Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. So for this session, we have Centessa Pharmaceuticals with CEO Saurabh Saha. Welcome. Thanks, Jeff. So, for those who may not be as familiar with Centessa, can you just provide a brief introduction? Yeah, absolutely. Well, thank you for the invitation to speak here. This is a very exciting time for Centessa. We have three programs in the clinic with a burgeoning orexin program, with a molecule that we just announced that is also soon to be in the clinic, our second one, ORX142. But more importantly, what gets us all excited and up in the morning is to work on drugs that are best-in-class and potentially first-in-class, depending on the indication, but really have the fundamental ability to shift that needle on where standard of care is today to what may be promising medicines for the future for patients who really need them. We have a number of data readouts coming up this year, and we have a very strong healthy balance sheet of around $300 million in cash. Great. Well, let's start with the ORX750, your orexin-2 receptor agonist. Can you just talk about the current treatment paradigm for patients with sleep-wake disorders and where you see 750 fitting in? Yeah, absolutely. So narcolepsy patients have a tremendous amount of suffering, and it's due largely to the loss of orexin-producing neurons. And this manifests itself as having excessive daytime sleepiness, cataplexy, disturbed nighttime sleep, and other issues. Now, it's important to note that the therapies that exist today as part of standard of care address the symptoms. They don't address the underlying cause of the disease. Now, here comes the orexin class of small molecules, the orexin agonists that target the orexin-2 receptor. Now, this is thanks to many of the folks who have made significant headway in the space in the clinic ahead of us, have really elucidated the potential of a transformational class of molecules that can address the underlying cause of the disease. And so in this population, the standard of care today is largely driven by stimulants, wake-promoting agents like modafinil and others, and if you have cataplexy, then you take antidepressants. But what the orexin agonists have the potential to do is trigger a cascade of neurotransmitter release, whether it's serotonin, dopamine, or histamine, to be able to then treat all the different sequelae of that disease, potentially and ameliorate some of the effects that we're seeing in these patients. Now, it's funny you ask that question because it was just a few weeks ago that someone gave me a book called Wide Awake and Dreaming, by Julie Flygare. We had spoken to KOLs. We've spoken to patients before, and you get a snapshot of the tremendous area under the curve of suffering that these patients with narcolepsy have. Until you actually read in a memoir, as in the case in this book, you truly understand how challenging it is to live with this disease and what the current treatments that are available for these patients really are not sufficient to address a number of the morbidities that these patients have. We desperately need this new class of drug, which hopefully can be safe and tolerable, given chronically, and address the underlying cause of the disease. Essentially, a pharmacologic small molecule replacement for the orexin peptide that's lost in these patients. To your point, we've seen a lot of interest in this area. So can you just remind us what you've seen preclinically that positions 750 for potential success? Yeah. So, I have to credit Mario Accardi, who's the president of the Orexin program, and his team, for doing something that frankly, has eluded many in the space, which is to break that chemistry challenge, to be able to target the orexin-2 receptor, this GPCR, and basically discover an agonist that can mimic the function of the orexin A peptide. And what Mario and his team were able to do is leverage some proprietary crystallography, where they introduced a point mutation in the orexin-2 receptor. That was very, very important because it slightly twisted the molecule in a way that allowed us to perform our screening efforts and med chem optimization to be able to then generate molecules which can agonize the receptor in a way that almost mimics what an orexin A peptide would do. So part of that screening cascade was also setting a very high bar for his team. A very high bar when it comes to having a molecule that is very, very potent, almost as equally potent as the orexin A peptide itself. Having a molecule that has rapid uptake, brain penetration, high brain penetration, and selectivity. And you want selectivity against the orexin-1 receptor, and you want selectivity, frankly, against any and all receptors. So Mario and the team did a really fantastic job in generating a number of different molecules that allowed us to then interrogate which of the molecules that have the right properties to be a once daily drug, minimize Cmax and trough ratio, and be able to work in the preclinical animal models both in narcolepsy and wild-type animals, to show that you have a drug that potentially can work just not in narcolepsy alone, but also in conditions where excessive daytime sleepiness is a comorbidity associated with a number of diseases, which maybe we can talk about later. You touched upon this in your last answer, but I guess with several competitors in the field, how is ORX750 differentiated on potency and safety? Yeah. So seven fifty has a potency of 110 picomolar. The peptide itself is around 30 picomolar, so that's exquisite chemistry to be able to achieve those types of numbers. What the team was able to do, and we recognized early on, that you don't get any benefit by having any Cmax-driven effects of this mechanism. The benefit comes from being able to stay awake, keep people awake by being above a threshold exposure level of your molecule throughout the course of the day. So there's a lot of wasted area under the curve, if you will, in a given standard small molecule PK profile. So by minimizing the Cmax to trough ratio, you potentially avoid tolerability and other safety issues to the extent you can. But you're then able to extend the duration of effect of the molecule so patients can stay awake in the desired timeframe that you'd like. In our case, we've targeted once daily oral dosing. In some of the competing programs, they've shown adverse events such as visual disturbances, liver toxicity, and cardiovascular events. So how should we be thinking about these? And is there anything that you've seen in the literature or in your preclinical work to suggest whether they are on-target or off-target events for the orexin class? Yeah. So first of all, I want to say that, you know, hats off to our competitors for really paving the way in this space and, and for patients, you know, showing that targeting this class of orexin, you know, generally this class of orexin agonist, can potentially be, what some have called a functional cure. So I think it's important that we acknowledge the work that the entire group of companies have done in this space. I'm not going to comment, and I can't comment on other people's toxicities. I mean, it's best that they describe that themselves. What we can comment on is, as I mentioned before, is that if you look at the totality of data today, from those molecules that have been in the clinic or are in the clinic today, you know, there's some patterns that are emerging. You notice that there are some on-target, adverse events that are effects that are happening, and then there are some that are off-target and some, you know, maybe just simply due to the molecule itself and not, generally a class effect. So, there's a mix of these out there. Now, our goal as a company, is to make sure we minimize all of these as possible, and we've described some of the, ways in which we've done that, to some extent, preclinically. We've actually gone above and beyond in terms of our screening of our molecule preclinically through the GPCR Max panel, the SAFETY47 panel, as well as, been very diligent, in how we assess in our GLP studies any, kind of effects that we might be seeing. And, you know, and we've been clear that, our GLP tox studies, have been clean, both in rodent and non-rodent, at the wide exposure range, which gives us a lot of confidence as we go into, as we are now into the clinic, in terms of what we may, see or may not see. So the proof of concept data in sleep-deprived, healthy volunteers are expected by year end. Can you just walk us through the study design? Yeah. So traditionally, in small molecule discovery, you do a SAD, a single ascending dose study, then you do a MAD, and then you do your efficacy study, a POC study, which in this case, would be the Maintenance of Wakefulness Test or the sleep study. And what we decided to do is, you know, having seen how the drugs have been developed ahead of us, is try to short-circuit that, process as much as we can, but by doing so, getting as much data as early as possible and cutting down the timelines, to get to meaningful data, obviously, as quickly as possible. So what we did, and it's, I don't think it's ever been done before, is the, ability at the very first dose that we give subjects. These are healthy volunteers. In the single ascending dose study, we have the ability to have them undergo a sleep study, actually, the Maintenance of Wakefulness Test study. The subjects, nine on drug, three on placebo, undergo a SAD. They get dosed, and we assess their PK, we assess the tolerability, their AE profile, and then we have the option at that point of putting them through a Maintenance of Wakefulness Test study, understanding in the context of a crossover design, whether they get, you know, they get drug or they get placebo. So it's very well powered to be able to assess how long are they staying awake on the traditional scale of zero to 40 minutes, the mean taken across four different sessions in an acutely deprived sleep study in the middle of the night. Very difficult. These are healthy people who are given drug at 11:00 PM, and then they're assessed at 1:00 AM, 3:00 AM, 5:00 AM, 7:00 AM, how long they're able to sleep on a 0 minute- 40-minute scale. And so we have that ability right at the get-go, right at the outset, to be able to peg the efficacy of our drug at that given SAD dose, along with PK data, along with safety and tolerability data, make an assessment and say, "Okay, here's the dose, here's the exposure, here's where that threshold of wakefulness, where what it looks, you know, what it looks like." And then be able to determine collectively, "Okay, let's go to the next SAD cohort at this dose." And so we go through this process iteratively again, and at that point, we're able to assess in another sleep study, if we choose to do so, and peg again the amount of time they're staying awake relative to the PK, the dose level, that threshold of staying awake, and keep doing this. And why is that important? We're not, we're not in the business of generating data from a cancer drug here, where you may want to go to MTD, and even then, you're in optimal biologic doses these days. You don't want to push the system as far as you can to try to get to an MTD dose, but rather, what's important for this patient population, and generally when developing these drugs, drugs that are going to be used for, you know, patients or people who are in their twenties, thirties, perhaps for the rest of their life on a chronic basis, you wanna get to the point of that sweet spot where safety and tolerability are paramount in assessing and minimizing any kind of issues, and then making sure they get to normative wakefulness. That is super important. And doing so with a once daily dose, and hopefully low doses. And given the potency of our molecule, the predicted human doses from preclinical data are expected to be low, but low doses also portend well when it comes to tolerability, tox issues, as well as the ability to combine with other drugs and minimize drug-drug interaction or DDI effects. So when you take all this into account, this sleep study, I should say, combined with the single ascending dose study, allows us to hopefully get to that ideal dose to take forward. And whenever you do a clinical study, the intent is for it to inform the next clinical study until you get to approval. So our phase I study and the design I just spoke about would hopefully allow us to peg. These are the doses or this is the dose range for narcolepsy type one or NT1. This is the dose range for narcolepsy type two and idiopathic hypersomnia. As you well know, Jeff, that NT1 requires a third of the dose that you would, you know, perhaps need if you were to establish efficacy in healthy volunteers. And NT2 and IH requires doses that are comparable to what you would want to achieve in keeping healthy volunteers awake. This phase I study design is, you know, one, it sets the highest bar possible because you are trying to keep healthy volunteers who are acutely sleep-deprived up at night. It then de-risks, in many ways, the dose ranges or I guess, you know, portends well in terms of the dose ranges that might be effective in NT1, a third of the healthy volunteer dose, as well as NT2 IH. And then it also gives you a good sense of the safety and tolerability profile of the drug, including around you know, the circadian rhythm of an individual, 'cause our SADs are dosed in the morning and our sleep studies are dosed at night. You're getting a very comprehensive view from this study design of what the future might hold. So you talked about NT1, NT2, IH. And so as you think about these different indications that you're planning to pursue, like, how do you think about the plan going forward in terms of would you consider running parallel studies for multiple indications or focus on developing 750 in one lead indication first? So we haven't yet disclosed our future clinical plans outside of the phase I for ORX750. What we have disclosed in our Q is that we intend to develop 750 in NT1, NT2, and IH. So ideally, have one molecule that treats these rare hypersomnias, if you will, knowing full well that there's a wide dose range required between NT1 and the other indications. We have since, as in the same press release, we noted that we've nominated our next orexin molecule, which is ORX142, which is intended to go into normal orexin indications where there's normal orexin levels. So that is really at this point, you know, a number of different possible indications. And as time evolves, we'll be able to share exactly what those might be. All right. I was just about, t hat was my next question I was going to ask you. Any other additional insights that you can provide on which types of indications that you're planning for 142? But maybe beyond that, what makes you most excited about that program? Yeah. So ORX142 was selected mainly as a drug that could complement 750 in terms of the potential indication space. It wasn't meant to address any liabilities of 750, as we have found no liabilities of ORX750 pre-clinically and ORX142. What I can say is ORX142 comes from the same provenance as ORX750 and obviously all the chemistry that Mario and his team have generated. And you know you're gonna see some data in a couple of weeks on ORX142 at the Sleep Conference in Seville, Spain. And you know we thought we'd showcase primate data for the first time. Actually show some data there. I think it'd be fun kinda to see how the dots connect between in vitro data, smaller species like rodents, with Narcolepsy Type 1 and wild-type animals that we've shown previously with 750, but now for the first time, showcasing data in primates, EEG data with 142. So you see how these drugs translate and the quality of the chemistry behind these drugs, now from two different 750 and 142. And then obviously, as we plan a data release this year, then hopefully one will be able to connect these dots even more fully. So with 142, you ask, okay, well, what are the potential indications? I think it's pretty widely known that excessive daytime sleepiness is a comorbidity associated with a number of diseases, particularly neurodegenerative diseases like Parkinson's EDS. EDS is fairly prevalent and well known, and there really aren't any good treatments for that. Everything from major depressive disorder, chronic fatigue, shift work, obstructive sleep apnea, and the list goes on and on and on. I think that's where there's a huge amount of excitement as to the potential of the orexin agonist class. I think, you know, again, credit to the folks who have come ahead of us, is that it's remarkable. It's almost like science fiction, frankly, to have shown that an orexin, a small molecule orexin agonist, can work and keep subjects awake who have normal orexin peptide. I think just take a step back. That's pretty remarkable. You would think in a Narcolepsy Type 1 patient who doesn't have orexin A peptide, you're kind of pharmacologically small molecule replacement, you kinda get back to baseline and be a functional cure for that population. Yeah, that kinda makes sense. But then to be able to keep normal individuals who are suffering from excessive daytime sleepiness awake, I think that's really exciting. That's why we are taking 142 into those indications. So stay tuned as we progress 142 and then shed some light into what we're thinking in terms of development plan there. Great. Let's move to your SerpinPC program in hemophilia. Can you just remind us of the data that you've shown to date, and that gives you confidence in this program? Yeah. So from our phase II data, we've been showcasing data over the last few years, and now three or four years in, we've been able to demonstrate with SerpinPC, completely first-in-class novel mechanism of action, depletes activated protein C or APC, that we're able to reduce bleeding ABRs by 90%+, 95%, which is really strong data in the space. But more importantly, where the unmet need comes from is in two, especially in Hem B. One is the current standard of care is IV factor. Our drug is given subcutaneously, so huge convenience advantage for patients. It's really potentially, you know, a significant leap, as you've seen with Hemlibra, as that's given sub-q, and it was previously given. The drugs were given IV, factor replacement. It made a big difference for these patients. The second is, it's very difficult to develop a hemophilia drug with a therapeutic index because what you're trying to do is create clots to prevent bleeding. But at the same time, you're trying to avoid overclotting, so you don't get pathologic thrombus forming and resulting in strokes or MIs, and we've seen other molecules in different classes that are more kind of pan-vascular anticoagulant agents. They knock down those proteins. They result in excursions in D-dimers from the normal range at virtually any doses, and they also result in thrombus formation, which unfortunately, you see. That is very different from our experience with SerpinPC to date, now that it's been in a number of patients over the last, you know, three, four years, is that we haven't seen any sustained elevation in D-dimer. And that is the most sensitive marker that portends whether or not you might have a pathologic clot forming. And we haven't seen a thrombus to date, which is also very encouraging. But at the same time, we've reduced bleeding quite significantly in this population by giving a drug that can be administered subcutaneously. So, it's very exciting. Great. And how have PRESent-2 and PRESent-3 studies been advancing? And, you know, maybe just talk about how enrollment's been progressing. Yeah. So we started obviously these studies that we call PRESent-2 and PRESent-3, which are for hemophilia B without inhibitors for PRESent-2, and with inhibitors, small, you know, smaller patient population for PRESent-3. The studies have been progressing well. What we've indicated is that we would have part one announcement on interim analysis for part one of our data, which is a study that was designed to select among three different doses, once a week, once every two weeks, and once a month. And that data is expected to be announced later this year, and the full data set at a conference at some point end of this year or early next year. But importantly, for part two of the PRESent-2 study, enrollment's already obviously begun there because the part of the study that you need to complete as soon as you can is the baselining of patients and understanding what their ABR is, not on SerpinPC, but whatever standard of therapy they're on today, whether it's on-demand or prophylaxis. And so those are being split apart, obviously. And then our primary endpoint after the sixth month of baselining is essentially beginning where these patients will get SerpinPC treatment. And then we follow them for six months and note their ABRs, their bleeding rate. And the endpoint really is in fifteen or so on-demand subjects, that's it. That's it for demonstrating activity in the hemophilia B population. And so for that interim data that's either later this year or early next year, how are you framing expectations there? Yeah, the expectation there is that we will have selected a dose, and then we will have basically commenced the part two of the study. Okay. And, and so with recent updates in the hemophilia development space, including approvals, how are you thinking of SerpinPC's positioning and differentiation? Yeah, as I mentioned before, we find ourselves in a unique place. So first of all, this is a unique mechanism of action. It addresses a number of potential shortcomings that may exist today, whether with standard of care or competitor drugs in the space, and that it's dosed subcutaneously. The second is that, if we can maintain the safety profile, this therapeutic index, which is rare with a hemophilia drug, and not see thrombosis or D-dimer excursions, that will be very important going forward. So while I can't comment on other companies' drugs in the space, what we do know from public data is that I think there have been challenges with thrombosis. I think that's fairly evident, whether in healthy people or even in patients. And so far to date, as I mentioned with SerpinPC, we haven't had that challenge, and that's by design. The mechanism of the drug allows us to dose these patients, be able to create clots, stop their bleeding, reduce their bleeding rate, annualized, and do so in a way that minimizes the chances of getting a pathologic thrombosis. Great. Maybe moving to LB101. Can you just talk about this program, how it's advancing and what, you know, what we should expect to see with the first clinical data? Right. So LB101 is a PD-L1 CD47, that has a linker in between that is cleaved in areas of high inflammation or in the tumor microenvironment. Not dissimilar from the linkers that you've seen with other molecules that have been reported in the T cell engager space or other. And so we've undergone a phase I study in dose escalation now, to understand how this molecule performs on two levels. One is, is the molecule staying locked and the linker not being cleaved systemically when administered? And that would, be evident because with CD47, if you're exposing, the CD47 in the blood, then you're gonna see anemia and thrombocytopenia. So that's something we're watching carefully to ensure, is this, technology behaving the way it should? And the second is, once the molecule goes into tumors, is the linker being cleaved? And if the linker is being cleaved, are you seeing any efficacy? Are you seeing tumor responses? And so those are the two, major, you know, aspects of the technology platform that we're attempting to validate in this phase I setting. Now, maybe one last question, circling back to the orexin franchise. Are there any questions that you get frequently from investors that, you know, we didn't discuss, or any other aspects about the orexin franchise that you'd want to highlight? Yeah, the biggest question we probably get is, you know, ideally, what do you want to see? What do you want to see that would make you differentiated? And I think it's a fair question. And what we'd ideally like to do or show, and this was by design when Mario and the team were selecting their molecules, are four things. One is, you want a drug that can be given once daily, so QD dosing. The half-life has to support that. The PK profile has to support that. PK is probably the most important differentiator of all the orexin agonists that will determine your success. So QD, one. The second is low predicted human doses, low doses. Do you differentiate on low doses? And low doses are important, and they're important because the less drug you take, the less chances of any kind of untoward, you know, tolerability or toxicities. And more importantly, our intention is that eventually the orexin agonists will be used in combination in polypharmacy, in settings where people are being treated for their major condition, whether it's like Parkinson's or depression or whatever it may be with future orexin molecules, but also their excessive daytime sleepiness with the orexin agonist itself. So you want to minimize dose, and potential DDI risk. The third is, you want to get to normative wakefulness. And we've seen numbers being thrown around, anything above twenty or so. I think if we can get to thirty, that's a really, really good place in sleep-deprived, acutely sleep-deprived, healthy volunteers. That would be excellent. It portends well for NT1, which you need a third of the dose, and it portends well for NT2 and IH, and certainly for chronic use in orexin people have normal orexin levels with our future molecule one four two, and then the last is you want a safety profile and tolerability profile that is differentiated from everyone else, and that with time will be determined, and we hope in this phase 1 study that we're gonna be able to assess all four of these attributes of the molecule. And if we were to hit on these four, then we'd feel very good about moving forward with ORX750, potentially ORX142, into their respective indications that we've spoken about. Great. We'll just leave it there. Thanks so much for your time. Great. Thank you, Jeff.