Thanks for the invitation, Andrea, at Goldman Sachs. We're very excited at Centessa. Momentum has never been stronger for the company, now with three programs in the clinic. And so we have announced that our most recent program to enter the clinic is ORX-750, an orexin agonist, which has obviously generated a ton of excitement and look forward to discussing that. In terms of our R&D approaches, we are a very R&D-centric management team. We love data, we love pursuing assets that have the chance to change patients' lives, not incrementally, but significantly. And all of the assets that we have in our portfolio can do that.
They're selected based on their potential, not necessarily the therapeutic area or modality, and each of the assets, we're excited about, to bring forward.
Awesome. Well, maybe we can jump right into the Orexin program.
Sure.
Mario, I'll bring you in here. Maybe speak about the Orexin class as a whole. Why has it garnered so much, so much interest, so much excitement, across the community? And then, talk to us about this, the phase I trial that you've initiated.
Yeah. So I'll start off and then hand it off to Mario, who's the expert in this space. So I think we should just take a step back and look at this class of drugs that are now being developed that target the Orexin 2 Receptor. It's been transformational for patients. We saw that at the most recent sleep conference. Everyone's talking about orexin, as they should, because this is a therapy that is now functionally, you know, curing these patients, if I can use that word, from the data that we've seen with clinical programs that have shown the effect size is tremendous relative to the options that are available to these patients today. And remember, this is a group of patients who have narcolepsy, who aren't effectively diagnosed, who aren't effectively treated.
Even when they are treated, their symptoms persist, and oftentimes they discontinue treatment, or they're on polypharmacy, where they need many different medications to at least try to stay awake during the day and lead somewhat of a normal life. This class of drugs is tremendously powerful and one of the best, if not the best validated neuroscience targets in recent memory in the last 20 years. Being part of that now at Centessa with our first molecule, ORX-750 in the clinic, is incredible. We think we have the best-in-class molecule, and we can get into details on why that's the case. I'll go on the record and say this today, is that we, as a, as a company, I think in the space, of, of every one of us who are pursuing this target and focused on narcolepsy, and I think that's tremendously important for patients, and, and as I said, there needs to be better therapies there. But I think we're only scratching the surface. And what I mean by that is this type of this class of drug, has potential to go beyond just narcolepsy. The diseases where excessive daytime sleepiness is a comorbidity associated with so many different indications out there. Potentially, diseases like Parkinson's, for example, where EDS is a, is a huge factor, major depressive disorder, chronic fatigue syndrome, shift workers, obstructive sleep apnea. The list goes on and on.
And so, what I like to tell our team and motivate them is that, look, you know, the GLPs are incredible, right? Well-validated now, but, you know, 10 years ago, however many years ago, they were diabetes drugs, and now it's blown up into obesity drugs. And I think it's not dissimilar with the Orexin class, where we're starting in narcolepsy, where it's well-validated. The underlying diseases, it's obviously established with Orexin loss, but the potential to go beyond into broader indications is incredible. And so I think, the investors and others who thought, "Oh, well, wish we had gotten into GLPs 10 years ago and saw the future," well, I'll go on the record and say that you have...
I think everyone has the opportunity now to look at the data that's being generated with the orexin agonist class, and here's that moment for all of us.
Okay.
Yeah, maybe just to add to that, we were at the sleep meeting in Houston last week, and in speaking to KOLs and physicians, I mean, the level of excitement that this class has generated is really off the charts, I would say. For the first time, there is the opportunity to treat the underlying cause of narcolepsy Type 1, which is the loss of orexin. Having a single modality, a single therapeutic agent that can provide this transformational efficacy we've seen in the clinic on excessive daytime sleepiness and on cataplexy is truly remarkable. We also heard at Sleep about the potential for orexin agonism to play a role in treating disturbed nighttime sleep and consolidating sleep architecture, and that could mean a potential monotherapy approach in NT1. So hugely exciting.
You know, to echo what Saurabh is saying, NT1 is really the tip of the peak of an iceberg here. It goes very, very well beyond into the common disorder. Any common disorders, anywhere where there is an excessive daytime sleepiness component, this could have a huge, huge role to play.
And then remind us, you have a broader portfolio of orexin agonists, but this ORX-750 is the one that you've advanced for the furthest to date. Maybe remind us, what was that selected based on, and what has been the profile that you've seen across your preclinical work?
Yeah, it's a great question. So taking a step back and why we're so excited about ORX-750 and all the molecules that will come behind it that we're working actively on today, is that if you trace back the origins of 750, it comes back to good old-fashioned structure-based design and having the proprietary crystal structure in hand to generate the chemistry, doing the appropriate med chem to agonize a receptor. That's been very difficult to agonize for decades, people have been trying, and generating a wide range of chemical matter for from which ORX-750 is derived, but the next set of molecules that we're bringing forward that are very distinct chemically are also being derived from.
So this isn't a kind of one and done ORX-750 randomly came up with this molecule, and that's it. No, this is an orexin franchise that Centessa is building today. It's a franchise that's based on, the comments I made earlier that we don't envision this just to be a narcolepsy drug, but have, implications in other diseases where potentially 750 or, and/or other molecules can have, different, different indication profiles. So with 750, what we sought to do, very early on is to have that in mind, where this drug can be used chronically and be used chronically, not just in the narcolepsy population, but envisioning it could be used again, broadly in, in anyone who has excessive daytime sleepiness as an, as a challenge.
So when we selected this molecule, we spent a lot of time thinking about it. We looked at, obviously, rapid onset of action, potency, brain penetration, all the factors that make a lot of sense, but also looking at the DDI profile, the drug-drug interaction profile. What kind of metabolites is this molecule generating? So that we could envision using this drug ultimately in diseases where there's medications that are treating, you know, disease X, Y, or Z, but you can still add potentially ORX-750 on top of that. Minimizing any Cmax related tolerability issues is important, and we have PK in mind as being the key differentiator of ORX-750 between 750 and all the other molecules that are in the clinic.
And so minimizing peak to trough was very important to us, to achieve as flat of a curve as possible. Again, keeping in mind that this is, a molecule, a pharmacologic equivalent or phenocopy of the Orexin- A peptide. And that's why we strove to have a molecule that is as potent, almost as potent as the peptide itself, but then have the PK profile mimic that, of the Orexin- A peptide.
Absolutely, Saurabh, and the binding pocket is extremely tight for this receptor, and it's fundamentally a medicinal chemistry challenge. The loss between orexin and Narcolepsy Type 1 was first identified by actually the chair of SAB, Professor Emmanuel Mignot, just over 20 years ago. If you can imagine where we are today with orexin agonist, it took quite a bit of time to be able to make progress and really crack the nut on the medicinal chemistry side. So back to ORX-750 and where we are today, we feel very, very confident about this molecule potentially being best in class.
And if you recall the World Sleep disclosure that we had last October, I think we put out a very comprehensive and thorough disclosure on the preclinical data, suggesting a high-potency molecule, a molecule that can essentially promote wakefulness and suppress cataplexy at very, very low doses in these highly translational mouse models. And the bar Saurabh set for extremely high, because we do live in a competitive space. So as a biotech, I think we of winning here. And of course, safety and tolerability was very much part of the focus of the candidate selection process. Off-target pharmacology and off-target receptors make sure that there was no relevant pharmacology seen in terms of potential off-target effects. That was very much part of the candidate selection process.
Yeah, we feel, we feel very, very good and very, very happy to be in the phase I setting now.
Maybe that's a good segue, since you did just initiate this phase I trial, you have a pretty unique design. Maybe just to remind the audience, why you structured it that way and what you're looking to see.
Yeah, I mean, we're super excited by the design of our phase I study. It's very different. It's unique. I don't think it's been done before. And so, just in brief, what we're attempting to do is, at the very first time, subjects are being dosed, healthy volunteers are being dosed with ORX-750 in the SAD, the single ascending dose, part of the phase I. We have the opportunity, we have the option to take those subjects, subset of them, in. And what that allows us to do is in a crossover design study, where patients serve as their own control, be able to assess how long it... they're staying awake. So it's an MWT study, and we're also measuring KSS. Those are actually, the MWT is actually the study you would do for a registration endpoint.
So we're getting that data at very, very early stages of a phase I study, at the SAD setting. And what that enables us is to peg dose exposure, PK, with response, with the—what kind of effect size we're generating at any given dose, and then allow us to then titrate up the dose to the next SAD level appropriately. And then be able to iteratively do that sleep study again, and then see what the results are, and then continue titrating up the dose, until we get to a point where we feel like we have normative sleep, awake-ness, if you will, restored in these subjects. And I think it's important to note that healthy volunteers is the highest bar possible because they have normal orexin levels.
So being able to keep them awake in a sleep deprivation study is very, very challenging. But if you are able to show that, then it again goes back to the very beginning of this discussion, is that all indications are on the table for you, not just narcolepsy, where you need a third of that dose, roughly, to work, but all indications where excessive daytime sleepiness in otherwise you know normal orexin. So we're excited about the design of study, but also appreciated is the total number of subjects that we're actually exposing the drug to. So for the SAD, it's 12 subjects, nine on drug, three on placebo at each SAD dose level. So at each dose level, you're getting good, good amount of safety, obviously, to move forward to the next SAD dose level.
But the POC is being administered to 10 of those healthy volunteers. So at each MWT that we're doing, we're actually going to get 10 subjects worth of data. So you can probably guess that as we're doing these iterative POCs, you're getting tens and tens of subjects of data, which is, I think, going to be very informative, both from a safety standpoint, but also from an effect size standpoint, hopefully in a dose-responsive manner. So the totality of data, which we hope to release in the second half of this year, will hopefully be very comprehensive.
Maybe what underpins your confidence that the safety signals that have plagued so many other agents in this class, you will not have an issue with?
So back to our molecule, ORX-750. A couple of things there, right? First of all, in terms of DILI, that I know there was a lot of focus on DILI and some of the orexin agonists in the past years or so. We have a very differentiated metabolic profile. And during the candidate nomination process, we actually brought forward a number of advanced assays and characterizations on the molecule to make sure that what we're bringing forward had the lowest possible risk in terms of DILI, coupled with a high potency molecule that drives very low predicted human doses.
And I think we can say this, in our, in our GLP studies in rodent and non-rodent, we actually saw no hepatotoxicity and actually, no clinical, in life observations, during the study, which I think bodes very, very well for the, for the safety tolerability of the, of, our ORX-750. And so that's, that's DILI. In terms of, of, more broadly, there's, there's a number of on-target AEs that we've seen recurring, right, over and over again in some of these clinical studies. And although we're not certain, we hypothesized that many of these are to do with the Cmax, with the, with the peak of the PK curve. And you see, Andrea, we—you don't really need to, to drive. Essentially, orexin works as, stabilizing the, the different states, right?
It's not so much it is a wake-promoting agent, but in many ways it just helps to stabilize wakefulness and avoid sleep intrusion, which is characterized as EDS, or avoiding REM intrusion, which is characterized as cataplexy during the day. So, you want you would like your ideal brain exposures to be above a certain brain wakefulness threshold in order to promote this orexinergic downstream activity and promote efficacy. When we selected 750, we wanted to make sure that the peak to trough was ideal in order to not overshoot, potentially overshoot in terms of these on-target adverse events, right? And this was very much part of the candidate selection process.
So a lot of, I would say, of the advantages are built into the ADME PK properties of the molecule. And I think a lot is also to be said about this really creative phase I study design that we have ongoing, right? Optimal dose selection, let's face it, is going to be key in order to hit the bullseye here. And this study design allows us to do exactly that, to find that optimal efficacy, tolerability profile. Because unlike many other crossover designs, where you're essentially flying blind, you have to select predefined dose ranges ahead of starting the crossover study design. And the reason why crossover is so important is because every subject is its own control, right? So it's very high powered.
With our study design, as Saurabh mentioned, we have the possibility to, rather than flying blind, but really help guide on a PK and on a POC basis, the dose escalation of the study. That's very powerful for the optimal dose selection ahead of patient studies.
May I just add that speed is also an added benefit of the study design.
Mm-hmm.
Instead of having to do many SADS, followed by many MADS, and then do the crossover study, collecting, you know, some doses.
Yeah
- without knowing exactly where your efficacy might be, saves us a huge amount of time. And that helps us also as we plan the next set of studies.
Maybe on that point, as you think about the next set of studies, what does that design look like? I guess maybe is it fair to think that what Takeda has done or what Alkermes has done, that sets the blueprint for the trial? And then maybe more broadly, as you think about which indication to pursue as your first, is NT1 a fair assumption, or could you potentially go to an area like idiopathic hypersomnia, where it's, you know, a little less crowded and there's more of an unmet need, you could say?
Yeah, I think I set myself up for that one. So we haven't commented, obviously, for competitive reasons on our post phase I, if you will, plans for clinical development of seven fifty. But what I will say is that for us, as a small biotech company, it allows us to be very nimble. We can pivot very quickly, and we're not faced with perhaps the constraints that bigger companies might have in terms of where we end up pursuing, which indications we end up pursuing. For us, it's the way I, you know, like to communicate to the team is that everything's an and for us.
I think when thinking about how, you know, we've set the bar high and going into healthy volunteers and hopefully being able to show that we're keeping them awake, and then it's truly possible. So we're not just limited to NT1 or NT2, or IH, the rare hypersomnias, but rather that and or possibly the broader indications that we've mentioned before. And so those are decisions obviously we'll make in time as the data emerges from our phase I study. But what I will add is that if you look at our phase I design, we did it very, very differently from what anyone else has done. You can expect more drug in phase II and beyond, that we're not gonna do the conventional way of developing a drug.
We'll obviously keep patient safety first and foremost in mind, but working back from where we need to be in terms of the approval and whatever the indication or indications may be, we will do it as fast as possible.
Is there a target product profile that you are looking for? I think one of the hallmarks of Centessa has always been that you've been able to make go/no-go decisions expeditiously. Help us think through maybe what the TPP would look like here.
Yeah, and as a company, you're right, we have done that very effectively in the past. We're very data-driven, and we will make the tough call when needed. In this case, we built that in again to our initial set of studies, and that we're going straight into healthy volunteers. That is the high bar. So, you know, again, I think if we showcase their data, that is very impressive, then certainly all these options are open to us. But our goal as a company and to patients is really to bring forward a drug that has the optimal effect size, coupled with as safe a profile as possible, safety and obviously tolerability, because what we see this as a chronically used drug in patients who are otherwise healthy, who need to stay.
I guess maybe to that point, as you think about this as being a chronic therapy, where does it fit in within the, the broader landscape? Obviously, there are agents that are approved right now, a number of other, orexin agonists under development. Where does 750 fit in?
I think if you take a step back and look at the orexin class in general, I hope folks probably by now realize that the effect size here is absolutely transformational. If you look at the sleep studies, the MWT, that are assessed in a, you know, 40-minute time frame and determining how long someone stays awake after sleep deprivation, the drugs that are currently being used give you, you know, a few minutes on that scale of improvement in terms of staying awake. However, the orexin class almost maxes out that scale. You know, so we're talking about a dramatic effect size. So, that being said, Mario, I think you might have a view as to how an orexin agonist might be used in-
Yeah, absolutely. So standard of care today is very much built on polypharmacy. Right. You have actually very few, very few treatments that are able to address both the EDS and the cataplexy component in in NT1, sodium oxybate being one of these, of course. So a lot of these patients find themselves either because of just not tolerating the treatment, or because of just poor efficacy. They're not able to find... They have to use a number of different agents in order to combat their daily symptoms. And I think with an orexin agonist, I mean, I think we can all, especially following the sleep data that we've seen of sustained efficacy all the way through to eight weeks.
I think we can be very, very confident of this class and the fact that it will definitely be helping EDS, and cataplexy. And we've seen that both with objective and subjective endpoints being met with transformational efficacy in the clinic. The big question is, of course, will it be a monotherapy? Right. Will it help treat disturbed nighttime sleep? And I think with some of the data we've seen from sleep meeting, again, very, very encouraging to see a potential effect there from what we heard. And that could be extremely exciting for the class because that means potentially monotherapy approach. And ultimately, I think a lot of these endpoints I think are excellent.
They're an excellent tool in order to compare different drugs, different mechanisms, and ultimately understand how well patients are doing. But there's a lot to be said about these patient-reported outcomes, and we've seen that again, this came up at sleep. And I must say, just the impact that these orexin agonists are having on these patients in terms of restoring their normal functioning, it's really dramatic, right? These patients are, from what we learned, they're feeling normal, which is very powerful. And we've also seen some of the clinical precedent with this mechanism having an impact on cognition and attention, and that, I think, of different avenues that could be really exciting for this class overall.
Maybe one last question on, on orexins here. You know, going back to your idea that this may not be limited just to sleep-wake disorders, and that you could potentially capture other indications that are comorbid with EDS. How do you think about maybe the strategic expansion into these areas in the context of IRA?
Yeah, so it's certainly something that's top of mind, that we're... You know, when we think about 750, we think about developing the molecules that are coming right after 750, which we're actively pursuing. We're thinking about a broad suite of molecules. So we spoke about indications. There are obviously ones that are more rare than others, the rare hypersomnias, and there is, you know, IRA implications for that versus going after more common disorders, where, as you mentioned, EDS is a component. But there's also the opportunity of-- there's opportunities for different molecules, obviously, to play in each of those spaces if one chooses to do that. There's also the opportunity within each of those molecules, to have different formulations for example, to have different products emerge, from those-...
from those molecules, where you may have a molecule that has a fast, really, really fast onset of action, and then the effect goes away very quickly. So, for example, you're driving home at night, and you feel like you're a little sleepy, and you need something to keep you awake while you're on the drive home. Maybe there's a product there, for example, not just a product, I think that we're all obviously developing for, you know, continuous during the day administration, where you can keep people, you know, awake. There's, I think the PK profiles of these molecules can be tweaked, if you will, to generate multiple different products. And there could, that could happen with one molecule, that can happen with different molecules.
So as we think about that, I think the dimensions, kind of the permutations are much more than just the constraints that maybe that IRA could impose on us. But I think there's a lot of opportunity here. That's why at Centessa, we firmly believe that this is a franchise opportunity with a number of different potential products that could emerge for patients who have excessive daytime sleepiness.
Maybe while Orexin has been clearly top of mind here, you do have a late-stage asset with SerpinPC. Remind us where you stand with the SerpinPC registration program, and when we can expect to see the next disclosures?
Yeah. So we have PRESent-2 and PRESent-3 that are enrolling. PRESent-2 is hemophilia B without inhibitors, and PRESent-3 is with inhibitors, which is a very small ultra-orphan population. PRESent-2 part one is enrolling, and its enrollment's going quite well. And for that part of the study, we are administering SerpinPC at three different dose schedules. So the 1.2 mg per kg given once weekly, once every two weeks, and then once a month. And that's the dose justification part of the study for PRESent-2. That's required. And so we are gonna select a dose based on the data that we're seeing there.
And then once we select that, whichever dose makes the most sense, to get the best, the most benefit for, for the patients, we will proceed into part two of the study, which is, where the primary endpoint will read out, which is in at least 15 hem B patients who have, received, have been receiving on-demand therapy. So it's actually a pretty small, number of subjects, and the total size of the study is about 120 or so. And that endpoint in those 15 hem B subjects who, were on, on demand, is only 6 months, so 24 weeks. And the endpoint is an ABR, where each subject is compared to their baseline, bleeding rate.
So, we anticipate this year to have made a decision at the interim analysis on which dose we're gonna bring forward into part two, and then we'll have more comprehensive data that read out at a conference at the end of this year, the major conference end of this year, or early next.
All right. So maybe just for clarification, has the interim analysis already happened, or is that still on the table here?
The interim analysis readout will be sometime this year.
Okay. Okay, and do you expect to share maybe the findings of that, or is the next time we really hear about the plan and the selection of the dose when we see the data at the end of this year?
The dose selection is what we plan on sharing, and then the data set, as I mentioned, at a conference.
Updates on phase III, how that's progressing. As you think about the regulatory strategy, would you really need to wait for phase II to read out, or could you move forward on the basis of a very, very small phase III data set, but is that a possibility?
Yeah. So enrolling Phase 3 is going well. It's an ultra-orphan. Obviously, I think there's probably 300 hem B subjects with inhibitors in the world, but very few are required to satisfy the Phase 3 study numbers. So our anticipation at this point is that both will read out, Phase 2 and Phase 3, simultaneously. Phase 3 will help in the context of the broader safety database that's being generated in Phase 2, as well as our AP-0101 study that's been generating data now for 3.5 years.
This drug has shown obviously significant bleeding reduction over the last 3.5 years now that we've been administering the SerpinPC, but also has shown a safety profile that's quite impressive when it comes to having had no thromboembolic events occurring, pathologic events occurring over that time period, but also showing no sustained elevations in D-dimer over that time period as well. So when you look at the totality of data that's being generated, both Phase 2 and Phase 3 will serve as the combined kind of data set for purposes moving forward.
And when you've spoken in the past about maybe what the peak sales opportunity could be and the market opportunity, and I think now your latest estimates are $2.6 billion+. Maybe what underlies that. You know, how do you get to that number? What are you assuming in terms of uptake, among the hemophilia B population?
Yeah. I think, so the easiest math for folks is take the hem A market today and then multiply by 0.25, and that's, that's essentially what the hem B sales are, and, and that is what the number is. Today, it's roughly about $2.6 billion. What we've seen with Hemlibra is that they grew the market. It was like an $8 billion market, I think, at the time, and they grew it, and they took market share away from the factor therapies, and they grew the market because of the convenience of the subQ option. We see SerpinPC as being really no different, the equivalent of hem B, because obviously, Hemlibra doesn't work in hem B. And so the hem B market, you know, needed something that's-...
kind of the equivalent of like a Hemlibra, where it could be administered subQ at a relatively infrequent dosing schedule and, have a safe profile. And so we anticipate, you know, getting a big share of that $2.6 billion IV factor market that solely exists today as the only route of delivery option for hemophilia B. And so that's how we get that number.
And what would be the extent of infrastructure as you think about, you know, you come up on 2025, 2026, positive data reads, approval. What is the extent of infrastructure that would be needed to commercialize this? And then maybe as a second part to that, remind us your appetite to commercialize it yourself.
Yeah. So half the potential revenue that would come from a hemophilia therapy, ours works in hem A and hem B, but let's look at hem B, for example. Half is ex U.S., the other half is U.S. So what's interesting, if you look at the incumbents in the U.S. right now, the sales force required to generate significant amount of revenues in the U.S. is actually not that big, you know, in the dozens for many billions, for example, of revenue from the hem A product. But ex U.S., is a whole different game. You obviously need to have a significant amount of infrastructure and presence across the world to be able to maximize access of this drug to patients. And that's the way we look at it.
We're obviously very patient-centric, as much as we are asset-centric, is, that is what drives us. And being able to ensure that the medicine gets to the most patients as possible is the number one driver. If that means, and it likely means partnering with someone when the economics are right, when the timing is right, to ensure that, our SerpinPC is distributed and patients have, you know, access all over the world to this, this drug, that's certainly something that we will strongly, strongly consider.
And then maybe quickly on LockBody. Obviously, you have a lot going on between your orexin program as well as SerpinPC. Any updates you can provide on the LockBody program, as well as your commitment to seeing continued advancement of the program?
Yeah. So it's great to see the T-cell engager space heating up again, and within that, a subset of the space where kind of this activated, proteasome-activated cleavage that allows for maybe a broader safety therapeutic window is now being realized with some of the folks who have shown good data, our competitors in the space. So we are in dose escalation with LB101, and when we have completed dose escalation, we will then share the data.
Any hints at when that might be?
We haven't disclosed that yet.
Okay. Well, maybe, as a closing question here, just as you think across the next 12 months, the catalyst path for your portfolio, what should investors be focused on?
Yeah, obviously, the big readout for us in the second half of this year is the Orexin data set that we spoke about, in healthy volunteers, showing what the MWT study results are, in a cohorts or multiple cohorts of those subjects. And then we'll have the interim analysis dose selection for SerpinPC.
Perfect. Well, with that, thank you everyone, for joining us, and thank you, Saurabh. Thank you, Mario.
Great. Thanks, Andrea.
Thank you.