, and then when we selected the candidate, we selected for molecules that could, number one, be given once daily. Number two, have a very, I would say, narrow Cmax to Ctrough ratio, because we anticipated that the lower the Cmax, the better the tolerability profile of the molecule would be. There's no advantage in being significantly above the wakefulness threshold when you first take the drug. That AUC, that Cmax is kind of not necessary. What's necessary is that you keep the tail of that curve above the wakefulness threshold at a certain concentration as long as you can so that subjects or patients ultimately can stay awake, for, for the duration that they, that they want to. In our phase I study, we've shown, or we've actually obviously seen the data where we could predict now, at a given point in the night, a time point in the night, what concentration is necessary at a given time of ORX750 to the nanogram per mL resolution, where they need to be above that number to stay awake for 40 minutes versus fall asleep in three minutes. That's the precision in which the PK/PD modeling can be done. It's not just modeling, it's real data that we've generated now in quite a few patients across quite a few doses. That, you know, portends well in terms of picking doses as we dose escalate through phase II and ultimately arrive at a dose range for our phase III study. Excellent, excellent. Have you quantified that, narrow Cmax to Ctrough? How narrow is narrow? Yeah, it's a good question. Frankly, it's a pri, I'll just say, I mean, at some point, it's good to be lucky in this industry. We picked a molecule which we thought would have a narrow Cmax to Ctrough, but I think it's very difficult to know what is that optimal PK profile until you get, you know, data empirically in the clinic. When we did our SAD, our MAD, and then we did the acutely sleep deprived healthy volunteer studies, as we were dose escalating, and I think everyone's seen the data, we've seen beautiful linear PK. It's probably the best PK I've seen of a small molecule in my entire career. I can say that. We've seen linear efficacy in terms of, in terms of response that's placebo adjusted as we went from 2.5 mg- 3.5 mg- 5 mg. To your point, we've also seen the safety profile and the tolerability profile that's not appreciably different from placebo as we've been able to linearly increase the dose and see a proportionate effect size increase. That to us basically means that we've landed on that optimal Cmax to Ctrough ratio, if you will, because we've nearly maxed out at 38 minutes. The max on the MWT scale is 40 minutes at 5 mg, in the most difficult population to treat with these healthy volunteers. Try staying awake at 5:00 A.M. after you've been up all night. Very difficult, very high sleep pressure. That, coupled with a very tolerable profile that's not appreciably different from placebo. I think to answer your question, empirically, we've shown that we've nailed the PK curve and once daily dosing too. Excellent, excellent. And so maybe you could talk about the, you know, the opportunities beyond narcolepsy and IH. So, you know, just talk about them at a high level, clearly significant market opportunities, but maybe tie in also just the biology if possible in terms of, you know, how you see the role. ORX750. That's just the appetizer, if you will, to go after a very large market opportunity in the rare hypersomnias. That market opportunity alone, I think conservatively, is at least $7 billion or more. I think one of our competitors has put down the number at $6 billion just for NT1. This, you know, I think folks should probably sharpen their pencils and do the math on this so-called rare hypersomnia market being a substantial market opportunity for just a few of us that are playing in this space. To your question on what is the potential for orexin agonists beyond the rare hypersomnias, that's precisely why we've done two things. One is, we've made sure in successive manner to put a follow-on molecule in that's soon to be in the clinic in ORX142, as well as other molecules that we've designed to follow 142 with the intent that there is a large market of indications out there that can benefit from treating excessive daytime sleepiness as a comorbidity of that disease. For example, Parkinson's EDS is a big issue for patients. These patients need help and they need an effective treatment for EDS. That's number one is that we've designed a number of molecules that could be used in different indications to go out for different markets. The second is that we made sure from the very beginning, again, this is credit to the chemistry team, that we wanted to go and generate molecules that are extremely potent, highly selective. In fact, we think we have the most potent and highly selective molecules and that combination of, of any, anyone out there. The intent for that was go knowing that we weren't going to stop at the rare hypersomnias. We wanted to generate chemistry that could go beyond. Why is that? Of DDI risk, because when you're dosing patients in the neuropsych and the neurodegenerative indication space and you're treating a comorbidity like EDS, maybe potential benefits in cognition, which would, which would be fantastic, you're going to be doing so on top of standard of care. Having drugs that are given, or agonists that are given in single milligram doses, maybe even less, just portends well in terms of what your safety profile and tolerability profile may be, when these drugs are combined with others. We had an eye toward that from the beginning, and that's why we optimized on potency and selectivity. Excellent, excellent. Could you talk about the additional details that we should expect to see on April 5th at AAN? Yeah, so that's a medical conference and the primary audience is intended to be the neurologists, KOLs, and physicians in the space, to increase their excitement even further about what the orexin class may hold and the agonist. As I mentioned before, we have an eye toward not just going beyond the rare hypersomnias, but toward all these other indications, which, you'll hear more color, as the year goes on in terms of where we think we might be best positioned in terms of outside the rare hypersomnias we may want to pursue. That market alone is, you can't even quantify what that could be. AAN is a good opportunity for us to showcase the data that we've generated in a phase I setting, get people excited about it. There's going to be some Easter eggs thrown in there. I'm sure the investor community will be interested and excited to see some of that data that we haven't shown at this point. I think it'll be a good, you know, kind of segue to portend well into what folks may see this year, as we promised in the NT1, NT2, and IH clinical data sets. Got it. Looking forward to the Easter eggs, but I think you have said that, you know, with respect to dosing, you haven't gone any higher than five, I believe, because you haven't needed to, because you already hit, you know, an MWT of 38. Is that correct? Yeah. Our phase I is open, and should we need to go higher, we have that optionality. I think it's just good practice, as you develop a drug. We are starting at 1 mg for NT1. There is significant headroom. Even at 1 mg, we anticipate that to be an effective dose, given what we've seen in the healthy volunteer studies. The equivalent healthy volunteer dose would be around 3.5 mg. You can kind of extrapolate what that MWT could potentially look like. We are starting at two milligrams for the NT2 and IH, which you extrapolate based on what we've seen in the healthy volunteer studies is around 2.5 mg-3 mg. These are very, you know, good starting doses that we're going after. Our job in the phase II is to have the confidence to be able to go into phase III, and define a dose range so that we give patients the ultimate flexibility, to, to be able to, you know, basically take a dose within that dose range where their, their unmet needed, medical need is satisfied. We, because we do not have a dose cap, it gives us that power, that flexibility that we can offer these patients where we hope that we do not lose 25%-30% of the population who are just not effectively treated on an orexin agonist because they cannot go higher than what the label dose is. where our hope is in a phase III setting and then ultimately on the label is that we have such a nice wide range, given the therapeutic index we've already been, you know, we're established in our, in our phase I study, that they can, they have that ability to go higher if they need to based on whatever their needs might be. Excellent. Since Takeda's going to be generating phase III data this summer in NT1 for its BID drug, could you just talk about that and why you believe the once daily is the better solution and just anything that you're focused on or will be focused on when you see the Takeda phase III results? Yeah. We're rooting for the competition. I mean, we hope that they generate great data because I think it's, first of all, it's super important for patients that they have an option as quickly as possible. I think good data in the space will further validate and cement the, you know, establish the orexin agonist, you know, class of drugs as being a game changer in the field. That being said, we believe that since we don't have a, you know, predefined dose cap, we believe that whatever numbers people may be putting up in terms of their efficacy numbers, we'll have the opportunity to hopefully exceed them. That's our goal and be able to present to patients an option that is simply a better option. I think when the discussion comes between QD and BID dosing, I think it's fairly obvious that if you have a drug that you can take once daily and you can stay above that wakefulness threshold at, you know, later time points in the day, which we can model very cleanly now in our, with our drug, that that's just a preferred option. I think the discussion should, and the question should really be, even beyond QD versus BID is do you have one drug that can treat NT1, NT2, and IH? Because that is what we're hearing from payers. That is what we're hearing from patients. That is what we're hearing from prescribing physicians is that there is such overlap between some of these indications between an NT2 patient who suddenly develops cataplexy, becomes NT1, between an IH patient, an NT2 patient where it's somewhat fuzzy in terms of the diagnosis, and a physician who's quickly treating these patients doesn't quite know they are going to probably want to pick the drug that's convenient once daily and that they don't have to really think and this one drug can treat all three patients, all three patient populations. To me, that seems like a better option to have if you had the choice between, between, orexin agonist. Great. Obviously you've shown no side effects to date. That's probably not going to be the case forever. For us just ahead of this data this summer, could you just remind us what the field believes is the on-target activity and the off-target activity just in case we do see side effects in the phase III data? Yeah, I think in this class of drugs, what you have seen is some really beautiful biology and that playing out with what your question is on on-target versus off-target. Clearly hepatotoxicity, the so-called visual disturbances and others, some are molecule specific, as most of you know. Some we just don't know. We can't explain why they're occurring. We haven't seen those cardio tox, visual tox, and hepatotox in terms of those. AEs that are more of the tolerability issues like polyuria, insomnia, hypersalivation, and others, some increases in blood pressure or that, that others have seen. We haven't seen those even when we're hitting the 38 minute MWT in any appreciable manner different from placebo. We do see them occasionally. What I've noted, what we've noted is that if you look at some of the published data out there is that these AEs all cluster together. As you go higher in dose, it's not like you see only insomnia and none of the polyuria or only polyuria and none of the other ones. Generally, they co-travel together. I think that's when you start getting to that part of the dose range where you're like, okay, now if these are on target, which some of them are, that okay, now you're getting into a part of the dose range where, okay, now we're pushing it. If you get your efficacy before you get to that point, that's ideally where you want to be. I'm not saying that, you know, we're absolutely not going to get to that point, but so far based on the data that we've publicly shown, we feel like we're in a really, really good part of that dose range where maximizing efficacy, but not seeing those, all these AEs co-travel together. I would say there's also a subtle nuance point here is here in the healthy volunteer studies, the AEs that you see even on the first dose are what you normally would see in the patients. You don't see patient AEs coming up that you don't see in healthy volunteers. I think that's important for people to understand is that the biology here is so exquisite that if you have an intact orexin system or you don't, generally these AEs are appreciably the same in, you know, qualitatively in nature. Now, quantitatively in NT1, because the patient hasn't seen a stimulation of their orexin pathway, for, you know, decades or so, there is a kind of first dose or first few dose effect where I think it's been reported you see some insomnia that goes away. You see some AEs that are on target, that they have to kind of get accustomed to. I think, you know, that's mainly in the NT1 setting because there's an absence of orexin signaling. The NT2 and IH population, I think should generally follow what the, the healthy volunteer safety tolerability profile looks like. Excellent. And could you talk about your ongoing phase II trial, provide a framework for that and when, you know, how and when you might disclose data? Yeah, we do get that question very often. The phase II trial is, I would say it's extremely creative, extremely innovative, really, you know, the team, I have to thank the team for coming up with design. They think about this 24/7. It would be very, it would almost be, I would say irresponsible for us, the patients, the community, if we did the exact same study that everyone else is doing and not taking into account all the data that's been generated ahead of us in this space. Having seen what the durability of these orexin agonists look like over time and understanding that between two to four weeks portends very well to how these orexin agonists, kind of, you know, behave in terms of the effect size over six months, we took that data into account. Understanding the effect size in general being so large, you can get away with fewer patients and be very high powered crossover design versus a parallel design, crossover design. You can't get better than the patient serving as their own control, which is fantastic to have that ability with and, and have such a large effect size. When you take that into account, on top of the ability to then unblind the data after each dose that we, each dose cohort for NT1, NT2, and IH all running independent of each other. Data can come from one cohort ahead of the other. We can look at the data, dose escalate accordingly in NT1, NT2, and IH independent of each other. That is creative. That is, and we can do that because we don't have a dose cap based on what we've seen in our phase I setting. We can basically titrate or calibrate the dose based on our PK modeling that we've learned from our phase I studies that we have to stay above X nanograms per mL at this time of the day. This is the dose we need to make sure that tail is above it. That's how development, that's how science is done. To do the exact same study as everyone else, I think that would be irresponsible. We feel our three studies are extremely well powered. Essentially the totality of data from a safety standpoint that we're getting from NT1, NT2, and IH in total gives us great confidence in terms of establishing a safety and tolerability profile. We are also incorporating a randomized discontinuation or withdrawal part into our phase I study, which hopefully will give us insight into potential trial design as an option for one of the pivotal studies for our phase III study. We will learn a lot. All the patients going on study will get drug, they'll get drug for four weeks, which is a great draw for physicians and the patients participating. It greatly helps in enrollment. I think all these things were taken into account when we designed the studies. I think the most important part is we can calibrate the dose after every dose level. We're not pre-specifying the doses. I think that's what is going to help us define that phase III dose range very well, going into registration studies. How do you handle that from a, you know, individual patient standpoint? Obviously, you know, individuals are distinct in different ways, et cetera. How do you think about that as you, you know, calibrate the dose? Yeah. That's precisely why we want to establish a range. Stay tuned when we define how we're going to be doing our pivotal studies. The same type of creativity that we incorporated into our phase I, which is three and a half months, we got proof of concept data. Essentially, we generated the primary endpoint for registration purposes in our phase I setting in three and a half months after opening the IND, established a safety tolerability profile. Phase II, very innovative design. Phase III, don't expect anything less. Got it. Excellent. I guess I'll end with a simple question because we are, we have nine seconds. I guess I'll just ask the cash question. Could you just remind us about current cash and the runway as you've described it? Yeah. $500 million of cash, which gives us a runway into mid 2027. As you all know, we have a number of key catalysts coming up just this year alone with 750, with data, as I mentioned, in NT1, NT2, and IH. We will have data, clinical data, POC data with ORX142 this year as well. Between now and mid 2027, you know, as the year goes on, we will give more guidance as to what to expect. Excellent. Thanks so much for joining us. Appreciate you being here. Thanks, David.