Okay. Well, thanks so much for joining our 46th Annual Healthcare Conference. I'm Stacy Ku, part of the biotech team with my colleague Vish Shah. We're happy to be hosting Centessa. With us today, we have Mario Accardi, CEO, and in the crowd, Kristen Sheppard, head of IR. Thanks to you both for being here today. Thank you. I still remember our first introduction to you as the founder of Orexia, and obviously a tremendous amount of progress since that moment. Really if we'd open up for some opening remarks on the progress that we've seen so far and really what are your goals in your transition to CEO? Thanks, Stacy. Great to be here. Thank you for inviting us. Obviously having started the original company back in 2019, to finally see where we are today with ORX750 in patients and aiming to commence registrational studies for the rare hypersomnias this quarter, to really get an opportunity to build out this multi-asset franchise across potentially multiple indications with these exquisitely potent and selective orexin antagonists is almost as I would say, is a dream come true. I think it's a unique mechanism. I think it's a incredible time to be building out this platform, and ultimately delivering a potentially best-in-class molecule, first-in-class, we're obviously aiming to be first-in-class in NT2 and idiopathic hypersomnia, and really getting a chance to build out the vision that I always had for the company, which is this incredible biology and wide platform to go after so many different indications is incredibly exciting. As we think about maybe some of the updates that we're gonna be expecting in the very near term, a lot of expectations coming into Q1, just talk about first, the data that's been disclosed so far in November, and help us understand how you all are thinking about the decisions underneath the next update. Yeah. Back in November, we disclosed data from essentially our lowest dose cohorts, right? Which was 1.5 mg in NT1, 4 milligram in NT2, and also some language on the 2 mg in idiopathic hypersomnia, those very first cohorts. This was our lowest doses. Already in the November PR, it was very clear, potentially best-in-class data, right? In narcolepsy Type 1, we achieved a greater than 20-minute change from baseline placebo-adjusted MWT. ESS dropped from, you know, 18 down to five, right, completely normalizing symptoms. 0.13 incidence rate ratio on the weekly cataplexy rate, which suggests good diurnal and prolonged symptom control all the way out to later part of the day. In NT2, we showed greater than 10-minute change from baseline on the MWT. There's no drugs approved today in terms of standard of care that have shown a greater than 10-minute change from baseline. Normalized ESS there, dropping it down to from 15 if I recall, down to eight. In IH we disclosed we saw statistically significant and clinically meaningful effects on multiple efficacy measures. All of this coupled with a very favorable safety and tolerability profile. Since that time, Stacy, since November, we've gone obviously much higher in dose. We've gone in some instances, multiples higher in dose. Again, not because we felt we didn't have potentially best-in-class data back then, but really it's because unless we really find a maximum tolerated dose, right, which we're hoping would be in the form of potentially insomnia, it's like, why stop there, right? We're really here not just to be best in class versus other molecules that are in clinical development today. The objective for us as a company here at Centessa is obviously apart from being the leader in orexin biology, but is also to be best in class versus who's yet to come tomorrow. That's what we've done since November. We continued the dose escalation. We've looked at both QD, split dosing across multiple cohorts, multiple indications in an effort to really select that optimal dose for registration studies. Is it fair to assume then for your goals of this phase II, you've clearly made it dose ranging, flexible. There's been a lot of different adjustments made to really fully interrogate the right dose to bring to phase III. How does that play into your decisions around the update in Q1? In Q1, we'll be providing obviously an update to the phase II study, and it fundamentally depends on which cohorts will be ready in time for the disclosure. It could be in one indication, it could be an update, you know, across all three indication. It really depends. Also, we're quite keen to show kind of the top end of efficacy of as what we believe would be in a specific indication rather than provide a cohort by cohort update. If we feel that for whatever reason we should go and do one more cohort in a specific indication, we'll take the opportunity to do that. It really depends. It has to be a data-driven decision. As part of the disclosure, we'll obviously also aim to give you guys some color on our registrational program design, which we're very excited about. We are again aiming to start registrational program in at least one indication this quarter. Again, it could be in all three, but at least in one, and give you guys some orientation on the design and kind of the, our regulatory strategy. I would say that is really the focus of the disclosure. On top of that, obviously we'll also use the opportunity to convey my vision for the company, my vision for the multi-asset orexin agonist franchise, and also give some color on these several other neuropsych and neurodegenerative indications that we're going to be entering in with ORX142 and ORX489, our follow-up orexin agonists. Okay. You talk about the registrational studies. Is it fair to assume that the updates will be aligned from phase II, the doses selected will align with the number of different indications that you're pushing forward in the near term? I would say that we'll be providing color obviously on, in terms of what this registrational study look like and obviously the phase II update on what we think, what ultimately we think the strategy should be in terms of progression of this asset. What I would say is, we're still aiming to be first in class in NT1 IH. We're gonna be aiming to start this registrational program this quarter. We could still start a program in a specific indication, because we feel very confident about the dose and because we feel very confident about the best-in-class profile. We could elect to keep the phase II open. For example, if we think there is still, there is still potential efficacy that can be gleaned from the mechanism, we could reserve essentially, an option, right? A call option that we could exercise if we decide to then add another dose later. That's something that we could very well do. Again, it really needs to be a data-driven decision. The goal is definitely to start registrational studies with best-in-class profile across efficacy and across tolerability. Okay. As we look to the phase II, we get a lot of inbounds from investors trying to understand what the efficacy bar could look like, in the constellation of narcolepsy. If we could just start first with NT1, seems like that is a more clearly delineated efficacy hurdle or, let's say competitor, profile. Just help us understand what for you, and the team, what you all are looking for NT1 when it comes to a best-in-class profile. If we look about differentiation between all of these orexin agonists, right? First of all, I think needless to say, based on the orexin agonists that are in clinical development today, there is step change in terms of efficacy compared to standard of care. I mean, this is a night and day difference for patients. Patients are awake for longer, they have cataplexy control, they're more motivated, right? There's also an impact that orexin agonists are showing on many other symptoms. At Centessa, we're actually sitting on a lot of exploratory endpoint data in our phase II study across cognition, executive function, fatigue, many other patient-reported outcomes that we look to share at some point because it's just fundamentally very exciting. This mechanism is really restoring a normal, healthy type of wakefulness, right? That's what sets it apart also from other mechanism of action. It's really very powerful. now, having said that, For NT1. For NT1, I would say that what we haven't seen to date, right, is on basic external datasets, is really that prolonged duration of action. That's where we think there is the biggest opportunity for differentiation, Stacy. The life of a narcolepsy patient doesn't end at 4:00 P.M., doesn't end at the last session of an MWT. We want to make sure that we provide the bookends of efficacy. Diurnal symptom control, both in terms of EDS and cataplexy. Right? We wanna make sure that we can normalize the mean sleep latency across the different endpoints of the MWT. Wanna make sure that we can control cataplexy all the way out to the later part of the evening. That is really fundamentally a fundamental opportunity for differentiation in terms of what best in class would look like. I would also add that from a tolerability perspective, right, although it's, I mean, these are very well-tolerated drugs, right? We've seen this from the uptake in some of the open label extension data on external datasets. What I would say is, again, having a drug that is extremely well-tolerated has, is obviously an added feature, but I would say most of the differentiation will probably come from efficacy. Okay. Understood. When we hear from investors, I think for NT1, they do believe from an absolute value, they'd like to see something over 30 minutes MWT. Now, when it comes to NT2 IH, we do get more pushback as to the KOL feedback we've gotten, which is if orexin agonists can achieve normalization, that would be an absolute value of over 20 minutes MWT or in that general range. Curious your view when you think about best in class, normalization and the big potential there. Yeah. Obviously, we've gone a lot higher in dose since the since the 4-mg update in November. We showed greater than 10-minute change from baseline. We've we're looking to explore the full potential of this mechanism. Obviously, I would say yes, normalizing wakefulness is definitely the goal. There is no reason why an orexin agonist could not get there. I mean, we have beautiful dose response. We've seen in their preclinical studies in wild-type animals, we've managed to see a very solid dose response across all doses tested. I think normalizing wakefulness is key. I think it's a very important feature. I would stress you to also look at the ESS. We've normalized that in NT2. We've dropped from 15, I believe, to eight. Obviously, there's many other patient-reported outcomes that we're also looking at. Obviously getting past that, past that 10 ESS score. Is that correct? That's key. Better improving past that. Absolutely. Okay. Understood. Maybe you mentioned the opportunity to look at both once-a-day and split dosing options. Maybe talk about the interrogation that you've done there from a patient perspective in NT1, NT2, IH. What are your views on how the different patient flexibility can play in? First and foremost, we have a QD drug, right? ORX750 has been designed from the get go to be a QD drug. We have a completely linear PK, rapid onset of action, and the opportunity of split dosing really comes into play in terms of providing additional patient flexibility. Right? Imagine patients that wanna further be in control and modulate their duration of action. They have a commitment later in the day. They need to drive back home later in the evening. That second dose allows just for that. This mechanism works very much like a binary switch. The moment the exposure is dropped below a certain wakefulness threshold, what happens is symptoms start coming back. You get patients experience EDS, patient experience cataplexy. That split dosing is really provides that additional flexibility to patients in the real world. It's very important when I refer to split dosing, it's because there is an equivalent QD dose, right? You can go from QD to split dose, right? You cannot go from BID to QD. BID is you need that second dose. For us, we have a QD drug, let's see is splitting that up in two at potentially, you know, not necessarily equal halves, whether that may actually promote additional flexibility and potentially maybe even some differentiated efficacy profile, tolerability profile. That's something that we're also looking at that in the midst. Okay. You talk about the potential to differentiate in the time course of ORX750 for the full day. Mm-hmm. We do get a lot of questions on the PK/PD profile. How do you provide comfort to investors here? Conceptually, broadly, how's it differentiated? The differentiation of 750 really comes into multiple areas. Back from a chemistry perspective, obviously, we focus a lot on the potency of the molecule, the exquisite selectivity at orexin 2 versus not just orexin 1 versus any other GPCR minimizing off target pharmacology. We always also really wanted a drug that could have the optimal PK profile. That means a relatively shallow kind of Cmax to AUC, with a profile that lends itself to QD dosing. You put all of that, right, you marry the exquisite ADME PK properties to the potency selectivity, and you get ORX750. This is fruit of, tens of millions of dollars of investment in chemistry efforts, as well as a unique structural biology platform that has really helped design the molecule from the get go. Okay. Understood. The data that we got in November was this two-week data, but obviously you all are currently extending the, let's say, collecting four-week data as well. Mm-hmm. You all also added an open label extension trial. To the extent that you're willing to comment on the OLE, what are you seeing there that's really giving you conviction that there's really continued efficacy in these patients? First of all, you're right. We did vary the design from a two weeks, we turned into a four weeks. This was very much out of a decision to bring the study more aligned to what a potential registrational program would look like. I think we've also made this clear that we saw no degradation of effect between two weeks to four weeks, right? That's a very important point. Somewhere between your first day of dosing to week two, there is probably a normalization of efficacy and potentially also of AEs. That's why a lot of times in these open label extension, the AE profile looks very different compared to the AE profile in a, for example, four-week phase II study. The OLE data, yeah, we're obviously very excited to have the open label extension. We're collecting. We're doing MWT there, so we're looking at efficacy. At some point, we'll be ready also to disclose that data. I think right now all I can say is that there is significant uptake into the OLE, and we're very happy about that. The work that you all have done when it comes to phase II, trying to really interrogate the potential dose, I think in the past you said you're trying to almost get to maximum tolerated dose when it comes to maximizing insomnia and obviously. Right. Pulling the dose back. just help us understand the AE profiles that you all are paying attention to. There's been a huge evolution over the last few years. where's the team most focused these days when it comes to tolerability? A couple of important aspects. I would start by saying that first of all, these are extremely well-tolerated drugs. Okay? Whether it's polyuria, whether it's insomnia, I mean, these are not AEs which negatively impact patients' lives, considering also the benefit they're getting from the underlying efficacy and mechanism. We would hope that in our dose escalation, we reach a point where the maximum tolerated dose is indeed in the form of insomnia. That tells us that we have the duration of action needed to go all the way out to 18, maybe plus hours, right? Provide, essentially cater for 100% of the patient population 'cause we're all different, right? We all have different circadian rhythms, different sleep patterns, so it's important to provide that extended duration of action. If you don't, what's gonna happen, Stacy, is that patients are gonna wanna go back on polypharmacy. We believe this is fundamentally a monotherapy mechanism, right? If you have the right molecule and if you've selected the right dose or dose regimen. I would say that obviously since the November press release, we did not identify an AE that limited the therapeutic index in any way, and we've gone much, much higher in the phase I study, we've disclosed that. Obviously we'll provide an update in the phase II study, but we're obviously very, very confident about the wide therapeutic index of ORX750. It's really how it's been designed. Okay. We do get still obviously some questions on visual disturbances, but our view is that folks have really now had the time to go and do their own clinician checks. Mm-hmm. In our checks, I'm sure you all are hearing the same, the feedback has been if it doesn't impact quality of life, it's not really gonna necessarily limit patient adoption. Just help us understand what you all have learned about visual disturbances or visual AEs in the last year or so, and maybe your views on how that's driven. Yeah. I know the street has been very focused on the visual disturbances question. Listen, we saw I think it was three cases in our November update. There wasn't a dose response in the visual disturbances there. They were all mild, transient, and self-resolving. Obviously it'll be interesting to see at the higher dose cohorts where we are. Obviously it's something that we're hoping to differentiate upon as well. We hypothesize that these visual disturbances, as Manesh says, they're really not an issue, right? I would stress that, and we spent a lot of time with physicians asking what these are, and they're not an issue, probably mydriasis and photophobia. What we were hoping to differentiate there as well, and again, this is because of the Cmax, probably Cmax phenomenon. Given 750 has been designed to have a Cmax, a relatively flat Cmax the way you see, we're hoping that a lot of these AEs are gonna show up at much reduced rate compared to kind of external datasets. What I would also stress, Stacy, and nobody's talking about this, is titration. The way in which to potentially improve the tolerability of these drugs, again, not because there's a tolerability issue, I'm really not implying that, but one way to further increase the tolerability would be to titrate, right? To work your way upwards in one week or two weeks as most drugs in the narcolepsy space are, right? Physicians, sleep docs are very used to administering a number of these drugs that are in any way titrated. Okay. That's a good segue back into the phase III design. To the extent that of course we're waiting for an update this quarter, what maybe high level talk about how you view your phase III versus competitors? Are you thinking about trying to differentiate in certain way, in certain ways? Just help us understand. Mm-hmm. How you all are thinking about that. First of all, we're always looking to differentiate, right? We're a very creative company. I think you've seen that since the beginning. Yes, obviously, not trying to reinvent the wheel, but there is definitely a lot of really exciting features that we're adding to our registrational program that we think will put us in a excellent position, not only to continue being aiming to be first in class, but also to fully explore the therapeutic index of of these of these molecules and what this biology ultimately has to offer. Watch this space, quarter one, quarter one release. Okay. To ask a very specific question, have you met with the FDA already to discuss your phase III? We've had multiple interactions with FDA and regulatory bodies. As of now, we have overall very good alignment in our registration program. Okay. Clearly the evolving opportunity for orexin agonists, I think there's increasing appreciation when it comes to, the narcolepsy space. Maybe provide your updated views there, and of course, we'll give you an opportunity to really think about, or educate us on what you think is gonna be the broader opportunity beyond narcolepsy. Yes. That's something that we're, and I'm personally very excited about. Obviously, you know, the foundation of the company here at Centessa is our ORX750 in the rare hypersomnias as best in class, first in class potential. That's really where we kind of our foundation, if you will. Obviously it's a, the mechanism is proving to be potentially a functional cure for NT1 and potentially work extremely well in NT2 and IH. Leveraging that, what we've done is that we've built this multi-asset orexin agonist franchise because we fundamentally believe that this could be a platform, what we like to call pipeline, in a pathway type opportunity. Going after multiple indications where we've already seen impact in some of the key symptoms of these broader neuropsych and neurodegenerative disorders in our phase II study in our narcolepsy patients. There's a lot of symptoms where orexin agonists could potentially significantly benefit patients, whether it's fatigue, whether it's mood, whether it's cognition, whether it's executive function. Having multiple assets to do that with very differentiated PK profiles really allows that, allows us also to fundamentally address these indications with very different commercial plays, very different commercial dynamics. We think some PK profiles may be very well suited for some specific indications. There is very strong scientific rationale for some of the indications. There is actually a orexin loss or lesions in the orexinergic system. In other indications, there just is such a, I would like to call so partial clinical validation from stimulants and wake-promoting agents that are already used in addressing some of these symptoms. Here we're coming in with a much more powerful mechanism across indications where we think alleviating symptoms will translate into unlocking significant value. You've disclosed that you plan to initiate additional studies and other indications in Q1. Are these the type of studies where you would expect to give proof of concepts relatively quickly, or are you thinking that these are gonna be more of studies that are kind of a slow drumbeat behind the scenes? Absolutely. They're proof of concept studies. Depending on the indications, some are gonna read out quicker compared to others. They will be very robust clinical studies, let's put it that way. We, again, don't wanna take shortcuts. We believe in well-designed studies and looking to unlock value and then provide and enable the later stage development of all these other indications. Okay. One last thing. You've all mentioned there's gonna be a increased focus on raising awareness within the clinician community on ORX750. Maybe as a teaser, what does the team have planned for the upcoming sleep conferences? I haven't really given any guidance on the scientific meetings we'll be disclosing data this year, Stacy. What I would say is that yes, one of our objectives for me as CEO of the company is also to provide more and more educations to physicians. Not just sleep docs, right? Also neurologists, psychiatrists, especially as we educate the world, not just about the rare hypersomnias, not just about ORX750, but also about the other indications. Obviously, we are, we've reached a stage of maturity as a biotech company that finally, I think, enables us to do that. Obviously we'll be attending a lot of the meetings that you, that are in your sight. What I'd like to say is that we're essentially, you know, morphing into a pre-commercial company, right? We're already thinking about commercial. We're already thinking about hiring a commercial team this year. Registrational studies can enroll pretty quickly based on what we've seen, so we wanna make sure that we are ready. As part of that, as part of those plans, obviously goes hand in hand with a very well-thought and articulated communication strategy. Okay. Looking forward to the imminent updates, as well as the progression this year. Thanks so much for your time today and for everyone for listening in. Thank you, Stacy.