Thanks for joining Jefferies Global Healthcare Conference in London. My name is Clara Dong, one of the biotech analysts at Jefferies here. Sitting next to me, we have Dr. Mario Alberto Accardi, the President of Orexin Class from Centessa Pharmaceuticals. Welcome.
Thank you, Clara. Great to be here. Thank you for the invitation.
To just kind of kick things off, maybe for those who are less familiar with Centessa's story, maybe can you start with a brief overview of, you know, brief overview of the company, the orexin drug class as well, and the disease, what the excessive daytime sleepiness disorders are?
Absolutely. Hi, everyone. Centessa Pharmaceuticals is a clinical-stage biotech company predominantly focused on a very exciting drug class, which is orexin agonists, orexin biology. The idea behind targeting the orexin system really stems from a disease called narcolepsy type 1, where individuals have almost complete loss of orexin tone. Orexin is a neuropeptide which helps regulate the boundaries between sleep, wake, and REM. The loss of this peptide leads to very debilitating symptoms, so excessive daytime sleepiness, cataplexy in the form of essentially sudden loss of muscle tone, fatigue, amongst many others.
The idea is pretty straightforward, but I think a lot more difficult to implement, which is mimicking this missing neuropeptide with a small molecule. It is very rare in neurosciences to find such a high degree of target validation. For us, it has really been about finding the right acid, the right molecule.
We invested a lot in chemistry. We used very differentiated and novel structural biology capabilities to get to where we are today with what is most likely the most potent and selective orexin agonists in clinical development today. As of last week, we recently disclosed an update on our phase two study across narcolepsy type 1, type 2, and idiopathic hypersomnia, on the rare hypersomnias. It was the first ever robust data set of an orexin agonist demonstrating clinically significant and statistically significant efficacy across all three indications: narcolepsy type 1, type 2, and the rare hypersomnia.
It is really demonstrating a potential best-in-class profile in narcolepsy type 1, in NT2. This was very much at our starting doses, right? Our first few cohorts from the phase two was just an update.
We're very excited about continuing the phase two and entering registration program in Q1 of next year.
Great. As you mentioned, you just reported data for ORX750 in NT1, NT2, and IH. We believe this is the first oral orexin agonist showing clinical benefits across all three indications.
Correct.
Maybe just to set the stage here, walk us through what's the difference between those three indications and maybe from the disease mechanism of action perspective as well.
Absolutely. Narcolepsy type 1 is the only of the three indications that are associated with an orexin loss. That's why we're very excited about our phase two data set of showing that orexin agonists also work in indications where there isn't necessarily a loss in orexin tone, improving wakefulness. Essentially, with an orexin agonist, what we're trying to do is restoring the normal biology. Across NT1, narcolepsy type 1 is really very much defined by excessive daytime sleepiness plus a symptom known as cataplexy, which is the sudden loss in muscle tone. Narcolepsy type 2 is very much more about excessive daytime sleepiness and not the presence of cataplexy.
You have idiopathic hypersomnia, which is a closely related condition to narcolepsy type 2. It has some differences in symptoms, namely, for example, symptoms such as sleep inertia.
The exciting thing here is with an orexin agonist, we really think we can normalize wakefulness and normalize symptoms across all three indications and provide something that could be a lot better than the polypharmacy options that patients need to resort to today.
Let's maybe talk a little bit more about your data. In NT1, you reported six patient data, and three out of six patients, even at a very low 1.5 mg dose, they have MWT over 30 minutes. Maybe just help us contextualize what that number means in a clinical setting and what does that mean to patients.
Yeah, absolutely. Let me summarize the data for you. At essentially the starting doses, this was our second cohort in narcolepsy type 1, 1.5 mg QD, single dose daily, we achieved greater than 20 minute change from baseline, which is a phenomenal impact on the MWT. You're right, half of patients were above 30 minutes on the MWT. In the ESS, which is the essentially patient-reported outcome, the subjective questionnaire around how patients are truly feeling in a real-world wakefulness scenario, we dropped, we managed to have a reduction of 13 points, down 18 placebo-adjusted, down of five. Now, achieving five on the ESS, if you can compare it to standard of care, is phenomenal.
What that suggests, because there are questions on the ESS around how patients are doing also in the afternoon, it strongly suggests that with a QD dose of 1.5 mg, we are already helping restore or rather normalizing symptoms also in the afternoon and later parts in the evening. We also showed a significant reduction in cataplexy with achieving 0.13 incidence rate ratio on the weekly cataplexy rate, which again suggests very, very good and excellent cataplexy control as we move also throughout the later parts of the day. This is NT1 alone. Highly, highly tolerable. We saw no visual disturbances in the 1.5 mg cohort, no pun intended, of course. In NT2 and IH, in NT2, we achieved a greater than 10 minutes change from baseline. A significant improvement on the MWT. It is really important to look at the change of baseline.
That is the key registration endpoint. It is the MWT change from baseline, right? Patients, especially NT2 patients, can have quite a variable baseline. Again, change from baseline is very, very important. A reduction down to eight on the ESS, right? An eight-point reduction. Now, the cutoff on the ESS is 10. Less than 10 means normal to this patient. The fact that already at our second dose of 4 mg achieved less than 10 on the ESS, achieved eight, is phenomenal data. In idiopathic hypersomnia, it was our first cohort, 2 mg, and showed clinically meaningful and statistically significant efficacy across different endpoints, right, beyond the MWT.
Maybe just talk about the dose level a little bit more. You mentioned the starting dose, 1.5 mg. Are you still escalating doses? At what point, at what MWT level would you consider stopping the dose escalation?
Yeah, our starting dose in NT1 was 1 mg. The data we just discussed was 1.5 mg. Starting dose in NT2 was 2 mg. We showed data at 4 mg and a starting dose in IH was 2 mg. Thank you for mentioning it. There are over 50 patients today as we speak that are currently being dosed across multiple cohorts across NT1, NT2, and idiopathic hypersomnia with the goal of really harnessing the full power of this mechanism and seeing where we can reach in terms of diurnal symptom control and really pushing that efficacy even further. Based on the data that we have today, we already demonstrated a potential best-in-class profile across narcolepsy type 1 and narcolepsy type 2 on its first robust data set across three indications. We are aiming also to be first in class in NT2 and idiopathic hypersomnia.
There are no AEs, no AEs that we've seen to date that define the therapeutic index of the molecule of ORX150. We are continuing the dose escalation as we speak with more than 50 patients being dosed. The idea here is really to harness as much efficacy as possible. We want to cater for 100% of the patient population, right? Here we're talking about diurnal symptom control. There are patients that would love to have symptom control all the way up to the later parts of the night. Maybe they have social commitment, right? Or they have just a different schedule. It is really important to cater for that prolonged duration of action. Everybody's different.
Here at Centessa, we want to offer that flexibility, both in terms of offering a bookend of doses as part of a phase two study that will then obviously help us select doses for the registration program starting in Q1 of 2026 in order to really help us get as much efficacy as possible and cater for 100% of the patient population. We are obviously determined to be best in class not only today versus the competition, but also in the years to come.
Great. As you mentioned about the safety, the various clean safety profile, and I know for the orexin class, a big focus is really on the visual disturbance. Can you maybe just discuss what your findings were in your study in NT1, NT2, and IH about the visual disturbance and what are the symptoms and how are they really resolved?
We saw three cases of visual disturbances across 50 patients dosed in this update. Remember, the data cutoff here was 23rd of September. We did not really see a dose response on the visual disturbances. All visual disturbances were deemed non-clinically meaningful. They were transient and mild. Definitely not an issue and definitely not an AE, which is defining our therapeutic index.
I think in the past, you've also mentioned one of the key differentiations for ORX750 is its flat PK curve. Maybe just tell us a little bit more about what does that mean with the flat PK curve. How does that translate into efficacy?
Yeah, we think we've hit the sweet spot in terms of pharmacokinetics of ORX150. We obviously have a drug that enables QD dosing. Now, whether it makes sense to take forward a split dose to help with that additional flexibility to patients, that's something that we're evaluating in our phase two study, but it is designed to be a QD drug. We have a rapid onset of action, Tmax is at two hours. We have a relatively flat Cmax, so you see at least compared to the competition. We don't have a biphasic profile. On the PK, we're seeing a very long and extended AUC coverage throughout the day. It is really, I think, in the sweet spot of what a QD drug would look like.
We do hypothesize that maybe this flatter Cmax, so you see, is also helping further improve the tolerability and helping reduce some of these untargeted AEs if they are untargeted. Ultimately, though, I would still stress that none of the AEs reported with orexin agonists with the class in general seems to be problematic. Something that I do not think people are really discussing is titration, right? I think if you were to introduce titration, like most narcolepsy meds today, the rates of these AEs could even be further reduced. Again, I do not think there is a tolerability question right now. It is more, I mean, we are excited to be differentiating based on efficacy and tolerability. Again, these are still all highly, highly tolerable drugs.
Got it. As you just mentioned, the ORX750 is designed as a QD drug. Maybe just talk about your split dosing. In which patient population are you evaluating split dosing? What do you think, which proportion of patients will ultimately benefit from this dosing regimen as well?
Yeah, I don't think it's indication specific. I do believe that a split dose could be beneficial for all three indications because it's all about diurnal symptom control. The idea behind a split dose is essentially that with a QD drug, you have really no bandwidth, no control on your symptom control, right? If the drug winds off at 9:00 P.M., 10:00 P.M., as you go to sleep, what happens if you have a social commitment and you drive back home? You really don't want to go back on polypharmacy, right? Because these drugs seem to be working so well. I think a step change compared to standard of care. Why not introduce a second dose where the patient could be in control of when to take that second dose and better modulate their real-world wake promotion, their real-world symptom control, right?
Ultimately allow also for potential differentiation there.
From your initial data, we saw that's a data based on the two weeks of dosing. Do you expect efficacy and safety to have any change with longer treatment duration? Do you have any plan to report data with longer treatment duration as well?
Yeah, the primary analysis of our phase two update was done on a two-week study. It was part of a randomized crossover study. That is why we hit such high statistical significance because every patient acted as their own control and allowed us also to be extremely efficient with patient numbers. The efficacy analysis was done at two weeks. By now, there is, I think, ample evidence in the public domain from external data sets, both in NT1 and NT2, showing that once you are past the two weeks, and it could be somewhere between first dose and two weeks, right?
Nobody has really just captured that time point. Our first time point is at day one, but then at two weeks. Somewhere between that time frame, you achieve essentially steady state from an effect size perspective, right? We have seen this with ESS.
We've seen it with weekly cataplexy rate in NT2 and NT1, which is why it's important to make dose selection decisions for dose escalation based on a two-week data set. Now, we have amended our study design now to move to a four-week parallel design. This is simply to bring it more in line with what the design of a registrational study would look like rather than any issues associated with a two-week crossover study.
Great. Let's move to NT2 and IH. Let's make sure we talk about that as well. As you mentioned, you reported data together with NT1 recently. Maybe just tell us why higher doses are needed for those two indications. In the context of we recently saw some competitor NT2 data as well, how do you think your data put the company differentiated among the orexin class comparative landscape as well?
Absolutely. First and foremost, I think that there is no drug approved today for narcolepsy type 2 that shows a greater than 10 minutes change from baseline. We have achieved greater than 10 minutes change from baseline on the MWT at our second dose. We are still dose escalating. We feel very, very good about continuing the dose escalation based on the therapeutic index of ORX750 and really to harness more efficacy and provide even more meaningful duration of action to patients. With our NT2 data, first of all, we saw dose response. We have a completely linear PK profile, which really helps, especially if you are dose escalating. It is just a really good place to be from a drug perspective to be able to really predict where you are going to be from a PK/PD perspective. Completely linear PK.
I think there is incredible unmet need right now in narcolepsy type 2 and even more so maybe in idiopathic hypersomnia. I think orexin agonists could really, really help patients and provide something very, very meaningful compared to standard of care. Another, I think, important point is that there is, to your point earlier around why look at the two weeks? There is a first dose effect. We've seen it in narcolepsy type 1, right? We've now also seen it in our own data set in narcolepsy type 2, right? On day one, at 4 mg, we hit 25-minute change from baseline. It is important because of that adjustment that happens in efficacy as well as these untargeted AEs, which tend to also wane a little bit in the first few days post-dose.
It's important to look at at least one to two weeks' worth of efficacy data to make decisions for dose escalation and dose selection. That's exactly what we did with our study design, which I think is also giving us quite some potential substantial competitive advantage because given that we are unblinding at the end of every dose cohort, we can really help narrow down that optimal dose for the registration studies. Let's put it this way. We've done, I think our R&D team, our chemistry team has done a phenomenal job of getting us a molecule that is probably the most potent and selective orexin two agonist out there. Yet I think there's still a lot to be said about picking that optimal dose, that perfect dose that really works best for patients.
From the safety perspective, as you mentioned, the safety profile looks very clean from the data. Maybe just when we're thinking about NT2 and IH, NT2 and IH patients are less sensitive to orexin, but on the other hand, the dose levels might be two or three times higher. How should we think about the safety profile compared to NT1?
Yeah, we did not see, so let me step back. When we escalated, the difference in dose, right, is like 2-3x between NT1 to NT2. We still need to confirm what the dose levels will ultimately be. IH, I think, could be somewhere close to similar to NT2 because of the lack of, or rather the baseline orexin levels. I think it's fair to say that if you double or triple the dose from an NT1 dose to an NT2 dose, you not necessarily are seeing a 2-3x increase in the rate of AEs, right? I think there's something about NT1 patients being just more sensitive to the mechanism, but also which leads to efficacy at lower doses and more untargeted AEs at lower doses. We don't know why that is the case. It could be an overexpression of orexin receptors.
We do not really know. That is why it is important to pick the right dose for these indications to really be able to control your inclusion criteria. You are recruiting NT1 patients, you are recruiting real NT2 patients in studies, and we are putting a lot of effort both reflected in our inclusion criteria, but also reflected in how we enroll our role as study from a clinical operations perspective. In terms of the AEs, you are right, I mean, very, very well tolerated. What we did not include in the update in the disclosure, because obviously there is still a lot of data and a lot of analysis being done by our Chief Medical Officer, is the onset offset of these symptoms, right? I mean, external data sets have shown that a lot of these untargeted AEs, especially insomnia, is concentrated in the first few days of dosing.
I wouldn't necessarily say if you're seeing 20% rate of insomnia, that that's the true reflected case of insomnia as you would see in long-term dosing. It may all be clustered in the first few days of dosing. Again, we haven't done that analysis, but that's what external data sets have shown.
With this very strong data in hand, what's the next step for the company to move the program forward? I think you've talked about the pivotal trial consideration. What could be the timeline? Are you going to focus on all three populations as well?
Yeah, obviously we're in a great spot. It's super exciting to finally be in patients after seeing this drug started really off an idea and discovery back in 2019. So extremely excited. We couldn't have a better setup. We recently raised $270 million to help supercharge the programs. The next update is Q1 2026. We've guided us an update, which could be in one indication only or could be in all three. We haven't really given guidance beyond that, but it'll be part of the 50-plus patients that we're dosing today across all three indications. We have guided for the start of registration of program in Q1 2026. Again, could be in all three indications, could be in only one indication. We'll need to see the data from the ongoing cohorts.
Obviously, what we have not touched base upon today is our pipeline, our orexin agonist franchise, as we like to call it. We have ORX142 in phase I that is looking very differentiated to ORX750, even more potent. This is progressing into patient studies in Q1 of 2026. We have ORX489, candidate enabling studies entering phase I healthy volunteers in Q1 of 2026. We spend a lot of time talking about narcolepsy and rare hypersomnias, rightly so. $18 billion market opportunity, huge, huge unmet clinical need. We are sitting on a mechanism here that has the potential to revolutionize the space and really help patients. I really see it as the tip of an iceberg of what an orexin agonist could do.
There's many indications where there either is an orexin link in neurodegenerative disorders, or there are symptoms where orexin agonists have already shown to have profound impact, whether it's fatigue, excessive daytime sleepiness, mood, cognition, executive function. I really like to say that this class of drugs could be the next GLP-1 of neurosciences.
What will be the next clinical development steps for ORX142 and ORX489, and when should we expect more data from them?
I know you guys keep asking for that, but we do not really want to educate the competition in any way. It is a competitive space, so we need to be pretty tight-lipped here around the indication selection. Super excited about starting patient studies with ORX142 in Q1 of 2026. At some point, it would make sense to provide you guys with an update, but we are just not ready to do so just yet.
Just one last thing I think we didn't touch on is the market size for NT1, NT2, and IH. Just maybe briefly tell us how large exactly is that market opportunity for orexin class?
Based on the EPI numbers and the list pricing of known agents today, you're looking at 620,000 prevalence and roughly an $18 billion market across NT1, NT2, and idiopathic hypersomnia. There is substantial room for growth. I wouldn't just look at the sales of branded agents today because those cater for only a handful of patients. We really see orexin agonists as a monotherapy that could help many, many more patients.
Lastly, your balance sheet and cash runway?
As of now, it's $620 million proforma based on including the proceeds from the last round.
Got it. Okay, that brings us to the end of this discussion. Thank you so much, everyone, for joining this session. Enjoy the rest of the conference.
Thank you.
Thank you very much.