Thanks, everyone, for attending Jefferies' London Healthcare Conference. My name is Kelly Shi, one of the senior biotech analysts here. And joining with us today is the Centessa Pharmaceuticals CEO and Director, Dr. Saurabh Saha, and Dr. Mario Alberto Accardi, the President of the Orexin Program for this first chat session. Welcome both. Thank you, Kelly. For the audience who are not very familiar with the story happening at Centessa, which is very exciting, maybe you two give us a high-level overview before we jump into specifics. Absolutely. Well, thank you, Kelly, for the invitation to speak today at the Jefferies Healthcare Conference. We are tremendously excited at Centessa for being in an incredible space, and that is developing drugs for sleep-wake disorders, and specifically the target, which is now gaining a lot of traction and excitement, which is the orexin agonists, and so at Centessa, we have multiple orexin agonists that we're progressing with ORX-750 that's in the clinic today, that's entered phase two studies. In September, if you'll recall, we announced for the first time healthy volunteer data where healthy volunteers were acutely sleep deprived, and we gave them ORX-750, and we were able to demonstrate that we were able to keep these subjects awake, and the data was of very high effect size. And we had some questions that we wanted to answer as a company, whether or not we can go even higher in doses and exposures and be able to retain the safety profile that we had seen with ORX-750 at the 2.5 milligram dose. And then we had a question on whether we could do repeat dosing and retain that safe profile. And then the third question was, can we achieve a dose-linear exposure response as we increase dose? And a number of questions came about, okay, well, if you can do all three of those, what does your phase II study design look like for ORX-750? Well, just last week, we announced data that address all those questions. First, we addressed the question of whether we could go higher in dose, and we did. We showed data at 3.5 and 5 milligrams from our SAD cohorts showing a very safe profile. And then we also dosed in multi-dose studies where we dosed at 2 milligrams and 3 milligrams with AEs that were not appreciably different from placebos. We also showcased data from our 3.5 milligram cohort in the sleep study. They're demonstrating even tighter data, even more strong data for efficacy in our sleep studies. And then we showcased, which I think we'll have time to talk about later, our phase two study design, which we believe is a very creative way to get to registration studies very quickly. Fantastic, so orexin agonist now is topical for investors to actually figure out how big the potential is, and we are familiar probably with NT1, but what about NT2, IH, and also even additional indications of sleep disorders orexin agonists that actually can tackle? Maybe before we get into data, you can also help us to understand. Yeah, so it's a great question, and the analogy I draw is to the GLPs, so many years ago, diabetes was the focus, and then overnight, obesity became the big market, and it's not dissimilar in what we think could happen to this class of drugs in that these rare hypersomnias, NT1, NT2, and idiopathic hypersomnia, or IH, is just the tip of the iceberg when it comes to being able to address excessive daytime sleepiness, cataplexy, but now we're seeing with data that mood, cognition, executive function, these other features that could be addressed with orexin agonism may play a role in not just the sleep-wake disorders or the rare hypersomnias, but even beyond. Yeah, absolutely, Saurabh. I think a few years ago, the focus was very much on narcolepsy type 1. This is an orexin agonist that treats the underlying root cause of the disorder, a little bit like insulin is to type 2 diabetes, right? Then the expansion into narcolepsy type 2 and idiopathic hypersomnia, and then now we're starting to see a lot of interest and a lot of focus on the high prevalence disorders. So anywhere where excessive daytime sleepiness and fatigue is prevalent, and there's a number of different conditions that we can come into it when we discuss our follow-up molecules, is really very, very exciting. In terms of market opportunity, we are forecasted north of $5 billion in the rare hypersomnias alone, that's NT1, NT2, and IH, and north of $10 billion in these high prevalence disorders such as major depressive disorder, Parkinson's, DLB, for example, very, very exciting indications where orexin could have a transformational role. Fantastic. Maybe just dig a little bit deeper into the healthy volunteer data. And we have experienced capital market actually gave a very positive reaction to this data set. And we also think safety looks very compelling. But one follow-up question from investors is, how does this translate to patients compared to healthy volunteer? And on top of that, compared to competing programs, what kind of safety differentiation on specific toxic signals you want to point out? Yeah, I think that's an excellent question, Kelly. So what we've shown in our single ascending dose data, so at one milligram, two milligram, 2.5 milligrams, 3.5, and five, is really great safety data when it comes to looking at what one would expect could be on target AEs, such as increases in blood pressure, hypersalivation, urinary urgency, frequency, insomnia, and others. And then we've also shown, as I've mentioned, the same to occur when we dose patients at multiple doses with two milligrams and three milligrams. What frankly surprised us is that we would consistently see this kind of trend in not seeing on target AEs at any appreciable rate as we increased in dose, but still at the same time achieve the efficacy that we've seen where it's been dose linear. So at the one milligram dose, for example, when we did our acute healthy subject sleep study, we saw a difference of eight minutes between ORX-750 and placebo. And when we did it at 2.5 milligrams, we saw 15 minutes of a difference between ORX-750 and placebo, and then 20, a difference of 20 minutes between 750 and placebo. So beautiful dose linearity, but at the same time, we're not seeing any real increases in the on-target AEs that one would expect. I think if you go back to first principles on how Mario and the team designed the molecule, which was having access to this proprietary crystal structure where they mutated, very cleverly mutated one, introduced one mutation in the structure, which altered the conformation of the OX2R receptor to allow the medicinal chemist to do their medicinal chemistry work on that small pocket and optimize a molecule that could be a very potent agonist, but still maintain that selectivity. I think that is really important. We didn't trade off potency for selectivity for potency or potency for selectivity. That was very important. Then the molecule that we ended up picking, we wanted to make sure it had a very narrow Cmax to trough ratio, because our hypothesis was that a lot of these on-target AEs were going to be driven by Cmax. We know that for orexin agonists, there is a wakefulness threshold, a concentration which you have to stay above to maintain wakefulness. If you fall below that, you'll start falling asleep. All the area above that threshold is kind of wasted space, if you will. That's where the Cmax to trough ratio comes into play. Now, how does this translate from healthy volunteers, to your question, into patients? There is a lot of good clinical precedent from others that have shown that at doses and exposures where you see effective MWTs and the concomitant safety profile in healthy volunteers, at those doses, you see good safety and good efficacy also in narcolepsy type 2, in idiopathic hypersomnia, in excessive daytime sleepiness associated with sleep apnea. That data is already out there, clinical data. We know from others that if you dial the dose back in healthy volunteers or narcolepsy type 2 or idiopathic patients down to about a third of that dose, that is going to be effective in NT1 subjects. We're the beneficiaries in many ways of seeing ahead of us how these molecules, orexin agonists, play out in the clinic in those respective indications. Okay, super insightful. So the intricate design in the molecules is the key to deliver the best safety and efficacy profile. Also curious, so a lot of discussion on the receptor 2, the target toxicity versus receptor 1, like off-target toxicities, and some programs trying to decouple this. And what are your take on this? We've seen orexin 1 being somewhat implicated, at least in preclinical studies, activating the orexin 1 receptor in some form of reward-seeking behavior in preclinical models, which leads us to believe that having a selective orexin 2 molecule is the best strategy here from a TPP perspective. And we've also seen orexin 1 antagonists being evaluated in clinical development for addiction, for example. So for us, it was very, very important to focus on a molecule that was extremely selective. And you've seen ORX-750 is 9,800-fold more selective at orexin 2 than orexin 1, and clearly a lot more selective at orexin 2 than any other GPCR in terms of minimizing some of the possible off-target pharmacology. So I would say that that's really the rationale behind the orexin 2 activation versus orexin 1. And what we've also seen, Kelly, is the fact that activating the orexin 2 does help really restore and relieve all symptoms in narcolepsy type 1, right? We've seen selective orexin 2 agonists manage to suppress cataplexy, significantly improve excessive daytime sleepiness. We've also started to see some early data in restoring sleep architecture in the earlier parts of the night. So right now, it's difficult to find a rationale to also go after orexin 1. I would say super helpful, and so the take-home message here is you saw a very clear dose-response, and you have a very wide window for safety, and you also don't need to worry about receptor 1 off-target toxicities, and so in healthy volunteer, you already dosed up to five milligrams. Curious for the next step in patients, what would your trial design be to actually deliver the best clinical profile? Yeah, so the team, we think about orexin every hour, every day. And part of the mandate to the team was come up with a phase II design that could be very informative, super high quality, and be able to guide dose selection, obviously, in phase III with the minimal number of patients and in the fastest possible way. So we are starting our phase II studies. We started our phase II studies at one milligram as a starting dose for one milligram for NT1 and two milligrams for NT2 and IH. And we believe those are expected to be very efficacious doses based on what we've seen in the healthy volunteer sleep deprivation data. The healthy volunteer data sets the upper bound or the ceiling kind of level of dose that you need to be effective. And we think NT2 and IH is going to be close to that. NT1, as I mentioned, is going to be a lot lower than that. But I'll let Mario comment on our phase two design. Thanks, Saurabh. Yeah, a lot is to be said around not only having a very good molecule, right? And I think we've been very transparent. We've shown all the different attributes of ORX-750 at a preclinical level and non-clinical, of course. But a lot is to be said about picking the right dose for these patient populations. And ultimately, that's what we are trying to address with a phase two study design, really giving us the best possible shot at finding that optimal dose for eventually registration studies. Taking a step back on our phase II study design, unlike traditional drug development in a phase II study where you are pre-defining the doses ahead of time, and then you're starting the phase II study with those dose levels and doing the unblinding at the very end of the study and really crossing your fingers that you will have hit your optimal dose to then continue on to phase III. With our study design, first of all, it's a basket study in narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. We have the opportunity to enroll on a cohort-by-cohort basis. The cohort is dictated by the dose levels. There are different dose levels, as Saurabh was hinting to, between NT1, NT2, and IH. Once that cohort is complete, we then have the opportunity to unblind the cohort and use that data set, which combines efficacy, PK, safety, tolerability, to then help guide the decision as to whether we dose escalate or dose escalate up or even dose de-escalate and move down in dose. Sure, we want to also find a dose response and show a dose response here with a phase II study. By efficacy measures in a phase II study, we're really taking here things to the next level, I would say, because we're not only looking at the MWT, the Epworth Sleepiness Scale, we're also looking at many other endpoints that are related to sustained attention, such as the PVT scale. We're looking at the DSST to assess cognition. We're looking at fatigue, for example, really a comprehensive set of efficacy measures to help find that optimal dose, and I would say a big advantage also of our phase two study, and Saurabh Saha was really pushing us to try and speed up enrollment as quickly as possible across NT1, NT2, and IH, was to guarantee patients at least four weeks' worth of dosing with ORX-750, so we're not asking patients to walk into a phase two study and have the risk of walking into a placebo arm, right, and end up being in placebo for a number of weeks. That's very difficult. Some of these patients are washing out of sodium oxybate. They're washing out of standard of care. It's very difficult for them to be in a placebo arm for that amount of time. So here, these little things are really encouraging the enrollment rate, and something that we really put a lot of focus on for our study. When do you expect this unblinded data set, and do you have a plan to disclose to the public? Anytime. We like to keep investors on their toes. But what we've said is 2025, we should have data for NT1, NT2, and IH. Great. And for the MAD dosing, do you mean, from a healthy volunteer, do we expect additional update? Yes, so for the healthy volunteer study, for the phase one study, we are doing the five milligram sleep study just to round things out and look at what that effect size looks like. We've already done the SAD for the five milligram, and it looks very clean from a safety standpoint, and then we'll have that data wrapped up for a conference presentation next year. Okay, fantastic. And on top of this leading molecule, 750, you are also working on 142, and you disclosed preclinical data recently. It seems even better. Curious, what are your thoughts, actually, to building a franchise? Actually, I need to mention you also have 489 in the pipeline. And what are the thoughts behind? Actually, the most important question first, are they sharing the same molecular scaffold? First of all, we are incredibly excited to be building our multi-asset orexin agonist franchise. You're completely right. These other molecules, ORX-489 and ORX-142, are being directed at these high-prevalence disorders. They're completely distinct chemical entities. We haven't disclosed how much overlap there is and whether they're part of the same series. But what we can say, I think, is that there were no liabilities we could find with ORX-750 that we wanted to improve upon. We really wanted additional assets, additional distinct molecules that we could take forward into these very exciting, high-prevalence disorders where orexin agonists could have a transformational treatment. We spent a lot of time in the past months looking at all these indications. For example, Parkinson's disease, dementia with Lewy bodies, the alpha-synuclein disorders, major depressive disorder, multiple sclerosis. These are all disorders where excessive daytime sleepiness and fatigue are a significant component of the disease. At the bare minimum, we're really hoping and aiming to help treat EDS and fatigue in all these different disorders. What we're also starting to see is orexin agonists as having an impact on mood. We've seen that with preclinical studies. It makes complete sense given the overlap between the orexin pathway and the mood pathway. At the same time, we've also seen orexin agonists in the clinic have significant impact on improving cognition and attention, decoupled from wakefulness promotion. As you can imagine, as you can appreciate, this opens up all sorts of avenues in, for example, ADHD, Parkinson's, MDD. Having different assets enables us to go after a very large market opportunity with very different commercial strategies. That's really the goal. Mario and the team have done a really exceptional job in generating more and more potent molecules. I think that's important as we go into these larger indications where people are going to be on their standard of care drugs. Patients are going to be on those drugs. The smaller the less amount of chemical matter that you're exposing your body to, the less your liver is having to metabolize, the less chances of drug-drug interactions is only a good thing. Being able to potentially get drugs in the sub-one milligram range for orexin agonists, I think, would be super exciting for a lot of patients. Okay, great. And any thoughts, BD front? Do you would leverage external efforts to pursue broader indications for 142? Yeah, so we're in a really good position to have over $500 million in cash that should get us into mid-2027. But along the way, we have a number of clinical inflection points where next year we should have data in NT1, NT2, and IH, as I mentioned, with ORX-750. We should have clinical data with ORX-142 next year as well. And then as we announced, ORX-489 is shortly behind ORX-142. So there's a lot of opportunity to generate value between now and 2027. And so we're well positioned with the cash we have today. Okay, great. Maybe it's a little bit early, but curious, how do we set a bar for the data next year on both safety and efficacy compared to competing programs? Yeah, so we like to think that what the profile we've shared so far has the potential to be best in class in all the indications that we've discussed in the rare hypersomnias. We hope to continue to generate that, obviously, with patient data. And I think the data will speak for itself next year. And we look forward to it. Maybe also to put a number on the potential opportunity, NT1, NT2, IH, and also other associated indications that orexin agonists can pursue. Yeah, very large and quite a significant market opportunity. If you think at the sodium oxybate that are doing almost $2 billion of sales with around less than 20,000 patients treated. So if you extrapolate that across NT1, NT2, IH, I think it's a substantial market opportunity. We think it's north of $5 billion in the rare hypersomnias alone. In the high-prevalence disorders, well, we've done a base case analysis when orexin agonists would work on the treatment of EDS in these conditions. And that market analysis has led us to put a north of a $10 billion market opportunity. But that doesn't even include the potential for orexins to help with mood, right, help with cognition, non-motor symptoms. So we think it's really quite a considerable market opportunity. And that's why we have also multiple assets to help enable that commercial strategy. It's something that is really very, very exciting. I think it's important to take a step back and assess the entire space. Standard of care today, while it is beneficial to patients, doesn't treat the underlying cause of the disease. An orexin agonist, from the data that we and others have shown, fundamentally shifts that needle in medicine and the standard of care of these patients so considerably. The effect size is so remarkable. You're talking about drugs today that have MWTs in the high single digits, low double digits to now 30+. These patients are not adequately treated today across the board. I think pegging numbers, market potential numbers based on what we see today versus what we could see with the drug that is essentially what others have quoted as functional cures, where patients feel normal again, they feel normal for the first time, actually, in their lives. It will remain to be seen as to how much that translates into an opportunity in the commercial space. Okay, super helpful. Maybe lastly, SerpinPC, you announced an update recently. Maybe share more with us on what actually drove this strategic change. Yeah, so this was a really tough decision for the company, but there was a confluence of events that happened in the last few months. So first, we had a competitor that generated some really good data that resulted in a great label. And then second, we looked at our interim analysis and looked at the profile of our molecule and what the investment it would take to be competitive with our competitor. And then third, we've been generating a lot of data from ORX-750. And then with the emergence of ORX-142 soon to be in the clinic and then ORX-489, we had to make a very tough decision that for every dollar we're spending on, let's say, SerpinPC, what would the return have been on the orexin program? It was very clear to us that even if you look at just expanding the label of one of our three orexin molecules by one indication, that market potential is much larger than the entirety of what we were pursuing with SerpinPC. So I think that made a lot of sense for us to potentially save $200 million over the next four years or so from what would have been an investment in SerpinPC and now moving that into supporting the orexin program. To max ROI, and it's a truly exciting time for Centessa, and looking forward to more milestones from the next 12 months, and thank you so much for this insightful discussion. Thank you, Kelly. Thank you.