My privilege to welcome Dr. Saurabh Saha, President and CEO of Centessa, and Mario Accardi, the lead of the Orexin franchise. Good morning, Saurabh. Good morning, Mario. Thanks for your time. Morning. Morning. Interesting press release yesterday, both on the SAD and the MAD data. Did the MAD data surprise you, given how clean the overall profile was? Oh, that's a great setup, Debjit. Well, first, thank you for inviting us to this wonderful conference. So, as most of you know, in September, we had a really exciting press release of data showing for the first time that ORX750 can be an effective drug, a safe drug, potentially safe drug, to keep healthy volunteers who are sleep deprived at night awake. And that was highly encouraging for us to continue to proceed as fast as we can to bring this drug ultimately to patients and to market. But in the interim, we were able to generate a lot more data, which we shared yesterday. And there were three, probably maybe three or four open questions that came about when we announced the data in September. The first question was, can you dose higher? Can you generate a therapeutic index where you can flexibly increase the dose if needed? The second question was, well, what happens when you dose multiple times or repeat dose the drug over time? And how will your drug behave in terms of safety? Can you maintain that clean safety profile? The third question that we received, and that we ask ourselves, is, can you continue to achieve a linear dose response, dose exposure response, while maintaining the safety profile that we showed in September? The fourth question was, okay, so you were able to complete the phase I in a matter of months after opening the IND. What does your phase II study look like? How can you close the gap between us and our competitors and possibly even move ahead? So we were able to answer all four of those in our press release yesterday. The first, we showed in our single ascending dose studies that we were able to dose beyond the 2.5 mg, where we showed the effective MWT of 32. We went to 3.5 mg and 5 mg and continued to show a very favorable safety profile. So that box was checked. The second question was, well, what happens when you repeat dose? Well, we also dosed at 2 mg and 3 mg in the MAD portion of the study, the multiple ascending dose. And there, again, we showed that we can continue to achieve this favorable safety profile. What's also notable in the MAD is that we're getting a little bit of a bonus there in terms of higher exposures, slightly higher. So our 2 mg MAD is equivalent to about 2.5 mg in the SAD, and our 3 mg MAD is equivalent to about 3.5 mg or so in the SAD. So this nicely lines up with the POC data we've generated at 2.5 mg and 3.5 mg. And then the third box that we checked off on our announcement yesterday is, well, do you continue to get an increase in effect size as you increase the dose? And we were able to show in a beautiful linear dose response. We showed an MWT of 32 and a delta between drug and placebo of 15 at the 2.5 mg dose in September. And we also did an MWT study at 3.5 mg, and we were able to show an MWT of 34, but most importantly, a delta of 20 now versus placebo. So a beautiful dose response. We've done sleep studies now at 1 mg, at 2.5 mg and 3.5 mg, seeing a delta in placebo of eight minutes, 15 minutes, and 20 minutes. And so that was the major gist of the press release, is basically answering, I think, the three open questions that remain from the September release that we had. So what's driving this differentiated safety profile? Because there was the expectation that, especially when you go into the MAD study, you would start seeing at least more incidences of polyuria and maybe even some visual disturbances. Yeah, I mean, look, to be, there's a lot of humility you have to have in this business, and frankly, it surprised us even to continue to see such favorable safety and no real difference between what we're seeing in the placebo arms. When we designed this molecule, and I'll refer to Mario and his team, I'm not going to take the credit for this. He can explain further. The molecule was designed with the intent of having a lower Cmax to trough ratio, a narrow peak to trough ratio. And that was the hypothesis that maybe we can avoid on-target AEs. Now, that's an exercise on paper, and then you do the experiments that you need to design such a molecule preclinically. But it really does make itself evident when you're in the clinic whether or not you got the hypothesis right. And so far, what we've seen is that we have. And so I'll turn it over to Mario, who can expand upon that. Sure. Thank you, Saurabh. Basically, with this mechanism, it's one of the, as you know, probably best understood biology mechanisms in neuroscience. And in order to drive orexinergic neurotransmission and essentially suppress excessive daytime sleep, well, improve excessive daytime sleepiness, suppress cataplexy in NT1 patients, you need to be above this wakefulness threshold in the brain. Anything above this brain exposure, it's really empty space, right? As far as we understand, there is really no benefit. And that's essentially your Cmax, right? Everything above that. So when we first nominated the candidate, we wanted to make sure that what we were taking forward had an optimal PK profile, not only in terms of duration of action, but also in terms of a Cmax to AUC in order to minimize that empty space, be above that wakefulness threshold, with the hypothesis, to Saurabh's point, that potentially we may be able to avoid certain, or rather minimize, certain on-target AEs. I think to see that data, both in the single ascending dose portion of the study and the MAD, was, to be honest, also somewhat of a surprise to us. But it's really great to see that hypothesis being validated. Before we go to your very interesting and unique phase II study, let's touch upon the speed at which you're nominating follow-on compounds and the white space that you see in the broader CNS as you drive potency and selectivity. Yeah, so the Orexin pathway now is clinically validated. Certainly, for excessive daytime sleepiness, there are a number of diseases and disorders where that's a comorbidity, often the most debilitating symptom for patients, and we've shown, as well as others have shown clinically, that we can address excessive daytime sleepiness with this mechanism, so it makes sense for us to capitalize on this space as much as we can by introducing as many molecules as we can, because the indication space is so potentially broad here, beyond just the rare hypersomnias, which in and of itself is likely a $5+ billion market, that's NT1, NT2, IH, but there are so many indications, such as EDS and Parkinson's disease, major depressive disorder, obstructive sleep apnea, shift workers, depression, fatigue, and MS, and the list goes on and on. It's an eye chart, and we've looked at this carefully, where there is an opportunity to generate chemical matter, generate distinctive molecules with distinctive properties that can address buckets of these kind of markets and buckets of these indications that are appropriate for a given molecule. I don't think it's the case where one molecule is going to satisfy the entire space of all these indications. I think, in our case with 750, we've targeted the rare hypersomnias as a drug that physicians can give to NT1, NT2, and IH patients potentially in the future, where they don't have to discern between the diagnosis being correct between NT2 and IH, which is often a gray area. And some NT2 patients become NT1 patients because they develop cataplexy. So having one single molecule that can treat all the rare hypersomnias, based on our discussions with payers, based on our discussion with physicians, that is the ideal situation. So they don't really have to think so much on the diagnosis and getting it right. And then you have the entire space outside of the rare hypersomnias, where multiple molecules can be well positioned to take advantage of related disorders, whether it's EDS or whether it's this entire space of attention, cognition, memory improvement, executive function improvement, that we've already seen evidence in the clinic with other molecules where Orexin agonism could be very, very effective. And that's why we're funding significant research efforts at Centessa to ensure that we continually generate very high-quality molecules. And as you saw yesterday, we've nominated our third candidate now, which is ORX489, which is the most potent ORX molecule of 0.035 nM, 35 pM, which is equivalent to the Orexin A peptide itself. So the chemistry gets better and better with time, and these molecules will be positioned accordingly in the marketplace. So when you think about the white space and all the other CNS indications, what are you actually chasing, given this basically native peptide binding potency that you have? This is going to be a polypharmacy market. Why is that important? Yeah, it's a great question, so the more potent the molecule translates roughly into lower doses, and lower doses translates into less mass of this drug being exposed to the body, exposed to organs, and less likelihood potentially of drug-drug interaction or DDI effects. And understanding that these broader indications outside of the rare hypersomnias may, in fact, be in Orexin agonists may be co-administered with an antidepressant, with whatever molecules or drugs being currently given to these patients as standard of care, where we're treating perhaps a symptom of the disease like EDS or cognitive benefits, we anticipate that polypharmacy will continue in those other indications, and so having a drug that's dosed at extraordinarily low amounts would only be a benefit. Yeah, we focused on nominating candidates as we did with ORX750. And remember, I want to emphasize that there's no liabilities that we really had to or wanted to improve upon with ORX142 and ORX489. We really needed additional assets to enable a commercial strategy in these high prevalence disorders. But definitely a lot of focus on dose, to Saurabh's point, also to reducing as really as little as possible the DDI risk. Polypharmacy will be more important in these high prevalence disorders than in the rare sleep-wake disorders. And to be honest, we're incredibly excited about the opportunity here. There's a number of indications where excessive daytime sleepiness is highly prevalent, such as in Parkinson's, major depressive disorders. We've seen stimulants being used in these indications. We've seen the overlap between fatigue and EDS in MS. But right now, we have essentially a scenario and a strategy very much focused on the EDS component. But at the same time, we're now starting to also look at the cognition plays, the effects of mood, the effects on fatigue. And a lot of these will also be looking in our phase II study directly in narcolepsy patients, also to help de-risk some of these other aspects for these additional indications. Awesome. So that's a great segment of this phase II design then. When I look at your design versus what your competitors have put out, this is a different planet by itself, both how efficient it's going to be and how quickly you can get to that time point. So walk us through the advantages of the way you designed it, especially patients don't have to be off their regular meds for six to eight weeks. Absolutely, so with our phase II study, we were looking to do something clearly very, very creative and elegant, as we did for the phase I, and fundamentally, to answer a very simple yet difficult question, is what study design is going to enable us to pick the right dose for the upcoming registrational studies that, by the way, we're planning also in the back end of 2025. That is really the aim of a phase II study, and then moving forward from that, how are we going to enable this with the design, well, first of all, in terms of dosing period, we wanted to guarantee that all patients that walk into the study and by the way, this is a basket study of narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. We wanted to guarantee that all patients walking into the study would be administered at least four weeks' worth of treatment with ORX750. This is incredibly important. Why? Because it dramatically increases recruitment speed. We're not asking them to participate in a six or an eight-week placebo arm. And remember, a lot of these patients are not going to be drug naive. They're going to be patients which have to wash out potentially from sodium oxybate and other medications. So for them to commit to a study can be difficult. So first, I wanted to address that. The second point in the study, which again is very important compared to a traditional phase II study, is that unlike traditional drug development and phase II studies, where you're pre-defining your doses ahead of time, ahead of the phase II start, running with the study, and then unblinding the data at the very end and crossing your fingers that you will have hit all the right doses for your registrational studies, here, very much in a similar fashion to the phase 1 study, was to segment it into different cohorts and have one dose group per cohort, where as part of the cohort, we'd be able to complete the cohort and then tie the efficacy data, which, by the way, for this study, it's not just the MWT. We're looking at many sophisticated efficacy measures, including attention, cognition, and including polysomnography to look at disturbed nighttime sleep. We'd be able to peg the efficacy with the PK, with the safety, with the tolerability, look at the data, and then use that data to help guide dose escalation up or down. Remember, we're studying the study already with one mg dose in narcolepsy type 1 and 2 mg in narcolepsy type 2 and idiopathic hypersomnia. So already very, very highly therapeutic doses based on our study and accuracy provided to volunteers. So this, I would say, is a very, very big differentiation compared to a traditional phase II study. The other aspect, which I think is also important, is we're looking at randomized withdrawal in this study. So basically studying what happens when you come off an Orexin agonist after a certain period of treatment with ORX750. Again, this is hugely risky because it also gives us the opportunity to look at randomized withdrawal as part of a potential pivotal study in a phase III. And so ultimately, it's a very efficient study design, even in terms of patient numbers. We're looking at six NT1 patients, six narcolepsy type 1, eight narcolepsy type 2, and 12 idiopathic hypersomnia patients per cohort. So it's not your traditional study with hundreds of patients for phase II, but it's really been optimally well calibrated to help answer the question that we're going to need in order to essentially move very, very quickly into registrational studies. And as I think we've disclosed in the 10-Q, we're looking to have data for the study already in 2025. Two points there. One, the randomized withdrawal segment. And then on the overall safety package, you have roughly 70 patients-75 patients' worth of experience so far. Probably add another, call it 50 patients-60 patients in the phase II segment. How many patients do you think you would need in the phase III, given that the effect size is enormous, so it's not a stats issue? How are you thinking about the phase III then? Yeah, so when we look at the phase three, we don't look at these phases, if you will, or these studies in isolation. We look at what is the total experience of patients on ORX750, regardless of what indication they might have. It's the drug exposure in a large enough patient group over a large enough period of time to give confidence on safety. So it's the totality of that. From phase I data to phase II data, plus phase III data, open label extension data, all of that together should comprise a safety package, which we feel, obviously with discussion with the regulatory bodies, would be sufficient for approval purposes. So we don't necessarily look at each individual phase or each individual study, but rather the totality of the package. On the randomized withdrawal side, historically, RWS is more of a post-marketing kind of commitment study. You think you can get an RWS as a primary study for approval? There's clinical precedent being used. We've seen it being utilized very successfully with sodium oxybate, for example, in idiopathic hypersomnia. So clearly, it's something that we've had interactions with the regulators further down the line, but it's definitely something where there's clinical precedent. Got it. And then since the data are likely, let's say, first half 2025, depending upon how enrollment goes, are you going to piecemeal out data, hypersomnia first, NT1 later? I don't know how to think about. Or it's coming all in one package? Yeah, so we like to keep everyone on their toes, as you've seen. We haven't yet decided how we're going to share the data. The most important aspect of all this for us right now is good execution, great execution, and just getting as much data as quickly as possible. And what we stated publicly is that we'll have data for NT1, NT2, and IH in 2025. Something that you mentioned right at the beginning of this conversation, the payers want to see one single molecule or medicine for all the narcolepsy indications. Given that Takeda probably gets to the market first with NT1, what do you think the payer landscape is going to be by the time you're ready? Yeah, so I mean, it's early to comment on the payer situation and just the commercial prospects at this point. But our goal, after having spoken to physicians who treat these patients, as well as some of the largest payers out there, is there is a clear preference to have one molecule for all three indications for the reasons that I just mentioned before. I mean, from the standpoint of being able to ensure that patients receive ORX750, regardless of kind of the definitive nature of their diagnosis, whether it's NT2 or NT1 or IH, this gives a lot of flexibility to ensure that one drug can cover all three adequately and that short of doing a lumbar puncture, which they do in maybe two clinics in Europe, I don't think anyone's going to be doing that to assess their Orexin levels. I think you're going to want one drug to be able to treat all three indications kind of with confidence. So that's one, and I think from the payer perspective, I think just from pure logistics and reimbursement potential and many other aspects, access, it just makes a lot of sense to have one molecule treat all three. Let's go back to the massive white space that there is at CNS. If you think about 2025 or 2026, rather, how do you fund these programs? Do you think these are going to be more basket studies? Just curious what the thought process is there, because this is going to be a pretty enormous undertaking. Yeah, yeah, it's a great question. We're certainly fortunate to have over $500 million in cash available. Largely, 95% or plus of the spend is dedicated to ORX and going forward. It's interesting because as we look at each of these indications in this massive white space, as you mentioned, given the effect size is so large with these Orexin agonists and given that the effect size can be determined very quickly, oftentimes within one day or maybe a week or two, it's actually quite efficient to generate that type of data across a number of indications with minimal spend. So you can get an idea very quickly which indication path to pursue. As Mario mentioned in our phase II study, we've incorporated a long list of endpoints, secondary endpoints that will give us insight into aspects which will help us determine what indications in the white space outside of EDS might be ones we'd pursue. Some of these are on cognition, attention, memory, polysomnography, and other aspects that we're going to get data on in the phase II setting with 750. That'll help inform 142 and ORX 489 in terms of what indications we go into. The other aspect of having multiple molecules, for example, with ORX1 42, is we can pursue a good number of these indications efficiently, as you mentioned, outside of the rare hypersomnias. But then based on what we're learning there, that's going to quickly inform how we want to parse out that indication space, a subset of that perhaps for 489, which is very close behind. So that's going to be each of these molecules is going to give us information on the subsequent molecule and how to develop it, which is very exciting. So obviously, the first launch is going to be in narcolepsy, which has the benefit of rare disease pricing. But the subsequent programs are going to be in a market where you are almost an add-on therapy in a largely generic environment. How are you thinking about pricing as you go from narcolepsy into those indications? I think it's early to think about pricing, but I think your thought process is correct. Certainly, the rare hypersomnias present an attractive commercial opportunity, as we've discussed, and as precedent is with the molecules that are currently standard of care. But as you rightly point out, you go into this broader and much more prevalent indication space. The opportunity is large. Certainly, the volume is large there. But they may be at different price points. That certainly is an aspect of it. But I think it's early at this point to comment. Right now, our goal is to make sure that we have three of the best molecules that could be first in class, best in class in those respective indication spaces. And then as long as they benefit patients and there's a benefit-risk profile that makes a lot of sense, then the payers and the physicians will dictate the opportunity, the commercial opportunity. Got it. So about a year and a half ago, the most common theme that we heard was, how is Centessa going to play catch-up? And now it's almost like, can the others play catch-up? So the secret sauce is something that you brought to the company. What's preventing your competitors from doing something very similar? Yeah, I mean, it comes down to first principles. And the reason why we were so excited to have acquired Mario's company, Orexia, back four years ago was the proprietary crystal structure that they had obtained in collaboration with Sosei Heptares, now Nxera, a single-point mutation in the structure which completely changed the game in how to be able to do the med chem and the work necessary to generate these molecules that we have today. It's twisting that structure just enough to be able to do the chemistry in that pocket that's so been challenging for decades for pharma to be able to overcome. Mario and the team have been able to do that with the help of this structure. So it's difficult. It's very difficult for others to jump into this space, especially not having that structure. You can't download it off the internet, but you can download it off the internet, but it's not going to be the right starting point to generate chemical matter and do those screens. So I think that is certainly a competitive advantage that we have. But it's also that at Centessa, we don't have many distractions at the company. Given the small size we have and the kind of flat structure, we think about Orexin every hour of every day. That's all we're focused on. And we just continuously try to figure out how can we get these patients as fast, how can we get this drug to patients as fast as possible. And that working backwards dictates our study design, the creativity that you've seen, how we're thinking about bringing new molecules forward that address the first-in-class, best-in-class nature of that white space you referred to. This is all we think about all day long, and there's nothing else distracting us. Awesome. I think we have run the clock. Thank you so much. Appreciate the time, and good luck to seeing more data in 2025. Great. Thanks, Debjit. Thank you. Thanks so much.