Thank you for—sorry, I don't know if it's so loud. Thank you for joining Jefferies Global Healthcare Conference. My name is Thank you for—sorry, I don't know if it's so loud. Thank you for joining Jefferies Global Healthcare Conference. My name is Thank you for—sorry, I don't know if it's so loud. Thank you for joining Jefferies Global Healthcare Conference. My name is Kelly Shi, one of the equity analysts on the Biotech team. In this first chat session, we are very pleased to have Mario from Centessa. Mario, could you give us an introduction of yourself briefly? Yeah, good morning, everybody. Great to be here with you all. Thank you for the invitation, Kelly. My name is Mario Accardi. I'm the President and the founder of the Orexin program here at Centessa Pharmaceuticals. Welcome. This is a very high-profile topic for the biotech industry. Also, from the last 12 months, we have a lot of new learnings. Could you share some insights for the orexin space? Where do you see these goals for the next 12 months? Absolutely, Kelly. First and foremost, it's going to be an incredibly exciting year here at Centessa, data-rich with many catalyst events. First and foremost, we are aiming to disclose our phase two data across narcolepsy type 1, type 2, and idiopathic hypersomnia with ORX750. That is most likely the most potent and selective orexin agonist in clinical development today. We are very much aiming for first-in-class opportunity in NT2 and idiopathic hypersomnia, and a best-in-class profile dictated by rapid onset of action, potential for QD dosing, linear PK, low doses, which ultimately, putting everything together, enables flexible dosing, which is really very much needed and important to patients. This, coupled with our highly innovative phase two study design, which allows us to not have to preselect and predefine doses ahead of the phase two study, like a conventional phase two study, but rather allows us to pick doses during the study as we see the data readout during the study, really enables us to, A, select that optimal dose, and also explore the full dose envelope of what ultimately patients really need, which is flexibility in dosing. You want doses that are going to be high enough in order to allow for these drugs to be highly efficacious and maintain the duration of action all the way up to the later parts of the evening. You want to cater for patients that maybe do not need that and need a lower dose molecule to cater for a shorter duration of action. That is ultimately how we really think about our phase two design that really enables us to do that. Now, what we have not talked about, of course, just yet, is also our wider Orexin agonist franchise, where the ORX-142, another highly potent and selective molecule, we are going to have sleep-deprived and healthy volunteer data at some point this year. This, coupled with ORX-489, another very potent and selective molecule that is currently in IND enabling studies, really cements us as leaders in the Orexin space and allows us to enter a white space opportunity outside of the rare hypersomnias and the neurodegenerative and psychiatric disorders. Now, taking a step back, Kelly, it is also a transformational year for the asset class as a whole. There are a number of phase two readouts from the competition, Alkermes, and phase three from Takeda. This is all moving in the right direction for patients. We're getting a step closer to finally getting these patients, these drugs to market and cater after, I think, a group of indications and patients where there is still significant unmet clinical need. As you know, Kelly, we recently revised our EPI numbers, and the opportunity is really very, very, very large. Fantastic. Maybe we can dig a little bit deeper on the data front. For sleep-deprived, healthy volunteer trial, you show pretty compelling efficacy and safety. Build on that, how do we set expectation for patients' data from phase two in NT1 versus NT2 and IH given different biology behind an OX2R receptor? Yes, we're very excited, as you can appreciate, about our sleep-deprived, healthy volunteer data that, as you know, has allowed us to essentially open an IND and get efficacy data in phase one in less than four months. What that allows us to do is to put us in the best possible position to then select doses for the phase two studies. That was really the goal of the sleep-deprived study. Now, taking a step back, looking at last month, we disclosed at the American Academy of Neurology some more granularity on the efficacy of ORX-750. What we showed is the MWT of the KSS at the 5 milligram, we showed the individual time points. Remember, dosing was at 11:00 P.M. We then carried out a maintenance wakefulness test that takes you through to the 8 hours, so it's 7:00 A.M. in the morning. What was incredibly impressive, Kelly, was at the last time point, the 7:00 A.M., if you look at the sleep pressure of these healthy volunteers, they're falling asleep that are on placebo. They're really falling asleep in less than 10 minutes on the MWT. That is very similar to a number, an MWT number on placebo of a narcolepsy type 1 or a type 2 individual. Yet with drug, with 750, those healthy volunteers are staying awake almost 35 minutes at that last time point on the MWT. That is extremely important because that tells you that with a single dose at 11:00 P.M., you can restore normal wakefulness. The drug also maintains the duration of action with a single dose. Coupled with that, if you look at safety table in terms of SAD and multiple ascending dose, we're really not seeing cases of insomnia there, meaning that we've hit somewhat of a sweet spot in terms of PK. As you know, PK is of fundamental importance for this mechanism. Fantastic. Maybe focus on MWT, one of the objectives and the points. What kind of range you expect for NT1, maybe on placebo, adjusted number versus NT2 and IH? Yeah, it's difficult to pinpoint an exact number. I would definitely look back at a standard of care today. On the MWT, you're really looking at single-digit minutes. With this class of drug, we finally see MWTs in the upper 20s and even in the 30s. This means that these patients, A, have completely resolved excessive daytime sleepiness, but most importantly, they're also feeling normally awake for the very first time. That is why the Orexin agonist mechanism is so powerful, because it sits upstream and helps the release of all these different neurotransmitters, such as dopamine, histamine, norepinephrine, and so forth. I would again stress to look at the time course of the data in MWT, because you could be hitting an MWT that is in the upper 20s or 30, which is phenomenal compared to standard of care. Remember, an MWT lasts 8 hours. That is the average from four time points over a period of 8 hours. If you're starting your MWT at 10:00 A.M., the last time point is at 4:00 P.M. You also need to look at what happens beyond that. That's when, Kelly, a lot of the other endpoints come into play, the ESS, the KSS. As part of our phase two study, we're also looking at patient-reported outcomes, looking at cognition, retention, putting everything together in order to really identify the dose that gives us a best-in-class profile. Great. From your message, we need to look at probably not just objective, but non-objective endpoints. When we're comparing and contrasting across different Orexin programs, do you have an equation? When you have a data release, can we evaluate across different programs? Yeah, obviously, great question, Kelly. I would stress that looking beyond MWT and also different efficacy measures is key. Looking at how well these patients are doing on the drug beyond those 8 hours in the test is important. Obviously, we have a very clear target product profile that we want to hit. We spent a lot of time with patient organizations learning about what they want. That's why I go back to flexibility and efficacy. It's very, very important that these drugs are able to satisfy the needs of these patients, of different patients that may need to be awake for longer durations of time compared to others. We've really listened to that. That's why we're thinking about that as we go through our phase two study on our dose escalation. Maybe on the safety front, first, can you share your insights on the learnings? What are the on-target toxicity signals? What are the ones from receptor 2 versus receptor 1? What are the most concerning toxicities from physicians for this drug class? Also, from a single dose to multiple dose and also longer treatment duration, do you worry about toxicity build-up over time in patients' trial? Taking a step back and looking at the tolerability profile of this drug, of this drug class, they're extremely well tolerated. Not only is the efficacy, I think, significantly better than standard of care, they're also highly, highly tolerated. Some of this information has also been given by Takeda and the high enrollment rate in their open label extension. This is extremely exciting. Now, as part of our big commercial assessment, we interviewed over 90 sleep docs. We discussed a lot of the efficacy profiles, efficacy measures, as well as some of these on-target AEs that have been seen in the class, such as polyuria, urgency to urinate, insomnia. The feedback was very consistent, which is these are highly tolerated drugs. These sleep docs are not concerned about these on-target AEs. Now, obviously, insomnia is the more delicate one because that is a direct function of the PK profile. Obviously, sleep docs, patients, they want to return to sleep at night. Getting the PK right is absolutely, I think, important. I would also stress that it is important to look at data in a holistic manner because to answer your question on how do we really view healthy volunteer data translating to patient data. Obviously, especially in the orexin loss indications like narcolepsy type 1, some narcolepsy type 2, I think we can expect probably to see more on-target AEs. I mean, that is what the data from other orexin agonists have shown us before. I would very much look at also the cadence of this data set. The on-target AEs and the orexin loss indications, they tend to occur shortly after dosing, especially in NT1, insomnia, for example. They tend to wane over time. It's also important to look at the time course of AEs and really see what happens at steady state in terms of effect size, so two to four weeks into dosing, which is why in our phase two design, we're doing multiple MWTs. We're looking and assessing patients all the way out through to at least a four-week duration. Fantastic. I think the first ever Orexin program actually encountered a liver tox issue and had to pause and move to next generation. What are the new learnings on liver tox? Are we 100% sure this is not on-target tox? So far, I think the competing programs do not show any liver tox. Do you have any concern remaining as the treatment duration extends? Yeah, maybe start from there first. Absolutely. Firstly, I think Takeda has done a phenomenal job, I think, educating the space and explaining that liver toxicity is molecule-specific and is not an on-target AE. There is a very good paper that was released some time ago that really explains that. What we've done here at Centessa with our molecules, there are really two things. First, we've focused on molecules that are extremely potent and selective. We are dosing below 10 milligrams, which dramatically lowers the risk of DILI. As you know, DILI is a function of dose. Among other things, there is reactive metabolites that GSH product formation as well. With 750 in our molecules, yes, we are focused on low dose. We have also focused on bringing forward molecules that have a very, very different metabolic profile. We've done that thanks to very unique structural biology capabilities that we exclusively licensed from Nexera, which has allowed our medicinal chemistry team to really understand the binding pocket and essentially unlock this mechanism by designing these extremely potent and selective orexin agonists. Great. Also, based on the discussion on safety and efficacy, it seems like on each, we have multiple aspects to consider. Even if you have a best-in-class molecule, it seems like optimizing dosing is very critical for you to reach an optimal profile. Do you have already a targeted profile in mind for each indication right now to guide your dosing regimen? 100%, we do. It is a very complete target product profile, which I'd love to share with you, Kelly, but unfortunately, we can't for competitive reasons across NT1, NT2, and IH. I think, again, I would really look to dosing flexibility. You want, and we've listened to patients' needs. We've listened to physicians. That flexibility in dosing is partly enabled by, obviously, the molecule itself, which is a great molecule enabled by structural biology and partly enabled by our innovative phase two study that allows us to find that dose. In the same way that, for example, you get physicians that today titrate and play around with different doses, especially in some of these indications like NT1 and NT2, it's important to make sure that we provide a number of doses and an envelope of doses. That is really what the goal of our phase two study is, to select those doses for registration studies that we are aiming to start after these. Narrowing down that dose envelope between low dose and high dose in order to give that flexibility. If you look at, for example, even wake-promoting agents like methylphenidate, there is instant release. There is extended release. Why? Because, obviously, there are different profiles that work differently for patients. We know Orexin agonists are highly, highly tolerated. It is about efficacy, and it is about providing that duration of action that the patient needs. Because otherwise, obviously, if an Orexin agonist, if a drug is only going to last until the middle of the afternoon, what is a patient going to do on their drive back home? Payers are probably not going to pay for another pill, another tablet. What's going to happen is that they may resort to combining with polypharmacy, again, like modafinil, wake-promoting agents. It's very important to be able to satisfy all the patient needs in order to control EDS throughout the duration of the day, suppress cataplexy in NT1. OK. Maybe fast forward to 750 market launch several years from now. You already have Takeda's drug on the market. What would be the primary driving factors for physicians to make a switch, in your opinion? Firstly, I go back to what I've been saying earlier, which is, first and foremost, it's about efficacy, and it's about duration of action, and making sure that patients have access to different doses and Orexin agonists that physicians can dose with confidence at high dose levels with linear PK, really the right part of the dose response curve. That's ultimately what you want to achieve here with a best-in-class profile. Now, having said that, it's also a huge market opportunity. If you look at our EPI numbers, it's 50,000 diagnosed and treated NT1 patients today, 100,000 in NT2, and 120,000 in idiopathic hypersomnia. We're talking about huge, huge numbers. We've revised the EPI numbers based on some latest claims data and based on our physician interview. Huge opportunity for potentially even more than one Orexin agonist. Again, we go back to the way in which we've designed 750 and the way in which we are executing on our phase two study, which is about flexibility in dosing. Fantastic. Maybe before we have the full data set from clinical trials, if we have the PK profile, how do you actually read the chart and figure out who has the best-in-class molecule? PK is obviously part of our magic sauce here. We are not planning to disclose our PK profile anytime soon. I would point out to the MWT curves that we have shown because that gives you a sense of the duration of action. It gives you a sense that we can confidently dose QD and keep patients awake throughout the duration of the night all the way up to 7:00 A.M. and beyond, looking at those curves. Fantastic. Maybe regarding the setting expectation of the timing and the venue to release your phase two data across three indications, do you plan to present the data separately or altogether? What actually helped you to decide the timing of data release? Yeah, we're obviously not trying to keep you on your toes here. We have, unlike a conventional phase two design where you're predefining those levels ahead of time, you know when you're going to complete the study and at that point release data. With our phase two design, we are obviously seeing data. We are blinding, seeing data, and then deciding the dose for the next cohort, finding that dose envelope, providing the flexibility in dosing, and finding that optimal dose. We want to reach our target product profile. We want to hit that and then obviously release data once we have that. Obviously, in terms of indication, we have the option to release data in one indication or across all three. That also depends on the enrollment. It's something that we still haven't aligned. At some point, we'll be providing more guidance. One more question on phase two trial design. We see different programs adopt a slightly different approach. For example, for treatment duration, Centessa actually have four weeks for NT1 and also other indications. Others for NT1 actually have six weeks and eight weeks. Does it make a meaningful difference? That's the first question. If you look at some of the other orexin agonists that have just started phase two studies, their treatment duration is also four weeks in NT2 and idiopathic hypersomnia. The reason for the four weeks is, if you look at clinical precedent, if you look at the data and largely driven also by PKPD, especially in NT1 and where there is an orexin loss, the system needs time to equilibrate. You need between two to four weeks to achieve a steady state in terms of effect size. We've seen that with narcolepsy type 1 and the recent phase two data. That is why the decision between the four weeks. At the end of the day, we want an efficient study, a quick study that gets us what we need, the confidence level that we need to select those doses to provide that full envelope of dose and coverage for patients and move as quickly as possible to registration studies. Great. Maybe on safety, how big of a data set you would feel truly comfortable on tolerability profile given that it seems like a really low frequency of each on-target tox signal? These on-target AEs are obviously highly predictable from what we've seen from clinical precedent in the sense that they manifest themselves, especially in NT1, shortly after dosing. They kind of wane over time. Now, obviously, we're assessing all of that in our phase two study. Ultimately, the objective is really to take forward a dose that provides all the flexibility that we need for the registration studies. Fantastic. Maybe lastly, Centessa owns the franchise of Orexin agents beyond 750. Maybe could you discuss the overall rationale for pursuing two additional more potent agonists? Also, do you have indications to pursue for these two following programs? Yeah, here at Centessa, we've amassed what we so call a treasure trove of highly potent and selective orexin agonists. We fundamentally believe that this could be, in many ways, the next GLP-1 of the mind. We've heard that from someone recently. In order to enable that commercial strategy beyond the rare hypersomnia, it's obviously going to be dictated a lot by different commercial dynamics and different pricing. We want to go after indications in the neurodegenerative psychiatric disorders where we know that there is a strong prevalence of excessive daytime sleepiness and fatigue, just to name a few: Parkinson's disease, major depressive disorder, OSA. These are all indications that have a big EDS component of fatigue and MS, for example. At the base case, an orexin agonist will have a transformational impact on EDS and possibly also fatigue in many of these indications. What we've also started to see, which is really very exciting, is that this target class is also providing improvement in cognition, in sustained attention, and is restoring a normal wakefulness, which could also help with brain fog. We've also seen preclinical data, which makes sense because the release of orexin helps the release of serotonin amongst other neurotransmitters, also in mood. You can actually see that in all of these indications, wake-promoting agents, modafinil, stimulants, they're already prescribed yet have limited efficacy. With an orexin agonist, you're basically going into an extremely well-validated number of indications, which are quite frankly very, very large. At the same time, with the target class that I think very uniquely in the neuroscience space is providing a significantly high effect size and a transformational treatment to patients. Now, a lot of these indications may have orexin loss. Others may not. That does not matter because we've seen orexin agonists have substantial impact in non-orexin loss indications such as NT2, IH. We've seen data also originally IV with Takeda for residual EDS in OSA. We've seen sleep-deprived healthy volunteers with, obviously, our drug, ORX-750. It is extremely exciting to be able to take forward a portfolio of molecules to cater after so many different indications. Would you be open for partnership for those indication expansion opportunities? Right now, as of the end of the last quarter, we have $430 million on balance sheet. We are executing on our clinical development plans. We are taking forward, obviously, these NT1, NT2, IH studies. We are fully financed to do a number of signal-seeking studies also in these other indications. We will see. Right now, obviously, we have full flexibility in the portfolio to do what is best for the company and harness as much value as possible. A lot of these indications in the neurodegenerative and psychiatric disorders, you can actually do some very, very robust signal-seeking studies to de-risk the indication early, early on. We have seen precedent of that before. We are extremely excited about progressing our portfolio independently. Truly exciting time for Orexin space. Looking forward to news flow from Centessa in the near term. Thanks, everyone, for attending. Thanks, Mario, again for a great discussion. Thank you.