Okay, let's get started, and thank you for attending Jefferies Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here. For this fireside chat session, we are very pleased to have Mr. Saurabh Saha, CEO, and also Mario, President for Orexin, join us for this discussion. Maybe we just jump right into the Orexin program, given like how the popularity in the biotech industry at this moment. And can you talk about your program, ORX750? How does it differentiate from other Orexin programs? Yeah. Well, thanks, Kelly. Appreciate the invitation to discuss Centessa today. This is a very exciting time for the company. The momentum is incredibly strong. We have three programs in the clinic, and as you referred to, our most recent program to enter the clinic is ORX750, which is an orexin agonist for narcolepsy and other sleep-wake disorders. We are very well-positioned with this program. If we go back to the origins of ORX750, the basis for selection of this molecule is on the acquisition of a proprietary crystal structure for Centessa to use to screen chemical matter, to be able to generate a molecule that we believe has the potential to be best in class. And what does that mean? It means that we have what we believe is a molecule that is very potent, it's very selective. The peak to trough, in terms of its PK profile, has been optimized. And we also believe that we have a molecule that can not only achieve a best-in-class performance in narcolepsy, such as narcolepsy type one, type two, but also go beyond into excessive daytime sleepiness, which is a component of many diseases that have that as an aspect of comorbidity. So the potential to take this molecule well beyond just the narcolepsy space is something we've kept in mind from the day one, since Mario and the team have been screening chemical matter. And given the clinical precedent, as you mentioned, there is a tremendous amount of excitement around this space. I think people are just getting up to speed on what this means for the class. We were recently at the Sleep Conference, not too long ago, a few days ago, and the data that was presented, the clinical precedent that's being set validates this class of orexin agonist, and the target is having exceptional effect size, but also transformative, most importantly for patients. This is a drug that for patients is—they've been waiting for a drug like this, especially narcolepsy patients. But as I mentioned before, an orexin agonist and the—and hopefully, a molecule that is developed properly can be taken well beyond narcolepsy into sleep-wake disorders. Terrific, and efficacy has been very promising. But investors actually brought in a discussion topic on the safety. So we have saw some visual disturbance and also elevated blood pressure side effect with orexin program. Could you comment on that? Like, what is the potential mechanism for action, and do you see 750 could be actually mitigate those risks? Yeah. On the safety profile of the molecule, we did an extensive preclinical characterization of ORX750, and baked into the candidate nomination process, a lot of key experiments and key targets, such as, for example, an optimal peak to trough profile, minimizing any off-target effects. We had really robust screens, and so no relevant pharmacology across GPCRMax or Safety47 panels, and the molecule is extremely selective at orexin 2, 9,000, almost 10,000 times more selective at OX2 than orexin 1. With regards to some of the adverse events that we've seen with clinical precedent, it's clear that some of these are indeed on-target effects, such as, for example, polyuria or mild increases in blood pressure or heart rate. A lot of these are likely could be Cmax mediated, which I think would position us very well with ORX750, given the predicted human PK profile of the molecule. With regards to visual disturbances, we don't really know much about this in terms of what's been publicly disclosed. We've seen it with two molecules, but very difficult to say whether this is on target or off target. What we can say is that based on our GLP tox studies, we feel very confident about the safety profile. We saw extremely clean profile across all doses and including no hepatotoxicity seen in the GLP studies. Okay, great. And, also curious, have you disclosed the molecular structure of ORX750, and, should we expect, the structure distinctly different or maybe share a similarity with Takeda's, 994 and 861? We have not disclosed the structure for competitive reasons for ORX750- Mm-hmm. -this time. Okay, great. And also, at the last World Sleep Congress, Centessa announced the preclinical data supporting ORX750 to move to clinical phase. And could you actually elaborate some like data details and the key findings? Sure. We published a comprehensive set of preclinical data that really makes it quite evident that the molecule has the potential for best in class, not only in NT1, but also in non-orexin loss indications. We showed that we have a highly potent molecule, 0.11 nanomolar, almost equipotent to the native orexin peptide, which is an extremely difficult task to do from a medicinal chemistry perspective. It's a very tight binding pocket, and this was really very much enabled by our structure-based drug design capabilities that we've assembled over the years. Second point is that it's extremely selective at orexin two, and really seeing no relevant pharmacology across any other GPCRs. We're showing also that we can achieve wake promotion and cataplexy suppression in the gold standard mouse models, in the ataxin and the DTA at extremely low dose level, which speaks about the high CNS penetration of the molecule. And indeed, we can even suppress cataplexy all the way up to the ceiling of the assay, which really was six hours based on the world sleep data. And then I think lastly and importantly, we also show that we can activate the orexin receptor system in very similar fashion to the native peptide, right? With unbiased agonism, so it's not skewed to beta-arrestin or G protein. And in terms of the EEG power spectrum, we're also promoting that gamma wavelength that is very much associated with an enhanced quality of wakefulness. I think the preclinical profile really bodes very, very well for what's to come. Kelly, what we've seen with the preclinical models in this space is that they're highly translatable. Mm-hmm. There's enough now precedent, both preclinically and clinically, to connect the dots between the two, to make it apparent that what you see preclinically does portend well to what you expect to see clinically, both in terms of how potency translate- Mm. Translates, and how allometric scaling translates in terms of expected doses and exposures. Yeah, terrific. I mean, as you highlighted the translatability of orexin biology, I'm actually curious your thoughts because we try to actually compare different animal models from different or across different orexin program. And curious, like, if you've done the similar practice and what are the learnings? Yeah. So we're actually fortunate in that, Sally Black, who is at Centessa, works on the orexin program, is actually one of the inventors of one of those models. Our team has a lot of orexin expertise. Indeed, we've been evaluating the Ataxin and DTA mouse model as part of our screening cascade to help select the candidate for quite some time. You're right, there is some variability. These are behavioral experiments, at the end of the day, so with all behavioral studies, you do expect to see a standard deviation. I would say, Kelly, that it's the data is very much consistent, right? These molecules are doing what it's supposed to do. They are promoting wakefulness in these animals, and they're reducing cataplexy. So I think that's important to note. Yeah. I think what's really exciting and really important to note is in the preclinical models, you see that you need about a third of the exposure that to get an efficacy in the narcolepsy animal models versus our what we call our healthy volunteer mice that have normal orexin levels. To get the same effective kind of ability to keep these mice awake, you need three times more the dose and exposure. That has translated clinically in terms of what one would expect to see in terms of dose exposure in people with healthy or normal orexin levels versus those who don't, with narcolepsy. And what's important and what really differentiates Centessa or development of this drug and ORX750 is not just the molecule itself, but how we are developing this. I think it's important to note that, our phase I design is very unique in that we're not doing traditional drug development, which is a SAD, set of SADs, followed by a set of MADs, and then you kind of randomly pick a number of doses, hoping that you are in that range to see effectiveness in a sleep study. Rather, our design is very much real-time assessing from the very first, potentially from the very first SAD dose cohort- Mm-hmm That we're dosing patients. We can go and do a POC, a sleep study. In fact, an MWT with sleep latency times, how long healthy volunteers are staying awake, and KSS straight from the beginning, and that's actually the primary endpoints for a phase III study. We're getting real time, potentially in our first dose cohort. Once we peg the efficacy in terms of how many minutes they're staying awake to the dose level, we can then titrate up the SAD to the appropriate dose we so choose, and then do another sleep study, and then be able to assess how much we're keeping them awake. That gives us, it cuts down our time and it increases our speed tremendously to be able to get to that next stage of development. 2, we're doing it in healthy volunteers, which means that is the highest bar because these subjects have normal orexin levels, and then it should portend well in NT1, because they need a third of the dose that you would in healthy volunteers. And then 3, it allows us to basically walk up in terms of tolerability and safety to make sure that we're at a dose that's optimal, both when it, when it comes to the effect size as well as the, the expected safety profile of the drug. Okay. I appreciate all the details you shared on the accelerated trial design. And as you mentioned, the healthy volunteer study actually has a higher bar to show clinical outcome. So, investor laser focused on your second half data update, and curious whether you can set a expectation on the data and also its implications on the development for the next phase. Yeah. So that's, that's a great question, and a good segue. So, we do anticipate sharing the healthy volunteer proof of concept sleep study data, both MWT and KSS, in relatively large number of subjects. So there's at least 10 subjects per cohort that will undergo these sleep studies, and that's anticipated to be in the second half of 2024. And to your, the second point of your question is, what does that mean for future studies for Centessa and, and the ORX750 program? Means that if we were to be successful in those studies, then we have tremendous optionality to pursue 750, not just in NT1, NT2, and idiopathic hypersomnia, but also beyond. Beyond into indications where excessive daytime sleepiness is a major issue, whether it's chronic fatigue syndrome, whether it's Parkinson's-associated EDS, whether it's obstructive sleep apnea, whether it's shift workers, basically anyone who has issues with sleep. Mm. The healthy volunteer POC sleep study that we'll be doing real time in our SAD will be able to give us the confidence that this drug may work in indications beyond just the rare hypersomnias. Okay, great. And also, upfront, you mentioned other orexin programs choose to go to either NT1 or NT1, NT2, both. So curious, from the healthy volunteer data, would it be informative enough for you to actually make a decision, or you already make a decision to get into both? Yeah, so, one of the advantages that we have, and that we started out this discussion, is that we started with this crystal structure that's proprietary to us. That has allowed us to generate a lot of very interesting chemical matter, various different scaffolds, and 750 being one of the molecules, obviously, that's now in the clinic. But we have molecules that are very close behind 750, and so we don't see this as a one and done ORX 750. This is a franchise opportunity for- Mm. Centessa, for the orexin program itself, which Mario leads. And so we have the optionality now, as we're getting data real time from ORX750 in the clinic, it's informing how we are thinking about progressing not only ORX750, obviously. Mm. and to your point, which indications make the most sense, but also how we're gonna position the next slate of molecules that'll immediately come after 750, whether it's due to IRA reasons, whether it's due to just, you know, having the right profile for a given indication. But what we've done with 750 and obviously the subsequent molecules, is make sure that the metabolite profile, the profile of the molecule itself, enables conmeds or medications to be administered potentially in combination with 750 for diseases- Mm ... such as Parkinson's and others, where you have multiple medications that you have to take, polypharmacy. Different kind of polypharmacy, where you wanna have a safe medication, being administered, not just a monotherapy, as perhaps it will be the case in narcolepsy. So we have a lot of optionality. For us, it's not necessarily an or. We're a small biotech company, so it gives us incredible flexibility to pivot quickly, to have our teams think about: Okay, where's the best place where we can be best in class and maybe first in class when it comes to different indications as well? So it's an and for us, not an or. Okay, great. And then maybe you can also help investors to understand the market potential of NT1 and NT2, and also competitive intensity in each. NT1 is roughly, well, NT1 and NT2, roughly 150,000 prevalence in patients in the US. But a lot of these currently are actually misdiagnosed or not diagnosed. Actually, only 50% are ultimately diagnosed, and 25% are diagnosed and on treatment. There's a really, really big gap there. I mean, if you can imagine that some of the branded sales in, for example, the sodium oxybate are doing over $2 billion of revenue. You can imagine that there's really quite a large market opportunity in narcolepsy alone. Idiopathic hypersomnia and the broader rare hypersomnias, I think it's also very somewhat less characterized, but definitely a very interesting indication where we have seen an orexin agonist could play a transformational, transformational role. So all of these rare hypersomnias really really overlap in many clinical features. Of course, cataplexy is the dominant feature of NT1, but excessive daytime sleepiness is very, very, very common across all. So having a single molecule, potentially, that could really work across all the rare hypersomnias, I think could be extremely powerful. Also, in terms of prescription, you know, most of these physicians do end up seeing NT1, NT2, and IH. So I think there are some strong benefits of having a single molecule that could address narcolepsy with and without cataplexy. ... Yeah, it's important to note, I mean, in neuroscience, there hasn't been a target like this come around in a long, long time that's this well-validated and this transformational for patients. So, it's remarkable that, as Mario mentioned, 50% of the patients are even diagnosed with narcolepsy, 25% get treated, 80% don't get treated well enough where their symptoms persist, and they desire something better, and 60% or more, I think, are on polypharmacology, so they're taking multiple medications to treat their symptoms. Huge unmet need, and here comes this orexin agonist class that completely has the potential to upend that, based on what we're seeing with clinical precedent. You don't see that very often. And these are massive effect sizes, where the drugs today keep you awake in a 0-40 scale, maybe single-digit minutes, and here you have an orexin agonist keeping you awake 30, 25, 30, 40 minutes on the scale. And these patients come back, and they report, and we've heard anecdotes, and we've heard, obviously, from the publicly disclosed data from others, that they feel normal. These are narcolepsy patients feel normal again. Functionally, functional cure, I think, was, was mentioned as, as the word to describe it. So, what that basically gives us confidence in is if you look at the potential of this, and I, and I bring this back again, is that you look at the GLPs. They started in diabetes, and then they ended up miraculously in this- Mm. obesity. And, and I think this is probably analogous in that you start in narcolepsy, and you prove this mechanism works, and you can bring people to a functional cure. But then you have the potential to expand into the rest of the world's population, where people need to stay awake, and, and that market is really difficult to even calculate at this point. So long as you have a safe, safe drug. Great insight, and, maybe let's move to SerpinPC for hemophilia. SerpinPC has a unique mechanism of action and clinical profile, but the competitive landscape of hemophilia is quickly evolving. So with the recent FDA approval of Pfizer's gene therapy and a positive, positive data from Novo Mim8, what do you see the most appropriate patient population for SerpinPC? Yeah. So we're really excited about SerpinPC because of two reasons: it's a novel mechanism of action, it's first in class. We've already shown data where blocking APC effectively can reduce bleeding in hemophilia patients, but also do it in a safe way, not just in an effective way. And this is what's missing in the hemophilia space because it's very difficult to thread this almost impossible needle where you're trying to promote clots, so patients don't bleed into their joints, for example, but at the same time, not overclot, so you have pathologic thrombi forming, which can cause strokes or an MI. SerpinPC is that drug that we've shown now with 3 years of data that can very well do that with 96% bleeding reduction and no evidence of D-dimers, which sustained elevation of D-dimers, which is kind of, you know, portends to potential clot formation, and we haven't seen any thrombus in any of our studies to date. So the competitors that you're mentioning are for hem A only. We work in both hem A and hem B. Our first entry into this space is targeted toward the hem B population because that's where the unmet need is highest. Only IV therapies, factor replacement therapies exist today, but the opportunity for a subcutaneously safe, delivered therapy doesn't exist today. That's where SerpinPC can really go after, you know, $2.5 billion market, which is not unsubstantial. Similar to what Hemlibra did, transforming the hemophilia A market. We feel very excited about the potential to address a huge unmet medical need again. Okay, great. And can you provide an update on the status of the ongoing registration of PresEnt-3 and the PresEnt-2 studies? And what do you think could be a reasonable, reasonable expectation on amount of data will be available when you report interim analysis from PresEnt-2? And besides confirming the dose for part two of the study, will any other important information be available from the this interim analysis? Yeah, absolutely. So we're obviously well underway with both the PresEnt-2 and PresEnt-3 studies. The PresEnt-2 study is looking at patients with hemophilia B without inhibitors, and PresEnt-3 is with hemophilia B with inhibitors. We are in part 1 of the PresEnt-2 study. This is the part of the study where we have 3 different doses that we're testing to see which one is optimal that we wanna take forward into part 2 of the PresEnt-2 study, with, you know, again, hemophilia B without inhibitors. And it's really part 2 of the study where we have our primary endpoint, which is a 24-week endpoint, where we're looking at at least 15 hemophilia B patients who are treated on demand. And then we'll assess their ABRs over that 24-week period, looking at what they were at baseline and then assessing after 24 weeks on SerpinPC, what their ABR reduction is. So that's an exciting, exciting study to get to. We have been making incredible progress, enrollment's going quite well, and what you expect to see, this year is, our interim analysis, which effectively is selection of one of those 3 doses that we're gonna move, forward into part 2, which is the primary, endpoint study. And so we expect to share that data and then a more fulsome data set later this year or early next at, at whichever conference makes sense, for the, for the hemophilia space. Terrific. Lastly, can you talk about a plan for the oncology programs, and, when do you expect to have the first clinical data? Yeah, it's great to see sort of a small resurgence, maybe a larger one, in the not only the bispecific T-cell engager space, but also in the protease kind of activated space for these modalities, which is great. Great for us because we have a very novel and exciting platform to generate these types of molecules. So LB101, which is our first entrant from the LockBody platform into the clinic, is progressing through dose escalation. And later on, when we have enough subjects enrolled, get through dose escalation, enough responses, and patients treated, that's when we plan on releasing the data set. Okay, terrific. Thanks for a terrific discussion, and we'll wrap up our session here. Thanks to everyone for attending. Thank you.