All right, we'll get started in just one moment here. My name is Dave Risinger. It's very much my pleasure to welcome Centessa to participate in the session today at the Leerink Partners Global Healthcare Conference. I'm very pleased to welcome and introduce Mario Alberto Accardi, who is the company's CEO, and very much looking forward to the discussion. Mario, could you kick us off with some high-level remarks on how you're leading the company and your vision for Centessa since being named CEO?
Thank you, Dave. Great to be here with you. First and foremost, I could not be more excited, not just about Centessa and our program, but about the entire class. You know, this is, I think, a defining moment for neurosciences and especially patients with rare hypersomnias. But it also goes.
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Yeah. Just repeat that. Yeah.
First and foremost, I could not be more excited about leading this company and also about the class as a whole. Right? This is a defining moment for neurosciences and for patients with the rare hypersomnias. Potential functional cure in NT1 and potential paradigm shift in the treatment landscape for the rare hypersomnia patients. Having started the original company in 2019, the whole premise was to design and really achieve the most potent and selective orexin two agonists and seek to take forward into patients a best-in-class profile. At the same time, realize different assets with different PK profiles to target the broader neurosciences indications. To finally have the opportunity to realize this vision here at Centessa is obviously something I'm extremely passionate about.
Excellent. The initial results last November drove significant enthusiasm about the potential for significant differentiation. Could forthcoming data later this month.
Absolutely. Back in November, we released data from our lowest dose cohorts, Dave. A very early and reported data at 1.5 mg in NT1, 4 mg in NT2, and also 2 mg in IH. These are very much our starting doses for the phase 2 study. Because 750 has been designed to have such exquisite potency selectivity, yet really an optimal ADME PK profile. This was really at the foundation and core of the company when I started. It was really to use structural biology to try to achieve this optimal molecule from a number of different perspectives. Already at those doses, we achieve a greater than 20 minutes baseline-adjusted, placebo-adjusted MWT. Achieve normal wakefulness there.
We dropped the ESS in NT1 down from 18- 5, completely normalizing patients, and achieved a weekly cataplexy rate reduction of 87%, 0.13 incidence rate ratio. Very clearly potential best-in-class profile, again, at the lowest dose in the phase 2 study. In NT2, we reported data at 4 mg where we achieved greater than 10 minutes change from baseline placebo-adjusted Maintenance of Wakefulness Test. To put things into perspective, Dave, in NT2, there are no drugs approved that have shown greater than 10 minutes change from baseline placebo-adjusted. And also obviously normalized the ESS down to I think eight, if I recall correctly.
In idiopathic hypersomnia, we described achieving clinically meaningful and statistically significant difference across multiple efficacy measures in idiopathic hypersomnia, and that was at the first cohort in 2 mg. Now, what we've done since then is we've gone multiples higher in dose, and it's very clear that we had already achieved the potentially best-in-class profile then. We were also the first orexin agonist to achieve multiple efficacy measures across the three rare hypersomnias. For my goal here at Centessa is to make sure that we're best in class, not just today versus as other assets in clinical development today in the present moment. I wanna make sure that, A, we're best in class also in the years to come. I also want to make sure, Dave, that we give as much flexibility to patients.
By flexibility, I mean duration of action. I wanna make sure that we cover the bookends of doses and ultimately provide a monotherapy approach and a treatment that can completely resolve diurnal symptoms across these three indications. In order to achieve that, given the drug 750 was designed to have a very wide therapeutic index from the get-go, why not dose higher? Why not continue the dose escalation, which is what we've done since November, in order to achieve that longer, I would say, and even more extended duration of action.
Wonderful. Could you provide some more context around your aspiration for best-in-class potential and maybe provide, you know, some details on how you would characterize that in all three indications?
For us, when we refer to best in class, and obviously it's been a you know topic of considerable discussion internally, right? For us, when we define best in class, obviously it has to be a holistic view across efficacy, safety, tolerability. Now, if we look at tolerability, obviously we are hoping to be different and provide a differentiated profile compared to the rest. 750 has a relatively flat Cmax to AUC and PK profile, which we think is what's generating some of the very favorable tolerability profile we've seen. But I would also stress that all of these, let's call them on-target AEs that have generally been cropping up with the class, such as polyuria, insomnia, and others.
You know, compared to standard of care, and if you look at the rate of enrollment into these open-label extension studies, they're highly tolerated drugs. For us, I think it's more, probably more, important to differentiate on efficacy and on duration of action, because let's put it this way. If there's an orexin agonist out there that completely controls symptoms, whether it's EDS, cataplexy or even sleep inertia in IH, but only lasts until the middle of the afternoon, what are patients gonna do in the middle of the afternoon? The life of a narcolepsy patient doesn't end at 4 P.M. Does that mean they're gonna go back on polypharmacy? Does that mean that they're going to try and save doses for a day where they need specific longer duration of action?
Maybe they have a longer drive home, maybe they're going out in the evening. We wanna make sure that here at Centessa that we cover for those range of doses, and we provide that extended duration of action. Payers are not gonna pay for extra doses. They're gonna be expensive drugs. It's really in the best interest of us, but also in terms of really satisfying patient needs to make sure that we can provide that long duration of action. How is that then manifested and seen in clinical endpoints, right? I assume that's what you're thinking about here. Well, it's dropping the ESS score to as low as possible, having weekly cataplexy rate that is low as possible, achieving greater than 20 minutes change from baseline placebo-adjusted on the MWT across all four time points, right?
You remember, the MWT is an eight-hour test. Every two hours, patients are asked to try and stay awake. If you can achieve the greater than 20 minutes normal wakefulness also at the last couple of time points in the MWT, that's really very important because that suggests that you've got a nice long extended duration of action, and that's really what we're trying to solve for here.
Excellent. Can you just talk a little bit more about polyuria, just how we should think about that?
Absolutely. We didn't really see a marked dose response in our November update. Now let's see, obviously, we've gone much higher in dose, so it'll be interesting to see if we can see a dose response in polyuria. I would say that generally with conversation among KOLs and patient groups, I wouldn't necessarily say that polyuria is a challenge, right, is a negative impact for patients. It's this is something that they can get used to manage, Dave, and it's also something that in some patients probably also could attenuate with time. I think it's important to note when we look at all these AEs, when you look at a safety table, what you're getting there is really AEs from the first day of dosing through to the end of the study.
What nobody really talks about is, okay, but what if, what if one employed titration, for example? What if you slow-walked your dose from day one? Could that be a way to further reduce the rate of AEs? You know, titration is something we're considering including in registration study. We're considering including in the remaining cohorts of the phase 2 study as a way to maybe even further differentiate from the others in terms of reducing potentially the rate of AEs. Which is, by the way, I think that the narcolepsy space is very accustomed to titration. Like, most drugs in standard of care today for narcolepsy patients are titrated.
Excellent. Let's pivot to the data disclosure that's coming later this month. How are you setting expectations?
Yes. Obviously very excited about the year ahead. We've gone much higher in dose since November, so we're aiming to report a phase 2 update, which could be in one indication, could be all three. It depends from the data that is gonna be available by the time of the disclosure. As you know, we have this phase 2 study, which is, I think from an IR perspective, you know, it's pretty challenging, but on the other hand, it really puts us into an ideal position to select the optimal dose. As you remember, we select a dose for a given dose cohort, we then unblind, and then that gives us the opportunity to see the data and then select the dose for the next cohort, right?
We've put a lot of work in generating what we think is the ideal molecule, but a lot goes into it about selecting the right dose, right? It's very important that the optimal dose is selected for these patients. That's what the phase 2 study has allowed us to do. Now in terms of the Q1 update, phase 2 update, we are also going to announce or aim to announce the start of registration studies across multiple, potentially multiple indications. It could be at least in one, but it also could be in all three. Again, it will have to be a data-driven decision that we'll be making at the time of the disclosure. What I'm also keen that we do, Dave, is really to show our registrational study design and also our regulatory strategy.
We have a very thoughtful regulatory strategy and registration of program design, which really puts us into an ideal position to still strive to be first in class in NT2 and idiopathic hypersomnia. Finally, what you will also get to see is my vision for the pipeline, which is very exciting because what I really see ourselves today, Dave, is leveraging all of the work we've done on the rare hypersomnias with 750. That is the foundation of the company. We're gonna start registrational studies. We are looking to be best in class and first in class a number of these indications and already thinking about building a commercial team. We're really morphing into a pre-commercial stage company.
Now that we have the foundation, I think it's important for us to really start also looking at the other indications where we think orexin agonist could have a tremendous impact for patients. As you know, we have 142 in the clinic. We have 489 entering the clinic this quarter. We're really pivoting from, I would say, a rare hypersomnia-focused company to a neurosciences company with a pipeline and a pathway type approach.
Excellent. How will you make the decision on what to disclose later this month?
It's completely data-driven. First and foremost, it depends on the number of cohorts and which cohorts are gonna be available at the time of the disclosure. Also, I think what we've also decided to do as a company is to provide an update that we think is close to the top end in terms of, for example, of efficacy in a specific indication. If for whatever reason we may still have obviously a best-in-class profile, otherwise we wouldn't be progressing to registrational study and seeing a specific indication. If we felt that there was still room to do even better, right, we may save that update to at some point for the down line.
What I'm hoping to achieve, Dave, with our TPP is that at the end of the day, even if we have a best-in-class profile, why not take the dosing higher? If the therapeutic index does allow us to do that, and remember 750 has been allowed to be dosed at higher doses and has a wide therapeutic index, why not try and reach, for example, insomnia, right? I'm hoping that the maximum tolerated dose will be in the form of insomnia for these patients, because that means that you have that extended duration of action that I think everybody's looking for.
If we feel that we may still be adding a cohort, for example, once we see the data, prior to the disclosure, we may decide to save the update for that specific indication till at some point this year. Obviously, there's also a number of scientific meetings this year, so we wanna make sure that we also pace potential disclosures.
Excellent. Can you talk about split dosing and how you see that across the indications?
We're evaluating both QD and split dosing. We designed 750 to be a QD drug. It has an optimal PK profile that really allows for that. What I would say is split dosing may provide an advantage to patients in terms of putting them more in control of duration of action and further allowing that second dose to really further modulate the duration of action, and which is specifically important to try and meet lifestyle needs and the demands of patients, which are, at the end of the day, very, very different. That's something that we're obviously evaluating in phase 2, and we have the option to include in the registrational study.
Obviously together with the phase two data, we'll also be looking at whether split dose could also have some potential other positive impacts, such as, for example, tolerability, given the Cmax is lower. For us, it's really about dosing flexibility. If that's an advantage, if that's what split dosing offers compared to QD, then it's something that obviously we'll look to consider in a registration study.
Very good. For the open label extension, could you comment on that?
Obviously open-label extension is open, and we have a large number of patients rolling into that. We're doing efficacy measures in the OLE. We're also doing the MWT, so we're looking at efficacy also a number of weeks into dosing. At some point, you know, we'll look forward to giving you guys an update on the OLE as well.
Excellent. All righty. The question has been asked a lot, but I'll ask it again, which is about tachyphylaxis. Could you discuss that potential risk and how you see that?
First and foremost, and you know, we mentioned this a number of times, we've seen no changes in efficacy between week two to week four. Somewhere between the first day of dosing and week two, obviously, we're not measuring efficacy between in that timeframe. The system probably achieves a normalization or rather a steady state in terms of effect size, both in terms of efficacy, but also potentially in terms of some of these on-target AEs. We've seen no receptor internalization and no signs of tachyphylaxis also in chronic studies, preclinical studies. Obviously, we've gone to very high doses. We've done extended duration of action studies, and so none of that. Obviously, if you look at other orexin agonists in development, they showed consistent data between week two, week four, all the way out to multiple weeks of treatment in the open label extensions.
I think this has largely been de-risked, not just by us, but by others as well. Orexin, in terms of how it works as a neurotransmitter, it's a tonic neurotransmitter, meaning there's always a baseline activation of the orexinergic receptor system, which is very different compared to other GPCR and other neurotransmitters such as dopamine, which is released in bursts, right? We believe that the risk of seeing tachyphylaxis is extremely low for orexin agonists. Obviously, you know, we'll need to see more and more long-term data. So far everything is looking based on what we've seen externally and the data we reported in November, I think everything is looking pretty good from that perspective.
Excellent. Remind us about differentiation versus Alkermes' candidate that you had previously disclosed, right? Related to visual disturbances. Just comment on, you know, the administration considerations. You know, the specifically differentiation and potentially the patient experience with 750 comparatively.
We put a lot of effort, Dave, at the fundamental chemistry level, right, when we designed the molecule. We didn't take any shortcuts. We put tens of millions of dollars of synthetic chemistry efforts, design, and obviously everything enabled by very sophisticated structural biology capabilities that I'd put together back in the day. That really provides us with a very high quality candidate. I would say actually multiple candidates with 751, FR-249 and others that we haven't disclosed. We have completely linear PK across all doses tested, and we've gone much higher in dose, not only in patients since November, but also in our phase 1 study. We're seeing completely linear PK, which is very important, especially as you dose escalate and try to get those higher exposures, which hopefully also drive higher efficacy.
We have a relatively flat Cmax to AUC. We think Cmax is probably what is contributed to some of these AEs, such as the visual disturbances. Obviously in the November release at the 1.5 mg, we saw no signs of visual disturbances, yet we achieved very meaningful and potentially best-in-class efficacy. We obviously have, I think, a differentiated profile from that standpoint. We have no clinically meaningful food effect that we've observed in some of the doses that we tested, which is why we also think split dose could work very well for us. Ultimately, just back to the PK profile, the fact that we have that extended duration of action is partly thanks to also very good metabolic stability in blood, which provides those sustained exposures over time. A sort of biphasic PK profile.
PK is just so critical for these molecules and these indications. Obviously, so is potency. That gives you kind of the comfort of just having low doses, reducing idiosyncratic risk, reducing DDI. Selectivity reduces chances of off-target pharmacology, which can be common in your pituitary GPCRs. Again, 750 is super selective at orexin-2. Then obviously that PK profile allows you for that duration of action. We think we're at the chemistry level, at the fundamental molecule level, we're differentiated in many ways compared to others in clinical development. Then obviously we have the big advantage of our phase two study that has allowed us to really find that optimal dose, and ultimately provide more and more benefit to patients.
Excellent. Let me pause there, see if there are any questions from the audience. All righty. With respect to the initiation of pivotal studies, could you characterize that with respect to, you know, still being in the process of exploring, you know, some higher doses, and just, you know, how you get the ball rolling with trials and whether you can modify them as they ramp up?
Absolutely. Obviously aiming to start registrational studies this quarter could be across multiple indications. Obviously we would only start studies where we had a very high conviction of being best in class, right? Again, we've gone to much higher doses since November. We're kind of quite excited about the opportunity of doing that. Now, I think fundamentally, Dave, if we still haven't hit a maximum tolerated dose, right? I mean, obviously we could decide that we're very comfortable to start the registrational studies because we think that the profile of the drug looks great, because we're highly differentiated, potentially best in class. But if we still haven't reached that maximum tolerated profile, why not continue the dosing? I could start a registrational study seeing a specific indication.
We could keep the phase 2 open, we could add an extra cohort at a higher dose, and then if by the time that cohort reads out, if it looks meaningfully different, and it has to look meaningfully different, right? We have the option to include that higher dose and slot it in our registrational study this year. This is something we've put a lot of thought into. It's definitely feasible from multiple perspectives. It really just comes down to would it make sense to do that? We have the option. You know, we see it as a core option to do that, to further enhance the profile if needed. Again, comes from a position of strength because, not because we need to, right?
It's just, can we get to a place where we fully explore the therapeutic index of the drug, which I'm hoping will be in the form of insomnia.
Hmm.
Right? Maybe it's an 18, maybe it's a 20-hour duration of action. That's ultimately where you wanna be, right? I hope we acquire the insomnia because then you can always scale the dose back down and you've provided the bookends of the profile, which is ultimately what patients are looking for, 'cause we fundamentally believe this is gonna be a monotherapy approach.
Excellent. Could you talk about the market opportunities across multiple indications?
Thank you for raising this. I feel the market opportunity is still something that is somewhat underappreciated, right? According to our own estimates across NT1, NT2, and IH, we're talking a potentially $18 billion market. There's a significant opportunity for growth. There's only very few branded treatments today on the market because most of the market is still dominated by polypharmacy in terms of standard of care. I think with orexin agonist, we finally have the opportunity to show something incredibly more meaningful and more tolerated compared to standard of care, which we think are gonna be a tremendous potential commercial success story.
If you look at the number of patients, there is around 50,000 diagnosed and treated NT1 patients in the U.S., double that in NT2, and then in IH, where there's a significant unmet need, there's only one treatment approved for IH, we're looking at about 120,000 patients diagnosed and treated. Tremendous market potential. This is something that, commercially, Dave, we could even look to build ourselves. There's been a lot of success stories of drug launches in the rare hypersomnias. There's about 2,500 sleep centers in the U.S. A few of these are driving some of the largest prescriptions and looking after most of the patients as a rare disease.
You know, that's some of the analysis that we've done and we're doing, right? We're starting to build a commercial team this year because we think there could be tremendous value in really building this ourselves and launching ORX750 across these three rare hypersomnia disorders.
Excellent. Could you touch on the pricing of Xywav? Obviously, that's approved in multiple indications and the potential implications for Centessa.
The great thing about Xywav is that they have basically equal pricing between NT1 and NT2 and IH, which I think, if I remember correctly, is north of $200,000 gross. Obviously, let's see where orexin agonist will be priced. I think what I can share is that there's multiple benefits of orexin agonist that go well beyond wake promotion, and we're looking at a lot of exploratory endpoints. In our phase 2 study, we're looking at cognition, we're looking executive function, we're looking at potential improvements in brain fog, and we're hoping that this totality of data really helps support a very, very strong commercial story.
Excellent. Just take the next step with that, if you would. Just talk about potential indications beyond, you know, your first three indications that you're targeting.
Absolutely. This is something that we're, you know, we've been doing a lot of work on, and we're incredibly excited to really build out our multi-asset franchise. First and foremost, there's many symptoms across fatigue, mood, executive function, cognition, where we fundamentally believe these drugs are gonna have significant, or could have significant, impact. The good thing, Dave, is that we're looking at a lot of these efficacy measures in our phase two study, which we think are actually translatable to some of these broader indications, which is really helping us there. What I would also note, obviously, we've done a lot of preclinical work looking at some of these symptoms on the broader neuroscience indications, which is also providing the groundwork for us.
If you look at stimulants, for example, the use of stimulants, the use of wake promoting agents, you see them used in multiple indications well beyond patients with narcolepsy. They're used in ADHD. They're used in fatigue-related indications. For us, really, it's about going after these very large neurodegenerative neuroscience disorders and looking to go after the underlying symptoms, right? For us, it's not about going after the EDS component. I wanna be clear, we're going after the underlying symptoms, which we think could provide a tremendous impact on improving patient lives in some of these indications. As part of the Q1 disclosure, we'll provide you guys with an update on which indications we're going for after and why.
We think our multi-asset franchise, which also has allowed us to create these beautiful molecules with very, very different PK profiles, lend themselves very, very well to some of these broader indications. You will see that the ways in which we've designed these studies, these proof of concept studies and these indications give us, I think, a very, very good opportunity to find a clear signal to then potentially move forward into later stage clinical development and ultimately build a fully fledged neuroscience company.
Excellent. I think that's a great way to wrap up. We are over time, so thanks so much for being with us here today.
Thank you, Dave. Thank you.