Time. Obviously, the recent news on Medicare Part D and IRA-related negotiated discounts is top of mind. So maybe that's a good place to start, starting with AUSTEDO. Just give us a quick refresher on those Part D discounts. And I know the majority of your business is Medicare, but there's also some commercial exposure. So how should we think about overall impacts to your commercial business as we think about 2026? And just thinking about long-term now that we have clarity on those negotiated discounts.
Yep. I guess I'll start, and Eric, you can feel free to chime in.
Yep.
We're delighted, obviously, that that's kind of, I'll say, behind us from the activity of the negotiation. It was a year-long kind of conversation, I'll say. And I think, listen, we had modeled this lots of different ways, and I think it netted out pretty closely to what we expected. So net-net, I think it's manageable. And as you say, most of our business is in that channel. And so we were prepared knowing that we'd have to manage this on an ongoing basis. And we think that that's still the case. So we had given guidance of $2.5 billion by 2027, and that was rooted in the fact that we thought we would land near this discount. So opportunistically, we still really believe that there's a lot of headroom in this space, primarily because of just the patient population.
About 800,000 patients, of which only about 15% are diagnosed, and unfortunately, only about 5%-6% are actually on treatment, so that's really the biggest remaining opportunity, and obviously, we'll navigate gross to net and all of the things that come with that, but I think we're really pleased that it's behind us. We didn't think we should be selected, but now we're turning the page and on to what's next.
Yeah. You mentioned the relatively low penetration of VMAT2 inhibitors and also the low rates of diagnosis, although growing compared to previous years. Can you talk to how you expect overall the TD population to grow, just given that there is more utilization of atypical antipsychotics? In other words, do you expect the population, the overall population, whether diagnosed or undiagnosed, to continue to grow? I know when the product launched and when your competitor launched, our understanding of the market size was a lot smaller than it is now. So how are we thinking about it over, say, the next three to five years?
Yeah, I do think it's going to continue to grow. And I think that's an unfortunate consequence of more people being, I mean, in a good way that they're treated, but that population is growing. So we expect that to continue. And I think that's why we look at this as the biggest opportunity. Eric and I talk about this a lot relative to why aren't people diagnosed. And a lot of it comes back to just how they were trained, but also because they don't necessarily recognize it. When the patient presents, they're there for their schizophrenia. And the physician's looking at it like, "I'm there to treat this primary condition," not looking at the consequences generated from it. And so we spend a great deal of time, to your question and provocation, of trying to make broader awareness.
A lot of that happens through certainly talking to physicians, but also just direct to consumer. Even ad campaigns that are disease state and not specific to a product so that we can raise that awareness. Some of the things that we've learned most recently as a big part of the patient journey, as some of the impetus for a patient to ask to be treated and recognizing that it's a disease that can be treated, comes from a caregiver or someone near to them, family member, spouse, someone that they trust at work that will point out their movements and the disorder and say, "There's something that can help you and you can be treated." Maybe you can just quickly speak to kind of the training and why.
Yeah. I mean, in my generation of physicians, we were taught that tardive dyskinesia was something you couldn't do anything about. It just happened and was permanent. And we were just happy to get the schizophrenia under control. But knowing it's all about disease awareness for me. Caregivers, practitioners, they just need to know that it can be treated. It needs to be pointed out. We have the largest registry study for TD out there. And we're learning that no matter what the severity is, from the worst to the even mild cases, it still has a lot of impact on patients' lives. It just has to be identified and brought to the awareness of the physician.
Yeah. So another Austedo question. You have cited on your previous earnings call higher growth on a per milligram basis relative to overall prescription growth.
So, wanted to get a sense for what that means going forward to the extent that more and more of your AUSTEDO business is going towards the XR product versus a twice-daily AUSTEDO?
Yeah. So it is a combination. And what I would recommend is that you don't look at any one quarter because as is evidenced by Q3, we saw about 11% TRx growth and about 25% milligram growth is what you're referencing. The previous quarter, it was inverted. So look at this over time because you're going to see that smooth out. But you're exactly right. The impetus is because of XR, which was very purposeful in partnership with Eric's team. We realized very quickly that, as we just talked about, diagnosis and treatment is super important at the top of the funnel. But then once you get the patient a script, you want them to stay on it and get to the most efficacious dose. And this is where XR comes in, is that it's one pill once a day across all of the doses.
In an ideal state, they get to a titration pack. They get to the best, most efficacious dose for them much, much quicker. That's kind of how this then plays out. It will be a combination over time of pure TRx growth and patient growth, and then also milligram growth as they titrate to that proper dose.
Sure. So your competitor recently talked to, and this is their phrase, how payers are catching on to per milligram pricing and have suggested that the competitor product, the AXIS, may benefit given the implied cost differential. So I wanted to get your thoughts on that. I know it's a question that came up and has come up. But what are you seeing regarding AXIS relative to the competitor product?
Yeah. So I'll start by saying it's an interesting theory that this catching on phrase. I mean, I've been in the industry 30 years, and it's very typical for products. Most products aren't priced the same across all their doses. That's just not principally how it works. So it's an interesting thing. But nonetheless, I mean, I think we look at AXIS very broadly, always have since we've launched. So we have about 90% access for patients with TD, and that will continue. But we continue to weigh that, particularly in light of IRA and the CMS negotiations of AUSTEDO XR and value. So the ideal is that you manage both of those side by side. And we expect that our GTN over the course of the next couple of years will certainly grow. But from a relationship perspective and payer access, we expect that to continue too.
So I think it's part and parcel of how we commercially launch and continue in this space.
Let's talk about the LAI antipsychotic franchise. Starting with UZEDY. Obviously doing quite well. I think you took up guidance earlier this year. I wanted to dive into the commercial dynamics surrounding UZEDY. Can you talk to the patient mix in terms of switchers from oral risperidone or switchers from other oral atypicals and maybe switchers from other LAI products? Just wanted to get a good flavor for where you're getting the most traction.
Yeah. It's a great question. And UZEDY has been one of those products that we have been really leaning into and delighted with the performance. I mean, Q3 as a surrogate for what we think is possible. We had 119% TRX growth year- over- year. It's extraordinary. And so where are we getting those patients? Mostly from oral, some from oral risperidone, some naive that haven't been on treatment, which is also pretty amazing. And then switches from other LAIs, including paliperidone. So it's kind of a combination mostly from oral at this stage. But what I think is unique about UZEDY, and you're welcome to speak to this as well, is because the product profile is so significantly different and better that as physicians are getting experience from a risperidone perspective, they're looking for other applications because the patients are happier.
They get to an efficacious dose within 24 hours, and these are some of the things, the gateways that prevent physicians going earlier to LAIs, and so when you address some of those things, it becomes a much broader appetite to use UZEDY more often and prolifically.
Yeah. It's just easy to use. I mean, it's subcutaneous. No oral supplementation. Gets you a rapid dose. No titration. Pre-filled syringe. Room temperature. I mean, it's about as easy as you can get. Yeah.
So that brings me to the approval in bipolar for UZEDY. How are you thinking about the potential impact of that label expansion? I think when we in the financial community think of LAIs, we think of primarily a schizophrenia market because there's such obvious compliance challenges. Bipolar doesn't get as much attention. But how should we contextualize that opportunity?
Yeah. I mean, I think bipolar is a meaningful advancement, I think. To have UZEDY benefiting from all the things that Eric just said is super important. I think contextualizing it from a revenue perspective, it's not going to be significant. From the fact of having another option, we think it's really important both for physicians and patients. Quite frankly, from our vantage point, also from advancing our leadership position in this space. People will then more broadly use UZEDY appropriately, and especially given that we have the indication now.
Yeah. And so there's LAI olanzapine. And obviously, that's sort of the next leg of the LAI antipsychotic story. So just at a high level, just how are you thinking about the opportunity here? Obviously, there's a lot of oral olanzapine volumes here. So I guess with that in mind, as you slice and dice this oral olanzapine market, and I realize that's not just the market here for LAI olanzapine, but that's a good starting point, at least. What portion of that oral olanzapine market do you think could be appropriate for switching to the LAI olanzapine products?
Yeah. It's a great question. And listen, we've done a lot of market research on it. Olanzapine, as you know, as a molecule, is really widely known. Physicians have a point of view on it and like it. About 20% of the orals currently in the U.S. are olanzapine, 30% in Europe. So it's not just a big opportunity in the U.S., but also globally. And physicians know this product. They like it. So we think at the start, for sure, the pent-up demand will be from oral to LAI. But I also think that physicians are thinking about it from the type of patient that presents and does really well on olanzapine. And what we've heard back is typically people that present with aggression or agitation do really well. And so you can imagine that an LAI in that setting would be particularly meaningful.
We feel it's an important advancement to now have a portfolio and have a wholesome view of UZEDY for those more mild, moderate patients, and then olanzapine for patients that are a little bit further down the continuum or present with different symptoms.
Got it. And do you expect eventually for LAI olanzapine, like you had with UZEDY, potential expansion into bipolar as well?
Yeah. That's definitely something we can do. In that case, we'd be running a study to do it, but that's certainly on the radar.
Okay. Just a clarification question. My understanding is with LAI olanzapine, you'd be able to leverage your existing commercial infrastructure focused on UZEDY. So as we think about sales force expansion, and this is a broader question about the CNS business, what is the extent to which additional commercial infrastructure expansion will be needed, whether it's for Ajovy, AUSTEDO, the LAIs? How do we think about that?
So you're right. We will absolutely be able to leverage our infrastructure and probably more importantly, our learnings and insights from UZEDY because this is a very complicated disease state in the context that, particularly in the U.S., patients get treated in a whole host of settings, whether it's hospital, kind of your brick-and-mortar office, physician's office, or an acute care kind of setting where they've had an incident. So our understanding certainly set this up to launch well for olanzapine. We have been continuously adding resources. I mean, since I've gotten here, which has been about two years across the whole continuum. So we're now in a place across AUSTEDO, UZEDY, in advance of launch of olanzapine, certainly with Ajovy as well, that we have a really solid footprint and we cover most of the opportunity. So I imagine we'll, around the edges, continue to tweak that.
But we're ready and prepared.
Okay. I want to spend the next few minutes talking about Duvakitug. So now that it's moving into phase III, that's certainly an exciting development. So you did provide on your last set of slides on the third quarter call, just I guess in broad strokes, the design of your phase IIIs in Crohn's and ulcerative colitis. So wanted to just get a refresher on the design in UC and Crohn's. And then I have a few follow-ups. Yeah.
Yeah. So we're very excited about it. With our partner, Sanofi, we're in the phase III now, fully initiated in both ulcerative colitis and Crohn's disease. It's called SUNSCAPE and STARSCAPE are the studies. I should start off by saying we were the fastest to go from phase II to phase III in this class of new molecules. Our study design, I think there's a lot of great elements in the design that I think are important to remember. First, two studies are 1,000 patients each. But it's about execution and patient centricity in these studies where we have an open-label feeder arm, which is really conducive to fast enrollment because people know they get on drug, and then we'll start the randomization part. So that's one good component. Second component is a re-randomized design.
So it's more reflective of clinical practice in the way that we assess patients after the induction dose. And then finally, the entire program is SubQ. The loading dose is SubQ. The induction is SubQ. And the maintenance is all subcutaneously given. So it's designed for speed and around the patient's needs about running it. So I'm really all in about execution. So having a well-designed study, going into a study with data from our phase II study, we posted the highest numbers from a phase II study in both ulcerative colitis and Crohn's disease. Both studies were well controlled and very well run with a nice dose response. So I'm really excited about it. I think it's a great well-designed program with a great execution plan.
Just to be clear, you're not in a position to disclose the specific doses?
No. No. We won't do that until we present the data.
All right.
Good try, though.
That's a good try. Got to ask the question. So you do have in your design a re-randomization of responders. And I wanted to get your thoughts, Eric, on the rationale for incorporating that into the pivotals.
Yeah. I mean, it's common to do it either as a treat through or as a re-randomization. I think one of the best things about re-randomization is, like I mentioned, it kind of more reflects clinical practice. Instead of just treating people who are non-responding on an arm for an entire year, you hit to a certain point, either you're responding or you're not, and then you get re-randomized. So in a way, it's more reflective of clinical practice. It's not completely the same, but it's a little bit easier and better for the patient.
Okay. So there's obviously a number of TL1As that are in development. And so you're competing with other investigational agents here. And also not just TL1As, other targets as well. So can you talk to your strategies to drive a reasonably timely pace of study enrollment? I mean, you're competing for patients. There are a lot of patients out there. But how do we think about that? And what are you trying to do here?
Yeah. So I'm fairly competitive in my thinking. We have the most potent TL1A. We've compared these things head- to- head and in vitro. We have the most selective. And we probably have the lowest anti-drug antibodies. We've had about a 3%-5% rate. So the fundamentals of our molecule are there. And we did a great job in phase II. The results were really, I think, competitive for sure. And our deltas were the highest reported in this class so far in the phase II study. So we're going into the studies very well. I mentioned a lot of great things about our phase III study about its patient-centric design and the way that we want to execute it quickly. Going into the study with good data is always good.
I think looking forward, differentiating, it's a brand new class of molecule that will potentially treat things beyond ulcerative colitis and Crohn's disease. But I think that having this option for patients who normally fail, only 50% of patients succeed to get clinical remission. Only 50% of those actually stay on a drug after one or two years. So these patients need options. So a whole new class is going to be very important. And I think the data hopefully will show that it's very competitive.
Yeah. So I wanted to ask more of a commercial question. So the IL-23s are gaining a wider and wider foothold as sort of a frontline advanced therapy option in both Crohn's and ulcerative colitis. So I guess my question here is, where do you think the TL1As more broadly would fit within the UC and Crohn's armamentarium? Do you see a place alongside, say, the IL-23s, perhaps ahead of a Rinvoq, or even on top of an IL-23 to confer additive efficacy? And I know different competitors in the space have different views. But where do you kind of come down on this?
Yeah. So a couple of thoughts there. So first, efficacy is king. We've got some great induction data right now, which I think is very competitive across the actual landscape. Safety also is huge. Other molecules have either black box warnings or some monitoring requirements for LFTs. Right now, the safety on these anti-TL1As where you're blocking an amplifier, it looks pretty good. We'll have to see what the phase 3 data shows. But efficacy, particularly not only on the induction, but what will hopefully show in the first half of next year when we get the data for the long-term follow-up, durability. Because remember, I mentioned 50% only get treatment remission. Another 50% don't stay on the drugs because of failure. So the durability response, I think, will be important.
Yeah. Any thoughts on potential evaluation of Duvakitug outside of IBD? I know you've talked about it before, but your competitors are casting a pretty wide net. So where do you envision development outside of IBD?
Yeah. So the options are so broad, you have to be thoughtful about how you do this. We bucketed it into three different ones: T2 class, non-T2 inflammatory responses, and fibrotic. So there's so much you have to be really careful. So we're going to choose an indication that unlocks each one of those categories, and then we'll expand on it. We'll choose indications that are obviously important for patients for unmet medical need and has a great opportunity and a speed to it. So I'm not going to tell you what they are today because we'll announce that once we've started the studies. But that's how we're thinking about it more broadly.
You think we'll have a better sense in 2026?
I think 2026 we'll know a lot more. The one thing I'd add to this discussion is it's great that we have data showing that it has great anti-inflammatory activity. The real upside is it has a direct anti-fibrotic effect. That's a differentiator for this class on top of everything else.
Yeah. For sure. I wanted to stick with immunology. And at your capital markets, I thought this was really intriguing. You cited a TSLP IL-13 directed therapy that's, I know, it's early, it's preclinical, but any update here or how to think about the progression of that program? And Sanofi has its own TSLP IL-13 in asthma, I think atopic derm, nasal polyps. So also a lot of white space here. How do you think about that molecule?
Yeah. The TSLP IL-13 molecule is one that kind of illustrates the strategy. We picked known science, put them together with high POS. So that was the one that we worked with Biolojic Design. We used AI to create an entirely novel molecule that can bind TSLP or IL-13 turn on each arm of the antibody. So it's something you couldn't even make in a mouse. The labs at Teva, though, then took that molecule and made it better. So we have a molecule with known science. There's some good POC data in asthma right now. But we've created a molecule that's easily manufacturable. We'll have probably a low anti-drug antibody level, but really can build on some great science rapidly. So we've started the pre-IND work at this point.
We're targeting an IND submission at the end of this year, and we'll move as quickly as possible with known indications that you already outlined. It's going to be pretty straightforward.
Okay. Helpful. So a couple of minutes we have left, just some additional pipeline questions. The ICS-SABA combination product, just remind us when we could see phase III data for that. And also, this is an evolving market given the GINA guidelines recommending dual-action inhalation treatment. So how should we think about the evolution of this market and ICS-SABA product?
Yeah. So this is another great phase 3 program we've got going. Enrollment's going very well. We'll be finishing up our targeted enrollment at the end of this year. We'll actually probably over-enroll to speed it up a little bit on the back end. And it's an event-driven study. So we can only predict that we'll probably have the final exacerbations by the end of 2026. So we're looking at early 2027, a readout. But getting back to the opportunity here, this is an asthma indication for an indication that you mentioned the GINA guidelines. We're going into an indication that already has the GINA guidelines asking for it. So I'm not going to try to change anything. I'm trying to answer the question. So we're going to bring in a combination product, a dry powder inhaler, very easy to use, no spacer.
We'll probably have the largest sampling of pediatrics and adolescents ever. We'll get that 25% in our label right at the beginning, going into a market that is big and meaningful.
Okay. And then last question. I wanted to make sure covered that as well. I think you've cited the potential for an accelerated pathway and multiple system atrophy. So you've got a phase two that's ongoing. Does that imply that that phase two could be a registration quality study?
Yeah. It starts with the indication of multiple system atrophy. It's a devastating disease. This is a molecule that's differentiated from others. It's a small molecule that penetrates into the brain cells and can really attack the alpha-synuclein at its very beginning. So it hits the intracellular, the extracellular expression of it. And if you see an effect in this indication, yes, I would be the first one to say that we should look for an accelerated approval on that. And the study is enrolling very rapidly right now, so that's good.
Terrific. Well, thanks so much for your time, Eric and Chris, and thanks to everyone in the audience.
Great.
Thank you very much.