Welcome, everyone, to the Takeda Session. I'm very pleased to welcome Andy Plump, President of R&D, and Ramona Sequeira, President of the Global Portfolio Division. There's a lot to talk about. Takeda actually is coming off of a wonderful piece of good news from this morning, so maybe we can start there. Rusfertide succeeded in its phase III trial. This is a program you have partnered with Protagonist Therapeutics. Maybe Andy can briefly give us the overview of that program and what we learned this morning.
Sure. So firstly, we're really happy. The results were really exceptional, as you saw in the press release that we jointly distributed with Protagonist. So rusfertide is a hepcidin mimetic, so it's a peptide. It's delivered by subcutaneous injection once a week. And it mimics the activity of endogenous hepcidin, which is the master regulator of iron metabolism in the body. It was being tested in the VERIFY phase III study, which is a study in patients with polycythemia vera, so all comers. These are patients with low and high-risk disease. We can talk about what that looks like. And these are patients that either have or haven't had prior therapies. What was necessary for enrollment is phlebotomy dependence. So the main state of treatment for patients with polycythemia vera, which is predominantly an overproduction of red blood cells, it's in a sense a premalignant condition, is phlebotomy.
These patients will have frequent phlebotomies. It's somewhat effective. Many patients don't respond to phlebotomy. It's somewhat effective, but it's a very poorly tolerated procedure. It actually leads to a major side effect, which is iron deficiency, which has a number of different secondary manifestations. The primary outcome in this study was phlebotomy independence. The patient presented patients that were phlebotomy independent. We saw that over 70% of patients in the rusfertide arm compared to 30% in the placebo arm were phlebotomy independent. This is not just placebo, but placebo plus standard of care. The bar for efficacy was exceedingly high. The last thing I'll mention, Michael, is that it wasn't just the primary endpoint, but every secondary endpoint was also positive.
The endpoint that the European Union will be looking for, EMA, which is the number of phlebotomies over a 32-week period, hematocrit controls, so the percentage of patients that are kept below hematocrits of 45%, which is a kind of a magic number because above which you start to develop very significant morbidity and mortality risk, and then probably the most interesting is there were two patient-reported outcome measures that were used, and both also were very significant. The bar for significance on those was quite high, so we're ecstatic.
Great.
This gentleman's mic doesn't seem to be producing very well.
You heard me. It's really interesting things happening.
Maybe while we're doing that, I can add a little bit on rusfertide. So we know that about half of these patients have regular therapy, meaning they have regular phlebotomies, and then they might go on to be on one or two cytoreductive treatments. And obviously, the data we saw is amazing for those patients. But we also know about half patients are actually sitting out in the community and have irregular phlebotomy. And so they're really not on a regular treatment regimen, but they have risk, right? They still have all of the thrombotic risks. They have elevated hematocrit. They have once in a while a phlebotomy.
Given the efficacy profile and the safety profile that we've seen so far and the patient-reported outcomes, it gives us an opportunity to really go to a very broad patient group, not just the ones that are treated today, but the ones that are out there in the community having less positive treatment experience. It really opens up the window for us, I'd say, on this one.
Great. I should have mentioned at the outset, but if anybody in the audience has a question, feel free to raise your hand, and we can call on you. Andy, as regards rusfertide, my understanding is that there were some lingering safety concerns that needed to be discharged. Did this top line do that, or are there more data that we should be looking out for in the future?
Both. So you can hear me now, good, because I can hear myself. So there was actually the most common adverse effect that we saw was injection site reactivity, and that was very low grade. There was some question of a cancer risk based on the phase II data, and it's important to note that this patient population has a significantly increased risk of secondary malignancies, particularly skin cancers, and there was some imbalance in the relatively small phase II study. I should mention the design of the VERIFY phase III study is three parts. We just completed part one, and that's the primary endpoint that we just alluded to, the second part will be safety, so all patients will cross over and receive rusfertide and continue to a full year so we can generate safety, and then the third part will be an additional two-year open label extension.
So we'll continue to generate more and more data. But we feel very confident, and this was mentioned in the press release, that we've discharged any concern about a cancer risk.
OK, that's good to hear. Well, Takeda has two other very important phase III readouts coming in 2025. Maybe you could give us a preview of what the other two are and a brief primer on those molecules for folks that aren't familiar.
For sure. It's a huge year for us, and actually, we had a chance last December to talk a little bit about the six molecules that we have in phase III, both from a clinical standpoint, a scientific standpoint, but also the commercial opportunity, so Ramona, please chime in, so of those six, three have phase III readouts this year in 2025. Rusfertide this morning. The next one will be TAK-861 or oveporexton, which is our orexin type 2 receptor agonist for narcolepsy type 1. That trial has been going extremely rapidly, reflecting the enthusiasm of investigators and patients for the mechanism. Those data will read out later this year, and then the third will be TAK-279 or zasocitinib, which is our TYK2 inhibitor for psoriasis, so three very significant events for us this year.
Great. Well, let's dig into TAK-861 to start with. The phase II data were highly compelling. Do you view that as roughly the bar for phase III for narcolepsy type 1? Should we expect those data to replicate, or is there some other consideration?
Of course, you never know. I've learned in this business, you always wait for the data before you get too far ahead of yourselves. I think there's, firstly, what were the data that we saw in the phase II program? So this is an eight-week study with a long-term extension. We're looking at measures of daytime sleepiness. We're looking at measures of cataplexy. And then we're looking at measures of nighttime sleep patterns, as well as a number of secondary criteria like attention, like cognition, like executive function. And across all parameters, we saw essentially normalization of these patients. So not only at eight weeks, but we actually have now followed these patients. The majority of these patients have received at least six months and many approaching a year of therapy. So we continue to see very similar efficacy at a year that we see at eight weeks.
The safety profile looks very strong. The phase III study is designed very similarly to the phase II study. Unlike most programs where phase II is short, very small numbers, phase III much longer, larger numbers, actually the phase II study and the phase III study for TAK-861 and narcolepsy type 1 are almost identical. 100 patients in the phase II study, 150 patients in the first phase III study, eight-week primary endpoint in the phase II, 12-week in the phase III study. We'll, of course, wait and see what those data tell us from the phase III studies, but I think we feel quite confident that we'll be able to carry forward the profile.
Great. Ramona, maybe you can give us an overview of the competitive landscape and what you see as the commercial opportunity in narcolepsy.
Yeah, absolutely. So I mean, I think we see a growing competitive landscape in this space, but really, we are quite a bit ahead of any other asset in the marketplace. And so I think Takeda, all along the way, has kind of been setting the pace for what good looks like with respect to what kinds of things you're going to measure in the trials, how are you going to design the trials, what are we looking for with orexin augmentation. So I think we will continue to lead the way, both in our trial design as well as in our shaping the market as we bring this to market. So we do know that patients with narcolepsy type I, these are the ones that have low orexin levels. And then there's narcolepsy type II and IH that have more normal orexin levels.
And so we're very focused on narcolepsy type 1. For us, this is going to allow us to kind of tailor this molecule to patients who have low orexin and be able to really give an outcome that you're looking at the daytime and the nighttime measures that we look at in all of the trials, but then we're also adding in some measures of cognition, sustained attention, functionality that we think will show that actually by treating the root cause of narcolepsy, you can have a transformative effect on these patients. And these are patients today who are on a lot of polypharmacy. So maybe something to help them stay awake and then something later to help them fall asleep, maybe something for comorbid mood disorders. There's many different medications that they're on.
Our goal is for 861 to allow patients, or TAK-861 to allow patients to be on a monotherapy for treatment of narcolepsy type 1, which is really going to be life-changing for them, the treatment itself, and then the impact of the treatment as well.
You mentioned the improvements in cognition and attention, which we had a chance to catch up with KOLs recently, and they were particularly intrigued by that aspect of oveporexton. Are those the kind of data that could make the label, or is that the kind of thing that sort of is just in the ether surrounding the drug as you launch it?
Label. Yeah. Yeah, why not? I mean, it of course depends on. They're not designed as exploratory endpoints. They're designed as predefined endpoints. So from a statistical rigor standpoint, there's no reason to think that they can't make the label. In the end, it will all be a function of what we see in the phase III study.
Those endpoints are included in the phase III.
Those endpoints are included in the phase III study design, yeah.
Another interesting aspect of TAK-861 is potential twice-daily dosing, which you mentioned tailoring to patients could have the added advantage of kind of boosting orexin levels around the time when a patient might need them when endogenously they would otherwise be spiking. And so there's the potential for an efficacy advantage relative to competitors. Do you think that that will play out in sort of a cross-trial comparison, or is that the sort of thing that might come to the fore during real-world experience?
I mean, I guess if you're thinking about cross-trial with other assets, they're still years away. So that's going to be time before we can actually start to look at that. I think we have enough confidence in TAK-861 that we'd be very willing to look at that. So we know that the diurnal tone of patients with narcolepsy has an ebb and a flow of orexin. And so we believe by doing two doses, it allows you to actually mimic the diurnal tone of a normal patient. And so I think this is, again, one other reason that it's going to be transformative in all of the data that we see from our phase II trials, which we're expecting to see in phase III. You see patients get into normative ranges. And we believe this is why.
You're actually mimicking the diurnal tone of a normal patient, a patient without narcolepsy. And so we believe this is why we get these patients into normative ranges. So I think, again, this is setting the bar for other products to come. You're not going to get better than normal. And so they're going to have a bar to meet in order to bring their therapies forward. Yeah.
This may be a premature question, but since you're the leader here, do you price it aggressively? I don't know if you're even thinking about pricing at this point, but being the first one out, can you be a little bit more aggressive on price? Or do you even consider that at all?
So we certainly have been thinking about and talking about price. And I think the key for us is to price it in a way that you're going to make sure patients can access it, because we are going to have to do some change management in the market. Today, patients with narcolepsy may or may not get a differential diagnosis that's accurate. We know about 25% of patients are diagnosed with type II but end up either progressing or actually having type I. And so we want to make sure we're broadening the catchment to get not only those patients that are diagnosed with type I, but actually might have type I but have been misdiagnosed with type II.
And so there's certainly an opportunity to get a good price, but at the same time, we need to balance that with the ability to actually get a larger catchment of patients in order to improve diagnosis in this space. So those are the things that we're balancing as we look at pricing.
We have an additional orexin agonist, TAK-360, that's in development for NT2 and idiopathic hypersomnia. How is that molecule different from oveporexton?
They're both very potent and highly active orexin II receptor agonists. They're both highly selective. They're both, in animal models, outstanding molecules. We developed TAK-360 purposefully after we had run into issues with TAK-994. You'll remember we had some hepatotoxicity, very severe hepatotoxicity with TAK-994. TAK-861 was a backup molecule that we had optimized, but we had not known that there was a hepatotoxicity risk. And so one of the key elements of TAK-360 was to create a molecule that we knew that we could dose to higher levels. And so it's not more potent, but it has a room to dose significantly higher than TAK-861. Actually, we put a very large team on that. It was a top priority and continues to be a top priority for us. And actually, we've just started our phase II program.
We went from candidate selection to start a phase II in less than two years. There are very few biotechs that can do that. I don't know that we can do that with all of our molecules, but when we really focus on something, this is a great example of it. We have an immense ability to drive forward.
Any questions from the audience? Great. Well, narcolepsy type II is not characterized by a loss of orexin neurons like narcolepsy type I is. What would you say is the probability of success for an OX2 receptor agonist in NT2 as opposed to NT1?
Rather than answering your question precisely, because I don't know what the probability of success is, I'll say that we know that orexin agonism will work. In type II narcolepsy, we have very compelling data from our earlier molecules. And certainly, we've seen this with some of the competitor molecules. I think the two key questions that remain outstanding are durability of activity. So we haven't seen activity beyond four weeks for an orexin II receptor agonist. And as an agonist centrally acting, you're always concerned about some degree of sensitization or tolerance to the mechanism. And the diseases are very different, as Ramona was commenting to earlier, because you have endogenous orexin tone in patients that have type II narcolepsy or idiopathic hypersomnia. So that's one.
And then the second will be threading the needle of the efficacy and safety of the therapeutic index, because there are mechanism-based tolerability issues. One is obvious, and that's insomnia. And then the second is some urinary tolerability issues. And so ensuring that you can get the necessary level of exposure to drive efficacy and minimize the tolerability. Personally, I think the likelihood of that is on the higher side, but we'll see.
Let's move to zasocitinib. You're a TYK2 inhibitor in development for psoriasis and IBD. At your R&D day, you laid out your expectations for the oral segment of the psoriasis market. Can you give us a recap of your expectations there, and how do we get from point A to point B?
Yeah, absolutely. So I think with zasocitinib, we're very fortunate. We have a very unique molecule that is going to be patients can take it when they're initially diagnosed with psoriasis, but because of the efficacy and the durability, they can stay on it. Today, what you have is patients will take an oral medicine, and it's more of a bridge. It's something that the doctors will prescribe very quickly early on, but often those patients will end up not being completely satisfied with what they have today and end up progressing to a biologic, which is OK. There'll still be, even with our molecule, there'll be patients that take biologics as well. But the benefit of zasocitinib is that it's got this durability and sustainability. And then you've got a third of patients that actually get in our phase II data, get clear skin.
And for rheumatoid arthritis, sorry, psoriatic arthritis, get minimal disease activity. So that's a full third of patients that are actually going to be fully treated with clear skin in psoriasis. And we know from the durability that they will stay that way. And so I think it's a huge opportunity to really transform the treatment paradigm in this space, where you can actually start with a safe, efficacious, once daily. You can take it with anything, other medications, meals, et cetera. And you can have a third of patients have a full response to that, which is going to be new and different and not offered in this market today.
Questions from the audience? So Andy, you mentioned zasocitinib's first phase III psoriasis trial reads out toward the end of this year. It is also a head-to-head trial versus deucravacitinib. When we see the first phase III readout, what is the one data point that would give you the most confidence that you will also succeed in the head-to-head trial?
I mean, first of all, if our phase III data even just mimics our phase II data, which there's a very high likelihood that it will, if not better, but very high likelihood that it will, that tells us that we've got something that does not exist in the marketplace today. And I think that gives us a lot of confidence. But it's not just the data that gives us the confidence. It's all of the analytical work we've done on the two molecules as well. And given the binding affinity for TYK2, given the selectivity for TYK2, so we know zasocitinib has a much higher selectivity for TYK2 than deucravacitinib does. And we know it's got a 24-hour binding. And both those things are different from what you get with deucravacitinib.
So the phase II data combined with the analytical work we've done give us a huge amount of confidence. And really, just seeing the phase II start to play out and replicate phase III, play out and replicate the phase II is all we need to have that confidence that we can go both to transform the treatment for psoriasis, but also to beat deucravacitinib in a head-to-head. Andy, anything?
Yeah. PASI 100 is where zasocitinib stood out in phase II. Is that the element of the phase III that we should be focusing on?
Yep.
Head nod. Great. So the oral IL-23 inhibitors are often held up as more the competitor to benchmark against, as opposed to deucravacitinib, perhaps. How do you think about oral IL-23 as a potential threat in the future?
So I would say the data that we've looked at so far on the market, talking to prescribers and kind of looking where the market's going to evolve, we know that the oral segment today is a very small part of the full market. So it's like 14%, 15% of the full market. We expect that oral segment to double. So it should be up to more than a third of the full market over the next 10 years. So that will be with our product plus other orals in the market. So actually having more orals come in will help us make the case that treating efficaciously with an oral just to start off is going to be very helpful to patients. But then I think what sets zasocitinib aside is the fact that it is once daily and can be taken.
So many of these patients have comorbidities, can be taken without regard to other medications that they may be on, without regard to food. So these are patients that are still relatively young. They have busy, active lifestyles. They may be on other medications. And this is just very easy for them to fit this into the context of the rest of the treatments that they may be taking. So as we kind of sit and look at the profile of this product compared to others, we think it's good to have more orals. We do want to see that oral segment really grow. We don't want to be the only one. But at the same time, we believe that our profile makes us very unique as a preferred, really, first-line agent. I don't see anyone adding up.
Great. zasocitinib is also in phase II IBD trials. How do you think about the commercial opportunity there and how that disease might segment?
Yeah. So right now, we've really disclosed a commercial opportunity for the psoriasis and psoriatic arthritis markets, because that's where we're doing the phase III data. And we have good phase II data. So that's where we can really project, because we have a good ability to project what we believe the efficacy will look like in the real world. For IBD, we still have to see that with our phase II trials. And so we're doing those now. And once we have a better understanding of what that's going to look like, we'll be able to start projecting. But we think the opportunity is really big here. So similar to the reasons that it's doing better in psoriasis because of the very high selectivity for TYK2.
And we know Chinwe was talking at our R&D event about the fact that there's people walking around with a genetic mutation that gives them better TYK2, in a sense, supplementation. And they tend to have lower incidences of IBD. So we do believe the mechanism works. We believe our ability to dose to a higher range because of the selectivity and because of the coverage is actually what's going to make the difference in IBD, because we do know that you're going to need a higher dose in IBD. And we believe we have a molecule that's shown the safety, the binding affinity, the coverage of the TYK2 receptor that actually is going to play well in the IBD market. But we haven't given those commercial assessment yet, because we don't have phase II data.
So that will kind of be the trigger for us to start looking at where we think we can make a difference.
Got it. And the phase II data will come in 2026?
26, yeah.
Okay. Great. We'll look out for that. Let's move. Are there any questions from the audience? We'll move the discussion to mezagitamab, your anti-CD38. In what ways do you hope for this molecule to differentiate from the competitors in the IgAN space?
Right. So I thought you were going to leave the question open-ended and allow me to talk about ITP, but you didn't. But I will anyway. So of course, IgAN is the main focus for mezagitamab, our naked CD38 antibody, because it's a larger indication. We're quite excited about ITP. And we're just about to get the phase III study started. These are patients with refractory forms of ITP for which there are no therapies. So it's about 20%-30% of the overall ITP space. And the data that we saw in our phase II study were really transformative. And just by reference, you see effects of about 15% or 20% with drugs like the FcRn inhibitors. And we were seeing effect sizes of 60%-80%. So it's really a transformative opportunity for these patients that have no other therapy.
IgAN is different because it's a very competitive space right now. Ramona can comment on this. Up until recently, the therapies were essentially ACE inhibitors and angiotensin receptor blockers, a little bit of steroid use, highly ineffective therapies. The majority of patients would progress. Substantial numbers of patients by 10 years were requiring kidney transplant, and actually, people should know it's the third most leading form of kidney disease after hypertension and diabetes, so it's not an uncommon disease. It's a fairly common disease. Today, there are three classes, I would say, three buckets of emerging therapies. There are non-disease modifying therapies. We won't talk about those, and then there are two classes of disease modifying therapies that both affect immune function. One are the APRIL/BLyS agents, and there are eight or nine of those in development, and then there are the CD38s.
There are two of those in development right now. I'd say based on the phase II profile's efficacy, they look kind of neck to neck. They look similar in terms of the benefits. There's still a lot that we need to learn with longer-term dosing. Within the CD38 class, we clearly have a more potent CD38 inhibitor based on a number of different parameters that we can talk about. Ramona, you can expand on this. I think the clear advantages are one is that we'll be a leader in the CD38 class. It's a second class. Second, patients who don't respond, let's say, to APRIL/BLyS inhibitors will have an option with a CD38 inhibitor. A second is safety. We don't actually affect the production of memory B cells. Things like vaccine responses, I'm smiling.
Hopefully, we still have vaccines when we get to market. Things like vaccine responses won't be affected by our mezagitamab, where there's a high likelihood that they will with these other agents. And then the dosing schedule, the APRIL/BLyS will have to be administered continuously, whereas the regimen that we'll test with mezagitamab going into phase III will be administered with a very long drug holiday of up to half a year. And then there could be some other secondary benefits in terms of ease of administration. Yeah, subcutaneous, exactly. Low volume subcutaneous, very well tolerated.
Great. We'll look out for updates on that front. One other product I want to discuss before we move to broader topics is fazirsiran. I think it's fair to say this is one of the probably more underappreciated assets in your portfolio. Can you tell us what this drug is, what indications you're going after, and what the commercial prospects are?
Sure. I'll start. So we certainly don't underappreciate it. So again, it's one of six. You mentioned the first three that we have readouts this year. You mentioned mezagitamab, fazirsiran. The sixth that we have in phase III is luspatercept, which is the activin A and B inhibitor for low-risk myelodysplastic syndromes in our oncology group. So fazirsiran is a silencing RNA that reduces the production of a mutant form of alpha-1 antitrypsin. Patients that have this mutant form form aggregates of alpha-1 antitrypsin in the liver. And a very significant percentage of those will go on to develop liver failure. And the only treatment that exists today is liver transplant. We have very interesting phase II data with our partner, Arrowhead. And we're now in a phase III study looking at clinical endpoints.
Yeah. I mean, I think truly transformative, this one. I mean, there is nothing out there today for these patients. They often don't get diagnosed until very, very late. And so we have examples of patients who have gotten diagnosed because they were literally in liver failure and put on a liver transplant list. And maybe when they're diagnosed, they have kind of weeks or months to live without a transplant. So a big goal for us is going to be improving the diagnosis so we can get diagnosed patients earlier, which should not be complex and difficult, because this is a simple blood test. It's a genetic marker. So it's a very simple blood test. And with the growing use of liver screening in the U.S. and around the world now with products for MASH and NASH and obesity products, there's just a growing use of liver screening.
And so we think as part of that liver screening, adding in a blood test to test for alpha-1 antitrypsin deficiency would be a very logical thing to do, be simple, not expensive, and allow us to find these patients earlier. And then we can stop them before they get to that very late stage. And again, as I said, there really is nothing else for these patients should they develop any kind of liver effects from this genetic mutation. So we're really excited to be able to bring this forward.
Great. Any questions from the audience? Please.
What do you see as the biggest opportunities and the biggest risks from the research that changes in administration?
Please. Hands off to you.
I think we're going to keep an eye on many of the same things we've been keeping an eye on all along. We need to keep an eye on PDUFA. I mean, with layoffs, changes in leadership, all of that, we want to make sure our PDUFA guidelines and timelines stay committed. We just signed a new PDUFA deal in the last year or so. So we're very committed to making sure that we continue, and so far, our personal experience has been our meetings have been progressing as planned. Our engagements have been positive, so we haven't seen an impact yet, but that's something we want to keep a really, really close eye on. I think the IRA, we've known that it's coming. How they decide to use CMS to set a price within the IRA once a product gets swept up might change.
But we don't see the mechanism of the IRA changing. Certainly, there's going to be risk if the IRA, maybe the timing changes. But right now, there's so many priorities that the administration has. It's hard to know if that's something that would really fit in and get a lot of congressional support to get passed. So I would say talent at the FDA, keeping our PDUFA timelines, just keeping an eye on they've talked about tariffs. And certainly, that's something that we want to keep a close eye on as well. We all in pharma, like it or not, have very global supply chains. I mean, once we put a plant in place, you've got multiple regulatory authorities inspecting each of our plants, billions of dollars to get a plant up and running, and often for biologics, live substance. And so it's difficult to put plants everywhere.
We tend to have very global supply chains, and so keeping an eye on how that might affect drug shortages and pricing would be something that we'd want to be careful of as well, but I think right now, it's probably too early for us to say there's any one particular thing that we're doubling down on. These are the things we're watching across the board as time progresses, and I think working very hard as an industry to make sure we're pointing out one of the challenges with health care is there's a lot of unintended consequences to any one thing that you do, so you can put tariffs on raw materials entering the country, but that might drive up prices or cost of goods.
So just making sure that we're really articulating some of those unintended consequences to help keep a more stable and predictable environment is going to be important. I think you hear a lot about companies. Some of the biotech companies, in particular, are very dependent on NIH work or research that's happening. And that's something that we've heard a lot about in Massachusetts as well. So I think that's another area. We love the fact that Massachusetts is such a hub of innovation and early-stage research and would really like to see that continue. We have, I think, gosh, Andy, 200 partnerships with companies. So we really do. We are one of those companies that tends to partner early and then kind of work with those companies to bring assets forward. And we have a lot of optionality in many of our partnerships.
So seeing that research environment continue is going to be important for us long-term as well. So it's probably more general the areas that you've heard of and nothing specific as of yet. And certainly, we haven't as a company, there's nothing right now that is a risk to us being able to do the business that we've been doing today.
Great. Well, we are at the top of the hour. Thank you so much for attending and thank you for your time and insights.
Thank you, Michael. Thanks.