Okay, great. Thanks, everyone, for joining on day two of the Oppenheimer Healthcare Conference. My name is Frank Brisebois. I'm one of the biotech analysts. We have the pleasure right now to have a fireside chat with Centessa Pharmaceuticals. This has been a very, very interesting story this year. So, Mario, I know how busy you guys are. Appreciate you taking the time. In terms of format, what we'll do, as I said, is a fireside. Feel free to send in some questions in the Q&A tab at the bottom of the screen. You can also email me questions. There's been a lot of interest in this one. So I'll let you, Mario, just in case someone doesn't know about you guys, give a brief intro of the company and your position at the company. And I think people understand why you're doing a lot of the talking these days Totally. Hi, Frank, everyone. Thank you for, yeah, for inviting us and setting this up. I'm Mario Accardi, President of the Orexin Program at Centessa Pharmaceuticals. Centessa is a company primarily focused today on developing orexin agonists for not only the treatment of the rare hypersomnias, but also bringing forward a number of other orexin agonist molecules into these very large high prevalence disorders in the psychiatry and neurodegenerative space. The Orexin program really started off from an acquisition, which Centessa made in 2021, acquired a company that I founded in 2019, called Orexia Therapeutics, which used sophisticated and very unique structural biology and structure-based drug design to discover and design and develop a very potent and selective orexin-2 agonist That then paved the way for essentially where we are today, which is our ORX750, a very potent small molecule orexin-2 agonist for the treatment of narcolepsy type 1, type 2, and idiopathic hypersomnia, currently in phase 2. We recently showed, Frank, as you know, phase 1 data very much a best-in-class profile, achieving 38 minutes on what is referred to as the primary endpoint for these studies, which is the maintenance of wakefulness test. We almost hit the ceiling of the test, 38 minutes out of the 40, and 23 minutes placebo-adjusted, and a safety and tolerability profile, which is very, very favorable tolerability. We're practically not seeing any on-target AEs that are distinguishable compared to placebo, which speaks to how we've designed the molecule in terms of PK profile, potency, and selectivity. And obviously, incredibly excited by how we've closed the year 2024 with phase 1 and with starting off our phase 2 study. But I would say even more excited about what's coming up this year. We've given guidance data in NT1, NT2, and IH for ORX750. We're going to have healthy volunteer data with ORX142 in a sleep-deprived healthy volunteer study, a molecule that we're taking forward for these other indications where excessive daytime sleepiness is still very, very prevalent. So it's really, I would say, cements and sets the foundation for building a multi-asset orexin agonist franchise here at Centessa Pharmaceuticals. Okay, that's great. And I like how you mentioned beyond rare hypersomnia, NT1, NT2, IH. I think everyone's trying to figure out when those readouts are expected. And I think the answer is complicated depending on the indication, depending on the way you guys are blinded and stuff and what you want to do here. So I guess maybe to start, the first release that you just had is more related to the phase 1 here. But the 5-mg, can you help us understand what that release was and the importance of it and how the 5-mg, maybe in the SAD, kind of looks a little bit like the 4-mg and the MAD, and just a little more details around the recent results? Yeah, so we cleared, we essentially completed our phase 1 study. We are leaving it open in parallel to the phase 2 if we want to further incrementally dose higher. But right now, we have everything we need for the phase 2 study and to execute on our phase 2 plans. With the phase 1 study, what we showed is, first of all, we did a single ascending dose and a multiple ascending dose. The SAD went up to five milligrams. The multiple ascending dose went up to four milligrams because of some slight accumulation of the drug, which is conventional for small molecules. The four milligram exposures are actually equivalent to the five milligram exposures, right, which is why the MAD is slightly lower than the SAD. The phase 1 study design was very creative, and I think fundamentally gave us a really good understanding of PKPD and dose selection. That's why we went from an IND to efficacy data in basically three months and a half with our phase 1 study. And at the top dose of the five milligram in the SAD, remember, after every single ascending dose, we also performed a sleep study in acutely sleep-deprived healthy volunteers. So we had the option of taking that dose in acutely sleep-deprived subjects, dosing them at night. As you know, you dose at 11:00 P.M., and then you do a Maintenance of Wakefulness Test over a period of eight hours. It's four naps every two hours. This is a high bar, high bar model, if you will, because you're essentially trying to replicate in many ways the excessive daytime sleepiness that patients and subjects with NT2 and rare hypersomnias experience. So it's a very high bar also because there is a, you're going on top of the native ligand. These are non-orexin, it's not an orexin loss indication. And we know from clinical precedent that the dose levels required in the acutely sleep-deprived study are very much equivalent to the dose levels required to drive efficacy in narcolepsy type 2, idiopathic hypersomnia, and non-orexin loss indication. So that's why we really wanted a study, Frank, that could de-risk the therapeutic window of the molecule from day one. That's how we designed 750, one of the molecules that could be taken forward for NT1, absolutely, but also gave us a therapeutic window, a full therapeutic window to go into narcolepsy type 2, idiopathic hypersomnia, really to harness the full power of this biology. At the 5 milligram, we showed 38 minutes MWT, absolute numbers. We showed 23 minutes placebo-adjusted, right, which is phenomenal efficacy, especially if you compare it against clearly standard of care, and at the same time, what also was incredibly exciting was to really see the safety tolerability that went along with that, which is, quite frankly, a very, very clean and tolerable profile, really seeing very, very limited on-target AEs that are almost equivalent to placebo, which speaks on how we designed the drug. So we not only have a drug that was enabled by structural biology and is giving us very low doses because of high potency, almost equivalent to the native ligand, high selectivity, almost 10,000-fold more selective for OX2R compared to orexin-1. But at the same time, we also have a PK profile that allows actually a relatively flat Cmax to AUC. And you know, one of the most beautiful things about this biology is that you can really pinpoint with PKPD where you're going to be in terms of efficacious doses. There is a minimal brain concentration that is needed for efficacy, what we term a wakefulness threshold, which is almost like a binary switch that we can really pinpoint to the nanogram per mL, that if you're above, you're promoting orexinergic neurotransmission and promoting wakefulness. If you're below, you're not really doing that. And with our PK profile, we have a PK profile that obviously allows for single dose, so QD dosing regimen. But at the same time, it's also relatively flat from Cmax to AUC perspective. So we hypothesize that maybe that could have helped us avoid or rather maybe diminish some of these on-target AEs that have been frequently reported by other orexin agonists. So the fact that we're not seeing them, right, or we're seeing very few of them is, I think, incredibly exciting from that perspective. And that's why we're so confident about a best-in-class profile for the molecule. I think, yeah, and thanks. That's a lot of detail in terms of understanding what you guys talk about, the high bar, what it means, and how important it is for NT2 and IH. And I think that's critical. But is there a reason mechanistically to believe in some sort of resistance where a patient might need a higher dose with time here? And this is where your kind of peak to trough and your PK profile can ultimately be like quite the differentiator if you cannot go, you know, if you need to go at certain levels with patients through time. Is that something that's discussed or that's thought about, or are we just not sure yet? That's a great point, Frank. Great point. So the fact that we've got such a favorable and clean profile means that we have such a wide therapeutic index. There's probably so much headroom, right, between efficacy and our drug level from a therapeutic index perspective that really gives us that confidence and that flexibility. Now, having said that, we've done preclinical experiments ourselves. We're seeing no cases of tachyphylaxis or receptor internalization. I think other orexin agonists out there have shown very robust and sustained efficacy all the way out through to six months or 34 weeks or so, and almost the equivalent efficacy between the four weeks and the six months in narcolepsy type 1. So I think this has largely been de-risked already. The fact that we focused 750 on being equipotent to a native peptide, not 100-fold more potent, equipotent to a native peptide, the fact that we can activate the orexin-2 receptor with unbiased agonism, neither skewed towards G-protein or beta-arrestin, it just helps to minimize those risks. We really wanted to replicate what nature has designed. That's great. And then so on the, like, this year, 2025, you guys have delivered data before people expected it in the past. And so now just help level set. I want to give you the chance, you know, at the conference here to remind people when, you know, we could expect data and what is so complicated here in order, you know, in terms of predicting, you know, is it a fourth quarter event, a third quarter event, is it events throughout the year? Just give the different optionalities that you guys actually have, you know, so people can try to gauge a little bit when to expect stuff. Yes, let's talk a little bit about our study design, which I think is a very nice segue into this. So if you recall, Frank, phase 2 study, the goal of a phase 2 study, let's not forget, is helping to select the optimal dose registration studies. Okay? So we thought, what type of design could put us in the best possible position to do that? There's a lot to be said about having a great molecule. And I think we've been very transparent with all the preclinical disclosures, just our confidence in the molecule, in the asset. But a lot is to be said around picking the right dose for these indications. And this is what the study exactly allows us to do. We have different dose cohorts, okay, of six weeks in duration. And patients are randomized according to two sequences within the cohort. The first sequence is placebo for two weeks and 750 for four weeks. The second randomization sequence is 750 for two weeks, placebo for two weeks, and then 750 again for two weeks. After this cohort is completed, and by the way, it's a basket study design, so we're enrolling NT1, NT2, and IH. Once the cohort completes, and every indication can progress at their own pace depending on enrollment, right, so we can close cohorts for IH before an NT2 study, for example. Once we close the cohort, we do the unblinding. And some people within the company will get to see the data. And they'll get to peg PK, safety, tolerability, and efficacy. And by efficacy, I don't just mean the conventional MWT, ESS, right? I'm talking about cognition, executive function, brain fog, patient-reported outcomes. We're doing PSG at several time points during the study, right, to help look at the serum orexin. It's a very holistic way of looking at efficacy. We'll put everything together, and then that will help guide the dose for the next dose selection for the next cohort, which could be a dose up or a dose down, right? Remember, we're going in with already therapeutic doses. We're going in with one milligram in NT1 for the first cohort, two milligrams in NT2, and two milligrams in IH, and I guess back to your question around data disclosure, so we've given guidance that we're going to have data released in NT1, NT2, and IH. We're, quite frankly, we haven't really aligned upon whether we're going to do it on a cohort-by-cohort basis or whether we just wait for all three indications to complete and multiple cohorts to complete this year before releasing the data. Interesting, so that the people at the company or whatnot that will be unblinded and see it, you know, I guess we move forward and we can kind of see if you go to a lower dose, it might mean something higher, so a lot of interpretations that can come from it that are complicated, but that's interesting. So the goal, it seems to me like the goal is like a classic phase two is to not forget that we're trying to get to the right dose for phase three. And first-to-market, it seems like being first, especially in NT2 and IH, is of high importance to the company. Is that fair? The goal of this study is to, as you say, help us select the dose for registration studies. We're really excited about the NT2 and IH. You know, we've largely de-risked that already with a phase one study in acutely sleep-deprived healthy volunteers. That's why we're so confident going into this study. We have a very, very clear idea of what success looks like from a target product profile perspective. We feel very confident with the study design. We're getting four weeks' worth of chronic treatment, which is by that time, you will have reached steady-state effect size in NT1. Every patient enrolled is going to be on drug, which is a huge, huge element to help drive up enrollment, right? There isn't the likelihood of patients going on a placebo for like six to eight weeks. And this is the case in NT1, NT2, and IH. And the fact that it's also randomized and crossover. So the first four weeks, every patient will end up first on drug, and then placebo, and then the other sequence the other way around. This really dramatically drives up the power of the study. So absolutely, I think having a single molecule, Frank, to go after NT1, NT2, and IH is a huge advantage, huge advantage from a commercial perspective, but also from a prescriber physician perspective. Remember, there's also a lot of time misdiagnosis and overlap, especially in NT2 and IH. Some NT2 patients end up progressing and migrating towards NT1. So it's just a really great place to be. Okay, great. And you talked about, you know, efficacy, not just MWT. Are you guys looking at the disturbed nocturnal sleep as well? Is that something that? We are. So maybe let's talk a little bit about that. We're doing the MWT and ESS as part of the screening, so part of the inclusion criteria, right? Maybe less important in NT1, but very important in NT2 and IH where there's more variability in patients. We are homogenizing patients by using the MWT and the ESS as part of the inclusion criteria. They really need to meet that threshold to be allowed in the study. And they're quite, you know, conventional thresholds, so it won't be an obstacle towards enrollment in any way. Now, we're also doing MWT at several intervals during the study. We're doing a day one, first dose. We're looking at after two weeks, four weeks, and six weeks. So five MWTs in total. Every time patients are coming, every time there is an inpatient test, like the MWT in the clinic, we will be doing the PSG overnight, polysomnography. So we will be looking at disturbed nocturnal sleep. Now, disturbed nocturnal sleep is a symptom of narcolepsy Type 1. It's not a symptom that you need to address for registration. Like registration endpoints are really EDS and cataplexy. However, it's something that we're monitoring and we're interested. We're interested because there's a lot of evidence trying to suggest that orexin could have a role in helping alleviate disturbed nocturnal sleep. We've seen that with other orexin agonists in the first parts of the night, normalizing sleep architecture. We've seen there's been studies showing that the severity of DNS is correlated with the loss of orexin tone. We've also seen it preclinically with showing that orexin really helps to consolidate that sleep fragmentation and that sleep architecture. Okay, great. And I don't, I think we only have 10 minutes left. I want to give enough time to move on beyond rare hypersomnia here and the pipeline. So 142, 489, and just maybe a touch on why 750 here might de-risk the other programs. And just maybe this touches on the high bar, but just, yeah, if you could go into beyond rare hypersomnia, what you guys are thinking. Absolutely. And this is really where I'm incredibly excited about the opportunities outside of this. I think when I first started the company, it was all about NT1, providing a functional cure in NT1. Then it was about the rare hypersomnia as NT2 and IH, and we really wanted to have a single molecule for three disorders. But the more evidence started to emerge on the role of orexin and the prevalence of EDS, fatigue, and all these other symptoms, the more I think excitement I think we got as a company, but also I think from you guys, from the street around these bigger, much bigger indications. And first, let me start from here. There is nothing that we wanted to improve upon with 750. Our pipeline are not backups, right? They're follow-up molecules to help explore a very different commercial strategy, right? Different pricing, different commercial dynamics associated with these much bigger, much bigger conditions, much bigger indications. ORX750, as all our other molecules, were designed to also have very low DDI risk, right? They all have very low doses, which is particularly important in some of these other indications. So ORX142 and ORX489, they are slightly more potent than ORX750. ORX489 is actually equivalent potency to the native ligand. And again, it's not because we wanted to improve upon the potency. I think we simply had more time to push the envelope of the chemistry and get us even more potent and selective molecules. There are these very large indications. I mean, Parkinson's disease is one of them, where excessive daytime sleepiness is present in 90% of mild to moderate Parkinson's patients. There is an orexin loss associated with Parkinson's. There's also a cognitive decline associated with Parkinson's. EDS is also prevalent in major depressive disorder, where we've seen studies with modafinil in these indications. And so we've seen studies with stimulants in fatigue and multiple sclerosis. For example, we know that a lot of these stimulants are used in this indication. So there's basically this huge opportunity where stimulants are used today. They have limited efficacy. And orexin agonists, given it works in non-orexin loss indications, could have a transformational impact. Now, we've also seen data from orexins showing improvement in cognition and attention decoupled from the wake promotion activities of the drug, which kind of makes sense. Orexin-2 receptor also expressed in the cortex. We've seen very low dose of orexin agonists having a big impact in that, as you know, the cortex is involved in cognition, attention, and all. Great, great opportunity to go beyond EDS also into cognition. And I'm sorry, I didn't know they're decoupled. When you say decoupled, how do you know that? You've seen. So yeah, there's been a study done out there. I think it was in Narcolepsy Type 1 individuals that showed it was, I think, at subtherapeutic doses for wake promotion, right? And they showed that at subtherapeutic doses, they were actually having significant benefits on improvement to cognition. I think it was on the PVT and the DSST scale, if I remember correctly, which we're using in our phase two study. And the last thing that I would say is because orexin sits very high upstream, the release of orexin helps with the release of serotonin, histamine, dopamine. So you've got all these drugs approved today that are very much focused on hammering that individual pathway, that individual neurotransmitter. The release of orexin, because it helps the release of all these neurotransmitters, it helps to promote that natural wakefulness, but also because you're releasing serotonin, for example, there could be some really interesting impact on mood. And we've seen that with some preclinical data disclosed by other companies showing just that improvements in mood because of the serotonin release. So I think this just puts us in an incredible position with these extremely potent, selective, low-dose molecules to explore all of these indications. And as you know, we've hired, I think since we last met in December, we hired Steve Kanes, our Chief Medical Officer, right? He has a wealth of experience in CNS. He's taken many drugs through to approval. As you know, he was one of the key leaders at Sage behind that story. So he is here really to help shepherd all of these strategies around these other indications that we think is going to be at least north of a $10 billion opportunity, but probably a lot larger. Okay, great. And is that a no to, I know you're President of the orexin program, but when you, I'm sure you've heard this strategically, you know, with new CMO, you know, who's been a big player in the CNS space for a long time, is this more of a, you know, Centessa is still a relatively small company compared to some of these spaces that you're going after here. Is this more of a strategic kind of partnership angle or if you could comment on that? You know, if not, I totally understand. Right. We've got $580 million cash as of end of Q3 and really well capitalized. We've got multiple indications that we're going to go after with these molecules. We're here to really build an orexin agonist franchise. We've seen it. We've seen it before of successful companies, you know, Jazz, Harmony, for example, building very successful companies out of the rare hypersomnias, right? So you only need a limited sales force to really drive a multi-billion dollar opportunity, and I think our cash enables us also to explore all these other indications and really cement our position as leaders in the orexin space and are really here to build a company around this multi-asset orexin agonist franchise. There will be additional key hires that we're going to need to do that. You know, Steve is just one of these key people. We've hired also a tremendous clinical operations team with significant experience in CNS and the rare. So we're really here to help build a company around the orexin story. That's great, and have you shared, you know, because there are stimulants used with MS patients right now, right? Like, you know, you talk, that's what you mentioned, and the efficacy is subpar, but there are things used. When you go beyond rare hypersomnia, how do you decide where to go? Is it, are you just looking for an unmet need? Is it too early? It's just, look, we're just trying to get our molecules as ready as possible, and we'll deal with that later on, or? Great, great question. You're right. There's a lot to choose from, but we need to prioritize. So we have, I would like to say, a very sophisticated algorithm, but it's not. It's a lot of team, it's a lot of team discussions looking at commercial probability of success from a scientific perspective and unmet clinical need. Okay? You put everything together, right, and that really helps guide the choice of indication, rather choice the prioritization of indications for the follow-up molecules. That sounds sophisticated. It sounds like an algorithm almost. Mario, in the last minute, anything that we should have talked about that we didn't mention here? I think it's been great. You really managed, I think, to cover all the key aspects of what we're doing here at Centessa. Thank you, Frank. Let me just say that we are incredibly excited about what's coming next this year, you know, data in NT1, NT2, and incredibly excited about at some point sharing more information on our follow-up molecules or strategy there, right? For competitive reasons, we really haven't done that yet, but there is just so much, so much opportunity for this mechanism to go beyond sleep. I don't even think it should be seen as a sleep franchise. It's really a neuro franchise with opportunities to go well, well beyond, and somebody the other day told me, you know, this is going to be the GLP-1 of the mind in many ways because it just covers so many aspects beyond EDS. It's incredibly excited to see this and see the progress that we've made over the past months. That's great. Well, congrats. I mean, there's been a lot of attention on the story. And one part we didn't even get to, maybe because you're the president of the orexin program, but people seem to forget that LockBody, which has a lot of promise, is also at Centessa in a different space right now. So a lot going on at the company. Congrats. It's been a good couple of months for sure for you guys. And so appreciate the time today, Mario. Thank you, Frank. Thank you. Great, great to see you.