Well, good afternoon, everyone. Welcome once again to TD Cowen's 46th Annual Healthcare Conference, welcome to the Takeda session. We're very pleased to welcome Dr. Andy Plump, who is the President of R&D at Takeda, joined by his IR team. Let me say at the top, if anybody has a question in the room, please feel free to raise your hand and we can call on you. I, of course, will take the liberty of the first question, it is a big-picture question. Setting the stage for Takeda, 2025 was really a phenomenal year for the company. You had three NMEs, rusfertide, oveporexton, and zasocitinib, all of which had positive phase III readouts. We're now headed into launches of those drugs. We're also looking at a maturing inline portfolio, you have a new CEO coming in June.
Maybe you can help us understand, as investors, how to think about the next chapter?
Yeah
... for Takeda.
Well, thanks. Thanks, Mike, and hello, everybody. I was in a town hall a week ago with my team, and I said I turned 60 last year. I don't know if I'm allowed to give that information out confidential.
It's an age check.
I spent a lot of years in this business, and I have to say that the last year was by far the most exciting and successful of any that I've been in for the reasons that you just suggested. Amazing time for us with Julie Kim coming in as CEO. Julie, I've been working with for six years now. I know her very well. She's just an amazing individual. We're all really excited about her transition. We'll miss Christophe immensely. I started with Christophe. He came 12 years ago. I came 11 years ago. This is a huge transition for me and for the whole organization, but I can't imagine someone better poised to take over.
Of course, an internal candidate tells you how enthusiastic the whole organization is up into the board to carry forward the momentum that we've generated. From a, just from a big picture, you know, the past couple of years, a lot of focus on Vyvanse, loss of expiry, 2024, 2025, took the big hits. 2026, that will start to level off for us. While at the same time, we have a group of products that we call our launch and growth products. I think in Q4, we'll come up with a new name for these because we're gonna have another set of products that are gonna be our launch products.
What we're seeing with our launch and growth products is that they're starting to mature, and so their growth starts to become much more moderate over the coming years. This is then where the excitement happens with these new launches. Three great readouts, I know we're gonna talk a lot about them, last year. We're really looking forward to approvals and launches starting this year, and we're already starting to lay the foundation for what those launches will look like. Of course, each of these three products from oveporexton to rusfertide to zasocitinib have a very different market, and a very different structure around the launch.
Great. Well, maybe we could start off talking about oveporexton in that market. PDUFA date in August. How should we think about the launch and, what's the sort of ideal candidate right from the get go for a drug like oveporexton?
By candidate you mean?
Patient candidate.
I see. If you have type 1 narcolepsy, you are a candidate for this drug. This is really one of the most exciting drugs that I've ever been a part of. The data that we've seen in our phase III study has just been phenomenal. Essentially, not quite, but essentially all patients benefit from the drug, and the vast majority normalize on whatever efficacy endpoint we've studied, whether it's daytime sleepiness, whether it's cataplexy, whether it's cognition, whether it's nighttime symptoms. This drug oveporexton has benefits across this whole spectrum. For the majority of patients, it's normalization. What we see in this market is that if you're a type 1 narcolepsy patient, you're likely to need one medicine to fulfill all of your needs, and that's oveporexton.
We're quite excited about getting it approved and launched. Of course, we have the PDUFA date set in August, but we're doing everything we can that's in our power to see how that can move up and get accelerated.
What should we anticipate in terms of the label? There's a pretty broad set of endpoints that was measured in the pivotal trials. What among those might make it onto the product label in the end?
Yeah. First of all, say that the amount of data that we have in this program is extraordinary. It's the endpoints that we can measure are just so quantitative. We've talked about the fact that we have in each of our phase III studies, 14 different endpoints we've hit with very high significance and clinical meaningfulness on every single endpoint that we've studied. In addition, we have a number of exploratory endpoints that are quite interesting. I'll say that for those of you who follow this field closely, we've disclosed a fraction of the data that we will be disclosing, less than 50%. Expect over the course of this year to see a large amount of additional data coming out.
We are keen to fully own this space since that means better understanding the journey of a type 1 narcolepsy patient. We're working very closely trying to unravel biomarkers, whether they're digital biomarkers or other biomarkers that can help us further understand patient needs. You've probably seen, we've announced a partnership with Beacon Biosignals using their Dreem device to help to measure sleep. That's both to help us with oveporexton uptake, but also our broader interest in sleep-wake cycle. I'll mention you asking about the label, and you're asking what we can expect from the label. We have that same question because, of course, that's still part of the process in the review.
I think our base case is that it's gonna be a very attractive label for physicians and for patients and include as many endpoints as possible.
Great. Before we move off the orexin franchise, maybe we could talk about TAK-360, phase II, NT2 and IH data are coming later this year. Are you more optimistic about prospects for this molecule given competitor data readouts? Maybe you could put the entire competitive landscape into some context for us.
Sure. I wouldn't say I'm more optimistic based on what we've seen from the competitors. I think we've been optimistic all along. We've had a lot of experience, not just in type 1 narcolepsy, but in type 2 and IH. You'll remember, Mike, and many will remember that we've done with TAK-925, the first orexin agonist to go into the clinic, our IV molecule with TAK-994. We've explored quite broadly a number of indications beyond NT1. A, we have a good sense, at least with short durations of therapy, what one can see with this mechanism across a range of different indications.
Then secondly, we have deep expertise internally, and especially that translational expertise that help us understand what kind of molecule one needs in the various diseases as much as one can, and how to develop those molecules across these diseases. We feel quite excited about our franchise of orexin agonists, starting with oveporexton launch in NT1. Likely, that will be the single indication for oveporexton. TAK-360, which, as you mentioned, is in phase II studies for IH and NT2. We hope to have data rolling out this year. Then a third molecule, TAC-495, that's just gone into the clinic. All three of these molecules has very different pharmacological profiles, that allow us to tackle these different disease states.
I will, if you don't mind, I just wanted to go back quickly. We are running one additional phase III study for oveporexton. It's a study that will enable registration in Europe, but it will also provide additional information that will help us to further position it in the U.S. It's a randomized withdrawal study, so we'll know how patients who are taking a medicine prior to wash out do when they transition to oveporexton. You know, I did mention that the vast majority of patients normalize with the doses of oveporexton that we've studied in our existing phase III program. There are some patients that may need a little bit more agonism, and so we have the ability in this now ongoing phase III study to test slightly higher doses for those small percentage of patients.
You said that trial is required for registration in the EU?
That's right. That's right. You know, it's gonna be a relatively small trial. You know, the studies that we've run have been about 150 patients each. This one will be slightly smaller. Given our experience with sites and with investigators and the excitement around this mechanism, you know, as soon as we open this trial up for enrollment, it'll enroll like that.
Okay.
That will happen fast.
All right, great. The rationale for higher doses is, potentially better efficacy, I imagine.
Right. As I said, I think that we've hit it for the vast majority of patients with the two doses that we've tested. Right now, just so everybody knows, we have two dosing regimens. We have 1 mg and 1 mg given about three hours apart in the morning. We have 2 mg and 2 mg given about three hours apart in the morning. You know, again, the vast majority of patients are fine, many at one and one, the majority at two and two. There might be a small percentage of patients that just need a little bit more. We have a chance in that trial to go a little higher. You can also imagine, I mean, everybody's physiology around sleep-wake is slightly different.
Having these two doses, having them administered three hours apart, at least by way of our trial, you can imagine flexibility.
Mm.
One dose slightly higher, one dose at a slightly later time point. We think that with that flexibility in the administration schedule, we're gonna be able to achieve the needs of essentially every patient with NT1.
Great. I actually failed to ask you about other indications that you might be exploring for oveporexton outside of NT1. Is there anything of note that we should keep on our radar?
Right now, our focus for oveporexton will be NT1.
Okay.
For 360, you mentioned we're looking at other rare sleep-wake cycle disorders like IH and NT2. Then as 495 matures and as additional molecules come in the clinic, think of it as a pyramid with NT1 at the top, then these other rare sleep-wake cycle disorders like NT2 and IH. Then it starts to open up to conditions that have larger patient sizes, have different market considerations. You know, our goal is to focus on any indication that would lend itself to orexin 2 receptor agonism.
Is there an example or two you could give?
Sure. There are a number of different conditions. I'll give you buckets.
Sure
... let's say. There are other rare disorders that we don't talk about, like, for example, Prader-Willi syndrome. There are disorders that this mechanism has unique biology and pharmacology and that are driven by respiratory issues. The prototype there would be obstructive sleep apnea, but there are many others that fall into this realm. Of course, the challenge there is that you need to maintain orexin tone probably beyond the daytime and into the night, perhaps more so than we do in narcolepsy. How you thread that needle requires a lot of precision around the pharmacokinetic profile, but also the pharmacology of the molecule.
You can imagine many neurodegenerative conditions that are characterized by either cognitive impairment, because we're seeing unprecedented results on cognition by sleepiness. My mom has Parkinson's disease, and her number one complaint, this is common for many Parkinson's patients, is the fatigue and sleepiness that she has through the day. You can imagine a broad range of potential indications. I don't think you're gonna find a single molecule that's gonna work across all of these indications, which is why our strategy has been start with NT1, that's oveporexton, move into other rare sleep-wake cycle disorders, and then start to expand and start to understand the pharmacology that you're gonna need.
Sure. Any questions from the room?
Are you highly confident that the FDA will not want to see the data from this additional phase III trial?
It's a great question. The trial hasn't started. We were cognizant of that question as we went into this. I think that based on the package that we submitted, because we had discussions originally with the FDA that one trial would be sufficient. We knocked it out of the park with the first trial. The second trial then finished five days later. We, of course, included both. We feel very confident based on the quality of the package we've sent in, the discussions that we had with FDA, before we started phase III, the interactions that we've had since. I think that would be highly, highly unlikely. Yeah. Eric.
Hi. There are so many different sources of idiopathic hypersomnia, sometimes secondary to medications that patients take for depression and other things. Where does that figure in your list of potential indications, and could you maybe size that opportunity relative to others?
Maybe we should repeat the question 'cause I don't think they were good mic scenarios.
Yeah.
The question was about idiopathic hypersomnia and thinking about the heterogeneity of hypersomnia conditions that don't have a clear etiology and then the size of that disorder. It's, I mean, I'll dissect that question in a few different ways, Eric. You know, one is that there is a condition that in and of itself is called idiopathic hypersomnia that has a code, a reimbursement code that's associated with it. There are other forms of hypersomnia that exist as part of other indications. You have a disease, and then you have symptoms, let's say. The size of that disease is small relative to NT2 and NT1, but on the larger side relative to rare diseases.
Maybe we're talking as opposed to 100,000+ like you'd see in NT1 or maybe 200,000 + that you'd see in NT2 to something in the order of 50,000 patients with IH. I'm ballpark that number for you. But as you can imagine, it's a difficult disease to diagnose, and it's extremely heterogeneous. We were quite surprised and actually excited by the fact that the first molecule we brought in the clinic, which you'll remember, TAK-925, we did a proof of concept study in IH. The levels of efficacy that we saw were essentially equivalent to what we're seeing in type 1 narcolepsy. I think that just speaks to the fact that regardless of why you're hypersomnolent, this mechanism will wake you up.
In terms of the size of the population of patients who have hypersomnolence as part of some other disorder, there you're probably talking millions, right? You're talking millions. If you look at diseases like Parkinson's or MS or even Alzheimer's, there have been estimates that suggest that 20%-30% of these populations could have hypersomnia. How you target those populations, how you access that market, not, not simple because they're so heterogeneous in there. You're not talking about the disease itself. You're talking about a symptom associated with the disease.
One more.
You talked about the competitive data, and you've always been optimistic throughout. Can you just maybe discuss the side effect profile and how you think oveporexton compares on visual disturbances and [inaudible] ?
Sure. The tolerability and safety profile of oveporexton has been outstanding. I would say that the issues that we've seen are known mechanism-based issues, and the two most significant are obviously insomnia and then the second are urinary symptoms. Interestingly, we now have data that extends out well past a year looking at patients, and you see efficacy that continues from day one to one year plus. You do see sensitization to many of the tolerability issues, particularly the insomnia. Patients that have insomnia, the vast majority, 80%-90%, will have it within the first week or 10 days of dosing, and then for the majority of those patients, it will go away. You do have some patients that have persistent insomnia.
It's hard to distinguish what those patients are experiencing than what any of us might experience. You do still carry forward that AE, that tolerability issue of insomnia. It's pretty much the same with the urinary issues. You see sensitization early, perhaps not 80%, 90%, but the majority of those patients then sensitize and no longer have those issues. We don't see visual disturbances. We haven't seen them in any of our trials. The first time we really saw them were in our phase III studies after there was just an immense amount of public awareness of visual disturbance that had come from our competitor molecules. Of course, when physicians are asking continually and patients are primed, you're going to see this.
Interestingly, we saw a fairly similar incidence of visual disturbance in our phase III trials between the placebo arm and the active arm, which is suggestive that it's a suggestive phenomena, not a real phenomena. Whether there's something there because you do see you've seen reports of higher incidence with some other molecules, particularly at higher doses, I can't tell you. You know, we've had a hard time explaining mechanistically why a orexin 2 receptor agonism would lead to visual disturbances.
Maybe we can move on to zasocitinib. You presented or at least disclosed the first phase III psoriasis data. The full data I think will be presented very soon. Can you recap what you've disclosed so far and how it fits into the competitive landscape in your mind?
Yeah, absolutely. Really, really excited. You know, we had a range of possibilities for what our phase III trial would look like, and I would say that this was at the kind of higher end, the results were at the higher end in terms of what that range would look like. They're very consistent with what we saw in phase IIB, almost identical, maybe even a little bit better, which I think is quite unusual when you look at the work that we do. You typically see some weaning of activity between phase IIB and phase III for a number of different reasons. zasocitinib is I think as everyone knows is a highly potent, highly selective TYK2 inhibitor. It's clearly once a day dosing with a beautiful 24-hour coverage.
You know, with the once-a-day doses that we are administering for psoriatic arthritis, which is our 30 mg dose, we have 90%+ inhibition of TYK2 over a 24-hour period. There's no food effect, which I think is gonna be quite important for this class. Saw a tolerability and safety profile that was very consistent with what we had seen in phase IIB. An efficacy, you know, as I mentioned, it was really just phenomenal. Over half the patients had complete or nearly complete clearance of their psoriatic plaque on skin. Slightly over 30% had 100% clearance. You know, it was really just phenomenal. As I said, it was as good as we could have expected.
We looked at almost 45 different endpoints across our two trials, pre-specified endpoints. Again, similar to oveporexton, all of them are significant and many with the number of zeros before the one beyond anything that I've ever seen before. It's a really highly effective drug and really quite excited about it.
Great. slightly over 30% PASI 100. When we get the full data at, I believe AAD, what data points would you urge us to focus on?
Yeah. We are presenting at AAD. We just found out that we're, we have a late breaker, so we're excited to have an oral presentation. I would look at, it's a lot. I would focus on the efficacy and the safety data, of course. On the efficacy data, I would look at a couple of different elements. One would be the rapidity of activity, right? Many of the biologics can take months before you start to see effect, and then can take even more months before you see plateauing of that effect. We see benefits as early as four weeks, which is quite unusual.
It's hard to do cross study comparisons, but I think our conclusion, and then you come to your own conclusion, is that we're as good or better than any other oral option that exists on the market today or that is coming onto the market in the near future. Yeah. We'll have a, an investor call as part of that, so it'll be the presentation from the principal investigator, and then I'll be out there as well. We'll do an investor call and share our perspective and be able to answer questions as well.
Great. Any questions from the room?
How do you think your data compares with the Alkermes data that we saw?
The question was how do we feel our zasocitinib psoriatic arthritis data compares with the Alkermes data? I mean, it's hard for me to say because all we've seen from Alkermes is a press release, and you see you get snippets. I think we'll have to wait and see what happens with their presentation. You know, just the one obvious differentiator that's just obvious is we're once a day and they're twice a day. I think in a market like psoriasis, having a once a day option is gonna be a considerable differentiation.
Zasocitinib is also in a phase II IBD trial, ulcerative colitis and Crohn's, which is due to read out later this year. What are the data that support the idea that other TYK2 inhibitors have failed in IBD because they didn't achieve sufficient inhibition of the target?
Yeah. Interestingly, the reason we brought zasocitinib in was because of our strength and history and strategic interest in IBD. We became interested in the immunology conditions, psoriasis and psoriatic arthritis, of course. There are three lines of evidence that suggest that TYK2 inhibition should work in IBD. The first is pharmacological evidence. You see biologics like IL-23 inhibitors that work upstream of TYK2 are highly effective. Now, they have other pathways that don't necessarily require TYK2, but it's a strong, I think a very strong rationale. The second is we look at animal models of colitis with all the caveats of an animal model, and they're highly effective. The third that has been by far the most compelling are the genetics.
We know that there are loss-of-function TYK2 variants that exist in a fairly high percentage of the population, one in 25 individuals of European descent. You have many patients who are heterozygous and many patients who are homozygous. For both heterozygous and homozygous, they are protected against Crohn's disease. Homozygous, but not heterozygous, are protected from ulcerative colitis. Yes, the existing TYK2s that have been tested in IBD have not been effective. We strongly believe what you said, Mike, was that none of those have been tested at the level of inhibition that you need to see efficacy. Interestingly, the animal models, the exposures that you need to see efficacy in colitis are much greater than the exposures that you need to see efficacy in models of psoriatic arthritis, right?
The genetics, the fact that you see protection and you see in the homozygous when the heterozygous suggests again that you need more exposure. The doses that we're testing in our phase IIB studies give us exposures that are probably three plus fold more than what's been studied previously. I... You know, we'll see what happens over the course of this year as those data read out, but we continue to feel quite optimistic about the potential in IBD.
Great. Questions from the room. When we get those phase II data, the first thing that people like me will do is put them in a chart next to other data. Should I include in that chart JAK inhibitors, or are they so different as to be an inappropriate comparator mainly because of safety issues?
Well, I mean, if I were in your shoes, I would include everything because why not? Because if you have a drug that's available, you wanna make sure that you're including it in your, in your thinking. It's not how we think about it. Firstly, I don't know whether JAK inhibitors are quite effective in IBD, and they come with the baggage that we know about, but the efficacy is quite substantial. In fact, as great as anything that's really, that's out there. Other oral agents that are used in IBD are significantly less effective. There are very few oral agents that have the efficacy, tolerability, dosing, ease and safety that we're expecting with zasocitinib. I think we'll have to see what happens.
you know, the other thing that we're looking into, we think that zasocitinib in and of itself has potential as a monotherapy.
Mm.
In IBD, that's how we've designed our phase IIB studies. I think if you look at where IBD is headed in the future, given the efficacy ceiling that we're seeing with every agent that's out there, you know, if we really wanna think beyond, as we're starting to think towards kind of having generic penetration, you have to start thinking about combination therapies. We think that zasocitinib, given its mechanism, given its tolerability and safety profile, lends itself nicely to combination therapies as well.
A good combination partner presumably would be Entyvio?
That would be one, of course, yeah. That mechanistically makes a lot of sense given the synergies between the pathways.
Oh, question from the room.
When it comes to IBD, I'm just curious how you think. You know, when we see limited efficacy, sometimes what we just fail to see is mucosal healing, right? I'm curious if you think that adding that second immunological agent is what will get us to mucosal healing, or do we need to do something else to get the regenerative capacity of the epithelium going again?
Yeah. I'll have to get someone who knows much more about this space to come and speak with you. Well, I think that the answer to your question is I think that we know that there's still even patients who respond to then relapse, they still have an inflammatory disease, right? They're still primarily an inflammatory disease. I feel with high confidence that coming at the immune system through different angles will give you added benefit and maybe the potential for more durability, right? Whether you need additional mechanisms to overcome other aspects of this disease, like the stenoses that we see or other aspects of the disease, I think absolutely for sure. That doesn't preclude the potential for combined immunological mechanisms. Yeah.
That question was about mucosal healing and prospects there.
Yeah.
I don't wanna neglect rusfertide in our last couple of minutes. That launch in Polycythemia vera is on the horizon. I think phlebotomy is the procedure that you hope to essentially replace. Can you just tell us a little bit about the competitive landscape there for rusfertide?
Sure. Well, essentially there is none. There is an a very effective, very inexpensive standard of care, which is phlebotomy with its limitations. Maybe I'm glad we saved time for rusfertide. I'll rank order what I see as the R&D head, as the challenge, the three programs that we have and the rank order of the challenges of our launch. The easiest, although nothing is easy, is oveporexton, right? Rusfertide, then zasocitinib, and that plays to really the market, how the markets exist today. Rusfertide, the profile is just incredible in terms of what we're doing for patients.
You know, we now have four years data, and we're seeing that with rusfertide, patients with polycythemia vera, 90%+ are still within normal hematocrit ranges at 4+ years, which is just extraordinary. The challenge is that, and this is by the way, rusfertide on top of standard of care. The standard of care would be hydroxyurea or other cytoreductive agents. About 50% of patients end up taking hydroxyurea. I don't know that patients will need to continue on both. It's just that physicians like as they start a patient on one, they add another, they tend to maintain that paradigm. The problem is that phlebotomy is about 75% of patients don't achieve hematocrit levels of below 45%, which is target with phlebotomy alone. A lot of that is compliance, right?
Why are they non-compliant? Because it's an awful procedure to go through at the frequency that you have to. Secondly, there are issues with phlebotomy, so iron deficiency, ironically, and there are a number of different sequelae of iron deficiency that range from organ defects to just constitutional symptoms. The third is that patients who have phlebotomy just don't feel better. One of the benefits that we've seen in the rusfertide phase III program is the benefits that on patient-reported outcomes that patients are reporting.
Great. Well, in our final moments, I just wanna ask a forward-looking question. If we fast-forward 10 years from now, what do you think will be most different or surprising at Takeda relative to how we see the company today?
Well, 10 years is a long time.
It's a long time.
I can't even think. If I were to think even five years, I'll take your question in five years.
Mm-hmm. Five years.
I think it'll be, you know, everybody's talking about this, and you and I had the conversation. I think it'll be how much technology is supplanting our ways of working today. I'll give you one just example in R&D, which is we're about to move into a new building from our Kendall Square, I'm sorry, from our Central Square location in Cambridge into Kendall, so it'll be completed in the next nine or 10 months. The 80% of our labs in the area will be in that building. 100% of those labs will be digitally enabled. The whole workflow of how you take a program from target discovery to candidate, not that every part of it will be digital, but every part of it will have a digital e-enablement, including everything that we do at the beginning.
It will look completely unlike any lab that we see today.
Great. Well, with that, thank you so much, Andy Plump .
Great. Thanks, Mike.
Thanks for your time. Thanks for joining us.