Jazz Pharmaceuticals Plc Aktie

Hello everyone. I really appreciate it. I hope the morning is extremely well. My name is Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. This is day 1 of at least the public portion of our New York City Healthcare Conference. Very pleased to have Jazz Pharmaceuticals, one of our high conviction bets in biotech and a company that I think is really at a point where they're seeing a transition to becoming really a full-fledged biotech story scaling and I think something that investors should be paying attention to. Rob, why don't I hand it off to you to give some introductory remarks, and then we'll get started with Q&A.

Thanks, Akash, for having us. And just a quick comment that Rob and I will be making some forward-looking statements today. So please do refer to our risk factors in our SEC documents and any guidance we refer to as our first quarter guidance that we provided.

Yes, Akash, thank you for having us. I don't have any introductory comments. Happy to get right into your questions.

I love it. All right. So look, I think this is a question that I think I'll often hear from investors, which is, I haven't looked at Jazz in 5, 10 years. Remember, they had some sleep drug. Has the story changed? And it's kind of remarkable to me because you've done the GW transaction, you have $1 billion oncology franchise, even ex the Ziihera acquisition. And yet I think intellectually, a lot of investors who haven't seen your story recently, still think about sodium oxybate as kind of the primary focus.

So this question is really like the Jazz of the last 20 years doesn't need to be the Jazz of the next 10 to 15. So when you think about your investment and your interest, whether it's in rare oncology, orphan, neuroscience or just wholesale Ziihera development, what's that mix in the next 5, 10 years for you as Chief Medical Officer versus what we've seen historically? What are investors getting wrong?

Yes. Thanks for the question. So for me, I started 7 years ago, this was my eighth ASCO as Jazz CMO and Head of R&D. When I started, as you said, we had some important products in oncology, niche products like Defitelio at the time, Erwinaze and Vyxeos and we had Xyrem, not yet Xywav and I came to Jazz really to build an innovative biopharma company and really expand R&D out so that we could be doing development in innovative areas from the very beginning of research through medical affairs.

And to your point, Akash, I think we've been even more successful than I thought we might have. We've done some very important things internally. So developed Xywav in-house as a safer oxybate for patients with narcolepsy and then extended its label in idiopathic hypersomnia, addressed a critical need for Erwinaze where there were drug shortages by developing in-house, a novel manufacturing process that gave us Rylaze and then began to build the pipeline around core competencies in new areas to diversify our business ultimately, and some notable things there.

One of the earliest oncology deals we did was for Zepzelca. That was intended to be a second-line product for small cell lung cancer. We had the vision of saying this really could be used in frontline maintenance. And that was something that had never been done in small cell lung cancer before because those patients have a pretty rough induction with chemotherapy and typically need a break. We -- because Zepzelca is well tolerated, we were able to weave that into a maintenance study, did that in partnership with Genentech and of course, now have a frontline label there.

Interesting data at ASCO this year showing that it's having a benefit even in patients with an immunosuppressed phenotype, so-called tumor-associated macrophage high. And really positioned well in that front line.

We, of course, brought zanidatamab in on the basis of biliary tract data, saw that through an approval executed on the frontline GEA study, which we're pleased is the first ever Jazz New England Journal of Medicine paper published last Thursday, I think definitively showing that this should be the HER2 agent of choice in frontline chemo and should be combined with PD-1 antagonist.

And so I think we've been able to diversify and get into new areas in oncology. Of course, there was the Chimerix acquisition last summer, and Modeyso is off to a terrific start as a pediatric oncologist to see that we now have a treatment option for these patients is amazing and very excited to see that action could bring that into the frontline.

Of course, a major transformative deal for us was the GW Pharma deal where we brought in what's now the largest grossing epilepsy drug in Epidiolex and importantly, created for us an in-house expertise from research, literally discovery chemistry through commercial in epilepsy, we're now leveraging. We announced we have JZP-047, which is an in-house invented, discovered molecule for absence epilepsy, and we've positioned ourselves as a real partner for choice in a rapidly expanding epilepsy field with new opportunities coming from our improved understanding of genetics and epilepsy. So deals like Saniona and others that I think we will be well positioned to be a partner of choice for it.

So in those, as you say, 5 to 10 years, I think we've shown that we know where to focus, we can select good deals for partnerships, we're discovering and developing molecules in-house. And we're executing well, not only on the commercial side, but when we have an opportunity like zani in GEA, we can go from data to a final submission in essentially 3 months.

Understood. One thing I do want to kind of close the loop on -- it's interesting, I cover Lilly, and certainly, I think their perspective on orexins and the importance of really modulating cognition and sleep is far more broad than just, let's say, an orphan market. We think about ADHD or 25% of patients with Alzheimer's suffer from somnolence, right? And I do think there's probably going to be that wider perspective. I know your team has been working on your own internal orexin programs that have had some safety issues in the past.

But it does seem like you may need different PK and you may need a different product profile. You're not thinking about just MWT, it measured 4x to have coverage in these other indications. So can you talk about your long-term approach in the view with what we're seeing with orexin biology.

Yes. Thanks for the question, and I think great insights about where the field is going and what the optimal molecule might be. So it's interesting. We certainly started by saying we're very interested in this because the early data showed it's a very potent wake-promoting agent, but also that it's likely to be complementary to Xyrem. It's not likely to improve disrupted nighttime sleep. And in patients with narcolepsy type 1 or type 2, idiopathic hypersomnia, the root cause is disrupted nighttime sleep. And there's no wake-promoting agent that can address that, and it's certainly not the case for orexins.

So we started to talk about that. And I think now that's taken more as a given. Your point also that whether you're talking about hypersomnias or other potential applications, it does matter the clinical pharmacology and the PK profile. And so for us, -- we think there's an opportunity still to have a best in class.

What we've seen so far is drugs that have a long enough half-life or even on that first day, you're seeing reports of insomnia. And to your point, NT1 is very, very sensitive to these agents because of the loss of orexin neurons and the massive upregulation that happens with orexin-2 receptors very, very sensitive. But what you get into other hypersomnias or diseases like ADHD or cognition in Alzheimer's disease, you're going to need to push that dose. And you're going to need to be able to do that and still have the exposure come down at night so that you don't disrupt sleep in any of those conditions, which would be counterproductive.

And I saw this when I was working at Merck on the H3 inverse agonist programs, where we had 5, none of which progressed all for the same reason. The half-life is just too long. And so we did -- with the Sumitomo collaboration, we did have a molecule that was in the clinic that failed due to safety reasons. We do have a backup compound that's preclinical that we hope to comment further on in the near future. And it's our aspiration to have a compound that's differentiated in many ways, inclusive of a more suitable half-life across indications.

So I do think there's time. Remember, the first approval is NT1 only. We still haven't seen any data even in other hypersomnia. Plenty of opportunity for the field.

Understood. Now maybe getting into Ziihera development, and I'll give you kind of a near-term question first, which is really the label that you expect with Ziihera. And the question we'll often get is like could there be a narrow label in ICH 2+ versus 3+. I mean, I have my own view given your clinical data, but I'd love to get your take, how should investors think about the label you'll be getting with your PDUFA date?

We wouldn't comment on specific label negotiations, and it's still early enough in the process that, that will pay out. I'll tell you my view of what I think the label should be. And I think that starts with what do we think we've proven with this clinical trial. So the clinical trial, first and foremost, was a test of zani versus Herceptin. And definitively, no matter how you measure that, we believe, Zani replaces Herceptin. I think there's a role in most of the -- really every GI oncologist, I speak to says that trastuzumab is a historical regimen here. The second question, even though it wasn't powered was, does trastuzumab as a PD-1 inhibitor had benefit.

I think those results are also clear. And not surprisingly to me, even though it might have been a surprise to others, we see benefit in the PD-L1 negative patients, which is notable because the prior studies with KEYTRUDA in HER2 positive and negative and nivolumab, atezolizumab in the HER2 negative populations, none of them showed benefit in PD-L1 negative. And we think this is because of the differentiated mechanism of action for zanidatamab, which is highly immune active. It's the only antibody that fixes complement and activates the complement cascade and also triggers ADCC and ADCP.

So you have this massive recruitment of NK cells and macrophages, causing inflammation at the tumor site and synergizing with immunotherapy.

So we think that is the new standard of care, the triplet. And your question about what to expect from the label? I expect both drugs to be approved. And I also expect it to be -- well, let me say this. I think the data support, because I can't speak for the FDA, the data support that both drugs will be approved, the data support its use irrespective of PD-L1 status.

And you asked specifically about IHC 3+ and 2+. Here, we have a trial where the great majority of patients, more than 80% were 3+, so a very small subset. And when we look at that subset of IHC 2+, the surprising results of the IHC 2+ overperforming, I think, can be easily explained by small sample size variation and then some compounding factors there. And we certainly are positioning it that way with FDA.

Understood.

Ultimately, if it's somehow the label is not inclusive of 2+, I think the data and information are out there in a meaningful way that docs understand that Zani is superior to Herceptin regardless of 3+ or 2+.

Understood. And that's something I think we hear with our KOL work is that biological questions has been seemingly answered. This is better than Herceptin.

Now when we think about really uptake, and I know you're not on the commercial side, but I can't help but think this is something where you've shown a clear benefit over standard of care. This is a well-defined patient population. And you have kind of pretty robust clinical data. When you think about your time at Merck and how fast KEYTRUDA uptake was in some of these indications, how should we be thinking about that for Jazz here in first-line GEA?

Yes. And this is the first study to show median survivals over 2 years. Over 24 months for Arm B and over 26 months for Arm C, we think it's definitively better, and we're acting with a great deal of urgency and so is the FDA. So we had data end of November, and our submission was complete even with the intervening holiday by the end of February. And so we're moving with great speed. The FDA gave us RTOR, which meant we were able to give them data ahead of the final -- ahead of finalizing the submission. They gave us breakthrough designation and priority review. So I also see them moving with speed.

We had submitted to NCCN based on the abstract, even knowing that NCCN typically likes to have the full publication, but we wanted to get them thinking about it at least. And as soon as we had the publication in New England Journal last week, we've updated it. And so the situation -- I won't speak to the commercial because that's not my expertise. But we're approved in BTC. These are the same doctors who are treating GEA. So we're on formularies. They have the drug in their hands. They know how to use it. This is a tight community. They're super excited about the results. You certainly appreciated that at the recent ASCO meeting. We hope NCCN acts quickly, and we feel the FDA should act on it before the PDUFA date based on where we are.

Okay. Very interesting. Now -- and then maybe just lastly, couple -- 2 other points on this. Number one, I know for the doublet, there's a potential other -- another OS interim that's occurring. Can you kind of frame expectations? You've already hit on OS on the triplet. What are your expectations for that second interim? Roughly when would that occur? And is that something we should expect a positive interim OS?

Yes. So first of all, the survival data are not needed for approval in the U.S., especially given the magnitude of the PFS benefit. But we also have an interim look at survival, even though Arm C and A was "statsig" and Arm B versus A was not statsig. Statistical significance has also to do with how much alpha you put against that. And this was the first of 3 survival analysis. So we clearly didn't put much alpha against it.

But still, we have the opportunity to see the data to see the magnitude of benefit, which was the median more than 24 months versus less than 20 months. And the precision around that, given the large size of the study and the number of the events, I think this is convincingly having a survival benefit even if it wasn't "statsig " at this first interim. And I believe the FDA appreciates that as well.

We do have a second interim that is still expected midyear this year. Will that come before the approval? In a sense, I hope not because I want the approval to come as quickly as possible. If it does come before the approval, we'll try to work it in. If it doesn't, there is a mechanism for a rapid update to the label through what's called a post-approval supplement -- label supplement. So we'll get the data out there as soon as we can and update the FDA as well.

But -- and just to be clear, I know, obviously, we have to see what the data plays out. Let's put 2 points on that. A, it seems like you're extremely confident that this will show an OS benefit, whether it's in the second or third interim. But b, it does seem like you're also reasonably confident, and I am putting words in your mouth, literally, so agree or disagree that you could potentially show that benefit in that second interim.

I think there's a -- we do our own probability calculations, which I don't necessarily share. But I would say it's still an interim. The biggest amount of alphas that's final, and that also is contributed to by the fact that you have more events. And so overall, you have more power. But I think there's a meaningful opportunity here where we wouldn't be doing it.

But I think the more important point is I'm not sure statsig is the important issue because from a statistics perspective, I look at the point estimate and the confidence bounds around that, and that tells me the precision of that estimate, and it's clear there's a survival benefit even after the first interim.

Understood. Now Rob, you previously at Merck, which you alluded to. And I think it's funny. We talk so much about the PD-1 VEGFs and this idea that, hey, wherever KEYTRUDA worked, we're going to replace that with a VEGF bispecific. But no one really says, "Hey, let's look at wherever Herceptin worked and why is zani there?" Or at least that discussion doesn't happen enough. And I think part of bridging into that -- when you really look at how KEYTRUDA makes -- generates revenue, I think there's a shockingly high amount, which is in a maintenance setting, which is neoadjuvant post resection.

And I don't think that's well appreciated by the Street. And you're actually developing that kind of adjuvant strategy with zani. And can you talk a bit about that? Like what are those big readouts you have? And what are the sizes of those adjuvant opportunities relative to, let's say, first-line GEA, where I think investors think about this as like, let's say, $1 billion, $1.5 billion opportunity?

Yes, that's a great question. And we are thinking about it that way. Now that we have head-to-head data with Herceptin, wherever Herceptin is the backbone, we think zani could do better. So I definitely think -- and by the way, -- there are places where Herceptin wasn't quite good enough to ultimately get a foothold where we also think. So that -- the example there is frontline BTC. No approved HER2 therapy. The strength of the data we have in second-line BTC suggests that our ongoing frontline trial has a high probability of success, especially since it's combined within immunotherapy.

So the lessons from 301, as you say, anywhere where Herceptin goes, we should be able to compete. But also, we think we're triggering a synergy, as I explained before. So the opportunity to combine with the PD-L1 may create synergies. So again, that frontline BTC trial bodes well.

To your point, though, on neoadjuvant-adjuvant setting, zani is especially well suited for that because remember, this is often a curative setting. So you want well-tolerated drugs that can contribute not only to the cure, but also to the overall tolerability of the regimen. So in the breast cancer space, we think we have an opportunity there.

It's a little bit crowded, and it certainly is a little bit complicated when you look at various subtypes, ER positive or negative or the various molecular subtypes, which is why we're starting with a Phase II. So we have our own Phase II in that setting as well as partnering with I-SPY and MD Anderson to generate additional data. And we do hope that on the back end of that, we will have an opportunity to do a pivotal trial in that setting, and that would be very valuable.

I want to come back to maybe other opportunities in breast cancer as well, but you asked specifically about neoadjuvant. So while we haven't committed to a neoadjuvant-adjuvant trial in the gastric space, if you're using the same principle you raised, which is wherever Herceptin is alone or hasn't yet had a foothold and wherever you can combine with immunotherapy, now we see how active it is in gastric, that's a logical place for us to explore as well. I want to make sure you get all your questions, but I'm also happy to talk about at some point, the rest of the development program, where we might go in breast cancer from here, other indications.

Yes. I mean actually, I do want to hit on kind of post in HER2 and talk to us about why you're so confident that, that study will be successful. Because again, I think a lot of people haven't done work on that study, that's reading out next year. That's 2027, a cost problem. But this seems like the next big revenue driver for Ziihera. What's the biology showing that makes you confident that, that trial is going to work? And how is kind of Herceptin and Perjeta done in a similar setting so far? Because I know a lot of people looked at the JACOB study and some of these prior trials with GEA and applied it, but zani obviously outperformed. What's the precedent here in a post-Enhertu trial?

Yes. So -- and again, as the principal you raised, which I think is very insightful, if Herceptin is the standard, you should be able to beat it. And so that is the premise of 303 is -- this is against Herceptin. Patients come in, they are assigned their chemotherapy, they get randomized to zani versus Herceptin.

A couple of important things around why that might work. We do have data with zanidatamab in a couple of different places, a late-line monotherapy study, combination with anti-CD47 and in the ER-positive group combo with fulvestrant and palbociclib, showing that we have activity after multiple prior HER2 agents, inclusive of growing data showing activity after Enhertu. And that makes sense because while there can be some mutations that occur that make cancers resistant to HER2 agents, broadly, typically, the resistance mechanism for Enhertu is resistance to the chemotherapy to the topo ones. So that's why we think there's a rationale to use it there.

The other rationale to study it for this to be the first major study we've done in breast cancer is how the treatment landscape is evolving. So you mentioned like what happens to CLEOPATRA. CLEOPATRA is the frontline regimen now, Herceptin, Perjeta, taxane. Well, if Enhertu becomes entrenched in the front line, Enhertu is essentially Herceptin with a topo payload.

The study actually included Perjeta, so patients might be getting Herceptin Perjeta upfront. So what haven't they gotten by the time they get to second line? Well, they haven't gotten a taxane. And they haven't gotten other agents that -- they haven't gotten zani, obviously, but other agents that might synergize with zani.

So we've become very interested in best-in-class HER2 TKI, which is why we have the partnership with Boehringer and the partnership with Iambic to look at what should be best-in-class. So if you're in that setting, zani plus a TKI that may actually increase receptor expression and play right into the MOA for zani, that's a promising combination.

So clearly, we went to 303, which is at the moment, a third line, fourth line study because it's the highest unmet need and docs were saying, we don't know what to give in this setting. We're also interested in studying breast in other areas, as I mentioned, in the neoadjuvant-adjuvant. But I think there's -- pending the data that we're generating in our Phase Ibs, I think there's an opportunity to be in an earlier line even, which could be helpful because the frontline GEA saw the amazing effects in a naive population. You want to give your best therapies upfront. As you get to third and fourth line, that's a more challenging population to study. And just like for Zepzelca, where it's effective in second line, but much more effective in front line, you want to progress the drug earlier if you can.

So a couple of points on that. What is your general confidence for the Phase III trial you have in that kind of more refractory post Enhertu setting? Are you confident that trial is going to be successful? And then number two, you mentioned you have data sets that are emerging with HER2 TKIs. What patient populations are you running those combination approaches in that might inform a frontline strategy there?

Yes. So I mean, I wouldn't have started a pivotal trial in Jazz, if I wasn't confident. We started it before the GEA data. And given how well zani did against Herceptin in GEA it does give me even more confidence for the ongoing trial.

The initial evaluation of the 2 TKI programs, the zongertinib and the Iambic compound is in breast cancer. And I think that could -- these are both brain-penetrant molecules that could address the specific problem of brain mets.

So if you think about HER2CLIMB, which is tucatinib, Herceptin and pen chemotherapy, you have the opportunity to replace Herceptin with best-in-class and replace the tucatinib with the best-in-class, not only for efficacy but better tolerability because of the greater selectivity of the new TKIs. You could then be better positioned in a second line inclusive of -- true second line inclusive of patients with brain mets.

Understood. So this is a like you talked to Exelixis and they had to develop cabo and now they're having to develop zanza, not as large cap pharmaceutical companies, and it becomes this idea that, look, partnerships are not a nice to have, like they're necessary because we need to get entrenched with standard of care and also how the field evolves.

When you think about potential partnerships with pharma, where you split economics in certain indications, let's say, similar to CheckMate 9ER with Bristol and Exelixis, is that possible when we think about the broader opportunity for Ziihera? And what's your take about potentially combining Ziihera with a PD-1 VEGF?

Yes. Great questions. Looking at the clock. So I'm very open to these partnerships. In fact, I think the Genentech partnership on IMforte was fabulous for both companies. We both had expertise we brought to the table. We have both had molecules that made sense to put together. We collaborated on the execution. We shared the cost and it was sort of flawless.

What happens then in the commercial setting may depend a little bit. In the case of Zepzelca and atezo, we are collaborative, but it's not a formal arrangement. And I think we're both promoting and that's working out just fine. But there absolutely is more opportunity to do that, especially when you get into novel combinations, and so if you think about -- so we published in our Phase I, only 5 patients with non-small cell lung cancer, but we had activity there. Now those are the overexpressing patients. There is a separate population of non-small cell lung cancer where there's activating mutations. That's of interest too.

But in patients who overexpress HER2, we think we're going to be active. And so in the basket trial that we have ongoing, we are enrolling lung cancer patients. We'll get some additional data there. But the path there, which is much more open than the patients with activating mutations would be in combination with immunotherapy. And currently, that would be with a PD-1 inhibitor. But if you're thinking about skating to where the puck is going, so to speak, you would consider a novel immunotherapy that might be more effective. And so very open to partnership development in that kind of setting.

Are those potential announcements we could get this year about broader partnerships with Ziihera?

We're having lots of conversations about this, so possible. No commitments there. But we have a fair amount of inbound interest, and we have a clear idea of how we think this should be optimally developed. So we're having conversations where it makes sense. .

Understood. Last question for me sneak it in because I'm seeing in the same room. In terms of the basket trial and that pan-tumor trial, I think a lot of people look at it, they're like, okay, well, cool, they're running a dose-finding, signal finding study. And your team has been very insistent. No, no, no, there's a registrational path forward with this trial. Talk to me about what that disconnect is? What is -- and how are you going to be able to take that data set and actually go into the market and start a tumor trial.

Yes. And just so you know, we've had interactions with FDA, so we are clear what their expectations are. So we know what we have to do to get there. And it includes having a broad enough range of patients and having strong enough data. And so time will tell. We do have interim analysis where we can go back to them and check how we do in here, how many more patients team, et cetera.

Remember also it is -- you described it correctly. It's a basket trial, the goal of which is to get a tumor-agnostic indication. But the other goal is also signal finding. So we have colorectal cancer patients being enrolled there. We have non-small cell lung cancer patients being enrolled there, who would contribute to the agnostic indication, but might in and of themselves, ultimately get an accelerated approval. So it can be used for multi purposes.

Got it. We're out of time, but I really did enjoy the conversation. Thanks so much.

Hi, everyone. Good afternoon again, and thank you for joining us at the 2026 TD Cowen Biotech Oncology Innovation Summit. I'm Joe Thome, one of the biotech analysts here on the team at TD Cowen. It's my pleasure to have with me today 2 members of the Jazz Pharmaceuticals team. We have EVP Global Head of R&D and CMO, Rob Iannone. And we have the Head of Investor Relations, John Bluth. So thanks, guys, for joining us today. Maybe to kick things off...

Nice to see you, Joe.

Nice to see you here, both.

And Joe, just very quickly, a little housekeeping. Rob and I may make some forward-looking statements today. So please do refer to our SEC filings to reference those. We also may refer to earnings and guidance. If we do, we're referring to our most recent guidance as of our first quarter update, and the same is true of any non-GAAP financial measures we discuss. You'll find a reconciliation in our first quarter earnings report. Thanks, Joe, and happy to be here with you.

Yes. Maybe just to start things off, obviously, a lot of progress at Jazz over the past year. Maybe kind of if you want to give us a brief update on kind of what we've seen with the business, where we're headed? And maybe specifically over the next 3 to 5 years, where do you see the oncology business headed for Jazz?

John, would you like me to start? Or would you...

Yes. Rob, why don't you dive in there as the oncologist.

Sounds great. Thanks for the question. Incredibly exciting times for us at Jazz. This is now my seventh year at Jazz, and it's been quite a journey, building a pipeline, building R&D and increasingly having an important stake in oncology across a number of different programs. For zanidatamab, starting with the approval in second-line BTC. This was a major accomplishment. We also saw an approval in -- for Modeyso in high-grade glioma, an area of extremely high unmet need and also expansion of Zepzelca into the frontline for extensive stage small cell lung cancer, where we think Zepzelca will be the most impactful.

In terms of our pipeline beyond the most recent approvals, I would emphasize zanidatamab and the incredible opportunity that, that provides. You've seen the top line data for the GEA trial, frontline GEA trial. We're expecting publication in a top-tier journal, hopefully, in the very near future. And our process for submissions globally are underway. We have breakthrough designation in the U.S. as well as real-time oncology review and priority review, giving us a PDUFA date of August 25, and we are expecting approval on or before that date.

We are also expanding out in other areas for zanidatamab. We have a trial in later-line breast cancer post Enhertu, which is accruing very well. And we said expected to complete its accrual midyear next year with results as early as late 2027. We also have an opportunity from a basket trial that we're conducting with zanidatamab, where we potentially could get a pan-tumor or tumor-agnostic indication, and that continues to progress as well. An early pipeline also that continues to grow and progress. And so for oncology, really exciting times for us.

Great. Excellent. Well, maybe just because it's been such a large investor focus, we can start off with first-line GEA. I guess, first, I have to ask, are there any sort of updates on the progress of the regulatory review for frontline GEA? And maybe what's the team doing now to make sure that you're ready for a potential launch given that it is under RTOR and could essentially come any day?

Sure. Yes. So without commenting on details of regulatory interactions, which we don't do, there has been a steady flow of information that we have put into the public. We said we had RTOR and we -- if you back calculate from an August 25 PDUFA date for priority review, we would have completed that submission at the end of February with Real-Time Oncology Review. We would have had the opportunity to provide data sets ahead of that to enable the FDA's review.

Now we only had data through the end of November. So it was a pretty rapid, very proud of our team for so quickly mobilizing to get these critical data and information to the FDA. So we didn't have a lot of time in there. But nonetheless, we were able to leverage RTOR to facilitate even -- the FDA's review even ahead of our completing the submission at the end of February, which is what set the PDUFA date.

We were pleased to get breakthrough designation and of course, pleased to get priority review. So we think we're on track for an approval by or even ahead of that PDUFA date. [indiscernible] We're expecting a publication in a top-tier journal. And as soon as we have that publication, we will update NCCN, and there is a possibility of NCCN adoption even ahead of approval.

Great. And when we think about a potential label, maybe can you go into maybe some of the data specifics that give you confidence that you can get a broad PD-L1 positive and PD-L1 negative label? Is that your expectation? And maybe when you think about in a triplet regimen potential combination partner, do you think you'll be agnostic to combination partner in real-world practice? Or how will that kind of factor in when you think about the PD-1?

Well, let me start by just telling you what I think the data showed. The study was -- the experiment was designed to test head-to-head zanidatamab versus Herceptin. And those results are clear with zanidatamab definitively beat Herceptin, however you looked at the data, which endpoint you looked at and Herceptin really should be a historical regimen. And I think that's the most important thing.

For these patients, the first decision a doc faces is how do I address the HER2-driven disease. And now there's a new standard of care, I believe, with zanidatamab in frontline GEA. The next question is, would patients benefit from a PD-1 inhibitor. Lots of prior data with PD-1 inhibitors in gastric cancer broadly, clearly established, although only in the PD-L1 positive subgroup, all of the labels have that limitation of use in PD-L1 negative patients.

And certainly, in HER2-positive gastric cancer, KEYTRUDA demonstrated a benefit again in PD-L1 positive patients. So lots of prior data that a PD-1 inhibitor is effective in gastric cancer, HER2-positive or HER2 negative. And so this trial was designed to look at that as well, as you know, with the third experimental arm where we added tislelizumab. And I think the data are also definitive across PFS, landmarks as well as overall survival that adding a PD-1 inhibitor and tislelizumab in this case is adding benefit.

The study wasn't powered to show a difference between the 2 experimental arms, but it certainly is definitive when you look at Arm C with tislelizumab compared to Herceptin chemo with a 26-plus month median overall survival versus less than 20 months. So clear that tislelizumab is adding benefit. And importantly, in both populations, the PD-L1 positive or negative, I think the data are clear there. They contrast all prior data, and you might say, well, why would that be the case? How do you explain this?

We think the differentiated mechanism of action that zanidatamab has is explaining this. We know, as has been published in Nature Communications that the mechanism for zani is different than even giving the combination of 2 antibodies like Herceptin and Perjeta. And the reason is that zani binds to 2 different receptors.

Once the antibody binds to one receptor, the other open binding site can't reach around on the same receptor, it has to grab another receptor. And that causes receptor clustering, internalization. It also creates an opportunity importantly, for complement to be fixed and the complement cascade to be triggered. So that, in addition to a highly active Fc fragment, which recruits NK cells, so-called ADCC and recruits macrophages so-called ADCP, we think we're creating inflammation at the tumor site that then synergizes with tislelizumab.

So we think the data support a broad label around PD-1 or PD-L1. And ultimately, the study was done with tislelizumab. That's where we generated the data. I think there's a lot of information that PD-1s broadly work in gastric cancer. We are generating data as well through an investigator-initiated trial with KEYTRUDA as well. However, really no obstacle to using tislelizumab in this setting..

Great. And how large of an opportunity do you think the frontline GEA opportunity, I guess, is in the U.S. and ex U.S.? And maybe has that changed at all after you've seen the full data from the trial in your mind?

Well, our estimates are there are about 8,000 HER2-positive patients with GEA in the U.S. And sometimes those data could be refined. But I think importantly, because the results of the zanidatamab trial are so definitive, there's a real impetus for docs to ensure that they know the HER2 status of their patients, and they have the opportunity to give zanidatamab with tislelizumab or another PD-1 inhibitor.

We are -- you mentioned about are you ready to launch? I'm sorry, I didn't answer that question when you mentioned it earlier, but we certainly are ready to launch by the time we get approval. And there are a number of things that have facilitated that. As you know, we're approved in second-line biliary tract cancer -- zanidatamab is approved in second-line biliary tract cancer. These are the same community and academic treaters as gastric cancer.

And so we're already out there in the market. We have the opportunity for an early NCCN adoption. And we are already able with our MSL force, we're obviously not promoting, but we're able to do critical education that's necessary to sort of prepare for the launch. So we do feel confident that it's going to be a strong launch.

Maybe on that, how rapid, I guess, do you expect the launch to be? Is it going to kind of roll out at physicians at targeted centers first before expanding? Or kind of how do you think this will be incorporated in terms of that? And second, the company does a really good job at kind of breaking out the narcolepsy and IH population with Xywav and you can kind of see the contributions from each indication in that therapy. Is that possible with Ziihera where you'll be able to see this portion is BTC, this portion is GEA? Or how will we know how the launch is going?

Yes. I'll be careful to stay in my swim lane, so to speak. As the R&D guy, I won't comment on things that I'm not familiar with. John may be able to help me out there. So again, it's not I'm not in a position to comment on the projected speed of adoption. But I'll just reiterate that the data is the first time we've seen survival data over 2 years with a median of over 2 years.

And this is a very poor prognosis disease. Half the patients don't make it to second line. And so we certainly will be out there with our medical affairs group, educating on the importance of doing the testing and adopting this therapy in frontline to Zanidatamab with a PD-1 inhibitor in order to ensure the best outcomes for patients.

And I think one thing that facilitates that, as I mentioned, is the data are consistent across PD-L1 subgroups. So there's no need to wait for that test result to come back to make a treatment.

And Joe, in terms of differentiating BTC sales from GEA sales, they are different dosing regimens, but the GEA population is much larger. So we expect the growth that we see in Ziihera to be really driven by GEA uptake. It's very hard for us -- Rob mentioned the overlap between the physicians. So it's hard for us to see sort of differences in prescriptions, BTC versus GEA. We'd expect it to be driven by GEA and really revenue is the biggest metric to look at as we start to see the launch unfold.

Perfect. And maybe we'll turn over to the breast cancer indication. I guess, can you just highlight a little bit what gave you the excitement to go into the breast cancer study? And relatedly, with GEA, it was pretty "easy" to kind of guess what the comparator arm was going to do because we had a couple of trials to go off of. Post Enhertu in the breast cancer setting, I think data is still kind of developing there. What do you think the comparator arm is going to show? Or kind of what did you power the trial for that comparator arm in breast cancer?

Yes. So just to start with, why go into breast cancer? Well, especially as we turned over more and more cards and that started with the second-line BTC trial that led to the approval, additional data in breast cancer, frontline, later line with chemo, combination with novel agents like CD47, combination with non-chemotherapy agents in the ER-positive group, all of this has been published with palbociclib and fulvestrant, for example, demonstrating that there's activity despite the fact that patients would have received multiple prior HER2 therapies, sometimes including not only Herceptin and Perjeta, but then T-DM1, possibly tucatinib and in many cases, Enhertu.

So the differentiated mechanism of action, giving us confidence that it would be active even in later-line breast cancer. We also saw an emerging gap in the data as Enhertu moved to frontline and many breast cancer oncologists approached us about this to say, as Enhertu gets to the front line, there will be a gap in the data as to what to use. And you alluded to the fact that how do you know how trastuzumab will perform in this setting because the treatment landscape has evolved.

And the fact is that we had to make some assumptions, but it probably is evolving. And over time, we'll have more data to substantiate that. So this was an opportunity for us to get into that later line post Enhertu space as an initial foray into breast cancer, not necessarily the only thing that we'll do in breast cancer, especially as we gain conviction around the molecule. And specifically to your point, we -- I won't say what our protocol assumptions were. We tend not to share that level of detail. However, we use the data that are out there, and we do recognize that, that's probably evolving as we see real-world databases coming out post Enhertu.

And maybe to wrap up the zanidatamab part of the discussion, the company historically had put out this sort of $2 billion potential for the asset. I guess now that we have more clinical trial data, I guess, when do you think the company might be in a place to revisit that number? Or do you think that's still the right number when you include BTC GEA and breast cancer? I guess how do you see that kind of peak potential evolving?

I'll stay with my pattern of giving all the hard questions to John. Maybe I'll start and just describe how I see the zanidatamab development program evolving, say, from the time we first made that statement, which was actually a $2 billion-plus statement. So a lot has happened in terms of data that we've generated. We've now been in the marketplace with BTC, and we're confident that it's performing the way you'd expect based on the data.

Our frontline BTC trial is progressing as planned. As John pointed out, that's a smaller population, but very important. For frontline BTC patients, again, many of them don't make it to second line. There's no approved HER2 therapy. So our experiment is versus nothing. And it's in combination with a PD-1 or a PD-L1 inhibitor. And we now know, as we discussed earlier, from the GEA trial that we're clearly seeing synergy.

So in an opportunity where you're against no other HER2 agent and you have the opportunity to synergize with immune therapy, we think that's a high probability of success trial, and that will expand our markets in BTC frontline and hopefully change practice around identifying those patients early.

We then saw the GEA data, which we've talked about. I'll speak for myself. I was optimistic about a positive trial outcome. I think this even exceeded what I might have predicted at this first interim for an overall survival. So the PFS benefit was substantial across both arms. The overall survival benefit was substantial. Of course, it was only the triple that was stat sig. But remember, stat sig is a function of how much alpha you put against it, and we only put a small amount of alpha as the first interim.

So Arm B still showed over 24 months median survival compared to less than 20 months. So I think the results are definitive. And I think that probably drives the level of enthusiasm, plus the idea that now this is the whole population in combination with a PD-1 inhibitor, where you would expect the duration of therapy to be longer. We've seen that in the trial. So I think we could be sanguine about the opportunity in frontline GEA.

Rising tide lifts all boats, as they say. And certainly, as you accumulate data and you gain confidence and conviction about the drug, then I think it increases your confidence in other areas. So breast cancer is the next area that's very important to us. We talked about the trial that's ongoing. You and other listeners may be aware that we're very interested in early breast cancer. We have a collaboration with I-SPY, collaboration with MD Anderson, and we have our own ongoing trial, which is a Phase II. And we hope that, that will ultimately lead to a Phase III in the neoadjuvant space.

Speaking of neoadjuvant. While we haven't made any definitive plans here, we certainly are interested in are there other areas of gastric cancer where Ziihera might be used. Again, early gastric cancer, no approved HER2 therapy. We now see that Imfinzi is approved there, very similar to frontline BTC where we would be against nothing in combination, possibly synergizing PD-1.

And then back to breast cancer, I think there's other areas we could explore. We have a partnership with Boehringer. We have a partnership with Iambic. As we see these novel TKIs come up and seem to be differentiated, good evidence that the combination of an antibody like zanidatamab with TKI could be also synergistic. TKIs tend to raise the expression level, plays right into zani's mechanism of action around clustering and immune activation.

So we see that combination potentially being studied in other breast cancer setting as well. And we'll see as the Phase II data emerge, what we'll be able to do there. I think that combination could be relevant in other settings as well. We touched on the basket trial. That's important for a couple of reasons. It is an opportunity to get a tumor-agnostic indication, which we know is possible in this area of HER2-positive disease.

It's also giving us a chance to further explore tumor types like colorectal cancer, non-small cell lung cancer, for which we had some prior data, but we're looking to extend our observation and understand whether we could get into those areas as well. We published frontline data at ESMO for colorectal cancer. We had previously published later line monotherapy data for colorectal cancer. It's an interesting space that we're following carefully.

So when we had said $2-plus billion, I think it was really around BTC-GEA and the one breast cancer trial that we had started. And I think we clearly are beginning to put into place plans that could extend the value of zanidatamab, though we haven't put a number to that.

John, what would you add from that?

No, I think you said it well, Rob. It's a $2 billion-plus peak sales estimate. And now that we have the data from GEA and we're in these new areas, it's an area we'll look at and see if it's appropriate to refine going forward.

And I think one of the nice surprises to the Q1 financials was Zepzelca's strong performance after moving into the front line. I guess how should we think about continued performance of that asset?

Thanks for asking about Zepzelca. We're really proud of that. We brought that asset in, which was positioned as a second line. We pretty quickly recognized the opportunity in frontline. We saw that patients progress rapidly after finishing their induction chemotherapy and an opportunity to use a drug like Zepzelca, which we felt was very well tolerated. There was some resistance to that because many docs said, coming off of platinum therapy, patients don't want to get another therapy. But we proved that you could do it and you could do it safely and with significant benefit.

And also that, that is the time to intervene. The progressions are so rapid, many patients don't make it to second line. But also to sort of preempt that progression or stall the progression, and that's important from a quality of life perspective as well. Of course, we also saw an overall survival benefit. And part of our rationale in addition to preempting that progression as a maintenance therapy was that we had Phase II data in second line, we had some preclinical data suggesting that there could be a synergy with immunotherapies.

So the ASCO abstracts are out now. I don't know if you had a chance to start to sort through them. But I'll call your attention to one on Zepzelca that looks at the impact of tumor-associated macrophages. These are immune cells that cause immune suppression and can interfere with the benefit that you might see from a PD-L1 antagonist like atezolizumab. So we looked in the IMforte study. And in fact, it proves what has been known before, tumors with high tumor-associated macrophages don't do as well when they get atezolizumab.

On the other hand, the combination arm did quite well. And so clearly, giving the combination for those patients who might otherwise be somewhat resistant to immunotherapy is rational based on these data. So again, evidence of synergy. And I think the key message there is Zepzelca is going to have its best effect in frontline. It's going to have an effect across the populations that were studied. It's not dependent on a biomarker, the way DLL3 might be. And it seems to be synergizing with immunotherapy. So give it upfront with immunotherapy, don't save it. And that really has been our focus at [indiscernible] front.

Great. And with that, unfortunately, we are out of time for the session, but thank you both for joining us. I know we also didn't get through Modeyso and the BD activity in oncology potentially this year, so give investors something to wait for, for next time. But thank you both again, and thanks to everyone for tuning in.

It's my pleasure.

Thank you.

Good morning with a great first session of the conference. We've got Jazz with us, represented by Rob, who's their Head of R&D and Chief Commercial Officer (sic) [ Chief Medical Officer ]; and Jack Spinks, who's the Director of IR. So thanks for being here.

Just one correction. I'm the Chief Medical Officer, not Chief Commercial Officer.

Sorry. Chief Medical Officer and Head of IR.

I'll stay in my swim lane.

Yes, I wanted to spend most of today's session talking about zanidatamab, where you've got some exciting data, and it's a core part of your program. So maybe just by way of a brief introduction of the molecule. And can you talk to us about what makes it unique and sort of some of the data that's been emerging that suggests that this is a really unique and differentiated HER2 approach?

Yes. Thank you for the question. I think that is a great place to start. Going back 3 or 4 years ago, we got very interested in this molecule based on what we understood about the mechanism of action, the preclinical data supporting that as well as the early emerging clinical data to support the differentiated mechanism of action. Now that we have the benefit of additional data, we think the thesis is being supported.

So let me just start with what's different about zanidatamab, we refer to it as a bispecific biparatopic antibody. That means that the 2 binding domains of the antibody, the so-called FAB fragments, are engineered to bind different epitopes of the HER2 receptor. And they were engineered to bind to validated epitopes. In other words, one binds to ectodomain 4 and the other binds to ectodomain 2, ECD 4 and ECD 2. Those correspond to the binding domains for Herceptin and Perjeta.

What makes this different? When you represent those binding domains on the same antibody, each antibody necessarily has to bind to a different receptor. So the antibody binds to one receptor, but the other FAB fragment can't reach that other binding domain on the same receptor. So it has to go out and get a second receptor, and that causes clustering. And you can imagine as the antibody stack up, you get this clustering. If you go back to the original Nature Communications paper, there's a really nice experiment demonstrating this and showing through immunofluorescence, you get this capping of receptors and then fixation of complement. And that's one thing that's entirely unique to HER2 antibodies. It's the only antibody at therapeutic levels known to cause complement fixation and initiation of the complement cascade.

Also has a highly active Fc fragment such that you get recruitment of NK cells and recruitment of macrophages, so ADCC and ADCP as well. So that's all highly unique. Also by representing or binding it to those 2 domains, you see interference of signaling of not only HER3 but interference of phosphorylation signaling through other human epidermal growth factor receptors. So for example, HER3 is a receptor that is a heterodimer. An active HER3 receptor is actually one domain of HER3 and one domain of HER2. And so it interferes with that dimerization. So HER3 is interfered with and there's even evidence that there's interruption of signaling through EGFR. So this is a really unique antibody that we felt differentiates from everything else that's out there.

The clinical data that we saw when we in-licensed the product suggested that this would be true. We saw more activity than was demonstrated when in experiments where Herceptin and Perjeta were given. In fact, the preclinical experiment head-to-head showed that it was better than that combination. But if you take biliary tract, for example, those response rates in -- you take the IHC3+ over 50%, certainly better than historical data with Herceptin and Perjeta. We also saw activity in patients who had progressed on prior HER2 therapy. So for example, breast cancer patients who had just progressed on Herceptin and Perjeta were responding to zanidatamab. So we were pretty confident going into the experiments that we had that this was differentiated, and it was in part differentiated by the immune activation.

Now fast forward to when we turned over the card for the frontline GEA study. And people sort of said, "Hey, were you surprised that it was active in PD-L1 negative patients?" After all, tislelizumab itself when tested in frontline gastric cancer was not active in PD-L1 negative patients, consistent with what was seen in all the other prior PD-1 or PD-L1 studies in gastric cancer, inclusive of KEYNOTE-811, which was being studied in HER2 positive patients. So we said, no, we weren't surprised because our thesis going in is that zanidatamab may trigger the immune system in a way that might synergize with PD-1 or PD-L1 inhibitors. So we think that finding, in fact, is consistent with the mechanism of action and a very critical finding because now once this is on the market, docs don't even need to test for PD-L1, which is certainly an advantage.

You don't have to test and wait. But we know that now we have access to that whole population. And it's critical that we educate around that point because we certainly want patients to get the full benefit of zanidatamab with a PD-1 inhibitor. We know that patients in frontline often don't make it to second line gastric patients. And so there's the synergy you want to capitalize on and you want to make sure that patients really get all their effective therapies upfront. So we think that's a critical finding.

Moving forward, we now have head-to-head data with Herceptin, where we're clearly better in that study. We show that tislelizumab is adding, and we think there's a synergy happening in the PD-L1 negative. We certainly are now looking forward to other opportunities where either Herceptin could be replaced or Herceptin wasn't quite effective enough, and we think we have an opportunity, especially when we're combining now with immunotherapies that may create a synergy.

Got it. Really helpful. And maybe just staying with the HERIZON-GEA study for one second. You guys showed pretty meaningful benefits on PFS and OS, and there's a second planned OS analysis for the doublet. I guess, can you talk about maybe weaving in a few things, I guess, sort of what the response has been from treating physicians to the data sort of the level of excitement that you're seeing there? And then maybe how you're thinking about that upcoming OS analysis? And then maybe if I can bring Jack into the conversation, how important OS might be for enabling full commercial scale up there?

Okay. Yes, I'm happy to start and turn it over to Jack. So the reception we've gotten has been very, very positive, starting with the plenary presentation at ASCO GI. If you were in the room, you could see all of the top GI oncologists were there to see it. You could hear the questions and the responses. They were seeing for the first time more than 2 years of survival in both arms. Arm B had over 2 years and then Arm C had more than 26 months. So unprecedented results in absolute terms and certainly compared to the control arm. So I think very clear that Herceptin is a historical regimen in this setting. And I would say, as people got into the details of adding tislelizumab and the value there and the benefit in PD-L1 negative patients, a lot of enthusiasm for using the triplet upfront.

We're very excited that the manuscript has been accepted in a major journal, and we're hopeful that those data will be coming very imminently. We'll further leverage those publication to ensure that we get NCCN guidelines as fast as possible. And we also look forward to ASCO where there'll be some additional analyses, especially around PD-L1 subgroups. You also asked about the next interim analysis. So remember, this first overall survival was planned as the first of 3 OS analyses. So we have 2 more left. The way the study is set up is on sequential testing. So once you hit a hypothesis, you don't retest that. So the analysis of -- so there's no more test -- formal testing of PFS. The analysis of overall survival in Arm B, zani chemo versus the control arm is what the next allotment of alpha will go toward. And then we have a third shot on goal later with the full alpha allocation if for some reason that doesn't hit. We still think this is coming about midyear.

Before I turn it over to Jack, we certainly have been clear in all of our regulatory interactions around what's required for approval. And certainly, OS was never required for approval. It very much helps that we have such strong data on OS even at the interim, but a large enough PFS, which is certainly the case here more than 4 months median with a supporting trend in OS in frontline where you have often significant confounding by subsequent therapies is generally enough. I mean we're quite impressed that we saw as large an effect as we did, even though Arm B versus A isn't yet statistically significant. It's quite an impressive difference in overall survival.

And keep in mind, different from the KEYNOTE-811 trial where immunotherapies weren't available to these patients, we see evidence in our study that the control arm patients more frequently crossed over to subsequent immunotherapy. And that's why we think when you compare PFS curves on our trial to KEYNOTE-811, they're practically identical. But when you look at overall survival, our control does a bit better, most likely because of the more frequent subsequent therapies -- subsequent immunotherapies. So despite that, we're still seeing very strong outcomes.

Yes. Thanks, Rob. And I think commercially, Leo, we're really happy that we have the triplet OS, which was positive and the data readout in early this year. And I think importantly, what these data show is a real differentiation here. I mean, as Rob was talking to, we have data that shows we have benefit in PD-L1 positive and negative HER2-positive patients. And I think commercially, that sets us up really well. Our label, we do expect to have that triplet OS, and we do have clinically meaningful results for the doublet. And we're already approved in second-line HER2-positive BTC. And so that's really important when you think about this launch because the overlap of treating physicians is 90-plus percent here. So I think from a launch standpoint, we're ready to go. I think Sam's team is ready to launch. And certainly, once we have that doublet data mid this year, we'll be able to update the label with that for the doublet.

But as Rob said, right now, we are approvable based on PFS. We have statistical significance and clinically meaningful results for OS in the triplet and certainly clinically meaningful results for doublet with near clinical significance. So I think our team is really ready to go. We don't expect that to be any issue at launch. I think Sam's team is really excited and ready to go to get this product on the market once approved. Again, our PDUFA date, which we received is August 25. We do have real-time oncology review and priority review that was granted by the FDA. So the team is really looking forward to getting that on market once approved.

Really helpful.

Yes. Maybe just would add that, of course, we're not promoting ahead of an approval. But as Jack mentioned, we have an MSL force who's educating around the data and the continued publications are going to be helpful there to have all the data out there. And these are really the very same oncologists who are treating -- currently treating biliary tract with zanidatamab and would be treating gastric as well.

Yes, makes sense. Obviously, GA is not the only potential indication that you guys are exploring zanidatamab in. So I wanted to touch on breast cancer and the 303 trial. It's maybe a challenging population post an ADC. I guess, how are you thinking about why zanidatamab should work there? And you've been pretty clear that it's a better binder but as the later line population may be more challenging, more compounding factors. I guess can you share that?

Yes. I mean, no doubt going into a later-line population has challenges that a frontline population wouldn't. Nonetheless, in breast cancer, which may be different than other tumor types, the experience with a multitude of different HER2 agents is that when patients progress with breast cancer, they typically still have HER2-driven disease. Now there are exceptions to that. But I think even the best data now suggests that after in HER2, the main resistance mechanism is to the chemotherapy warhead, not necessarily to changes in the tumor biology.

Even if you see, let's say, transient changes in receptor expression level, you give a TKI, those levels may go up, you give a depleting antibody, you may see those levels go down a bit. But over time, I think they sort of normalize. So the hypothesis is that even later-line breast cancer patients have HER2-driven disease, and they'll benefit from the most effective HER2 agent in combination with the most effective chemotherapy. And that is the premise for the trial. We're in a line where patients would get Herceptin in this case, really for the third time because they've gotten it upfront and then they've gotten in HER2, which is essentially a Herceptin antibody with a warhead and they have really nothing left.

So while you wouldn't expect to see the kind of results you get in a frontline trial, we do still think there's an opportunity to differentiate with a more effective antibody like zanidatamab. And that was just a very obvious first place to go. I mean, pretty much to a person, every KOL we spoke with said this is the big unmet need because after ENHERTU, there's just not going to be any data. People will try various agents that maybe they hadn't gotten but there's just not going to be any data. And that still remains to be the case.

Now I wouldn't say that, that's the only place that we want to be in breast cancer but it was an obvious first place to go. And as we accumulate data, as we have shown, let's say, increasing our confidence in zanidatamab, we're likely to initiate new trials. You're already aware that we've been working in the neoadjuvant space. And we think zanidatamab could have a real advantage there because there's flexibility around what to combine with. So you might get improved efficacy, but you also may be able to combine in a way that there's reduced toxicity in that curative setting. And the ENHERTU data notwithstanding, it's important that we have good salvage regimens for those patients who don't achieve a full pathologic complete response after surgery. But really, the goal is to increase the proportion of patients who do achieve that so that you don't need to go to a more intense therapy that carries with it risk like pneumonitis or fatal pneumonitis.

So there's a real opportunity in breast cancer. That's a little bit more of a complicated space. So we're being deliberate around getting good Phase II data that we can learn from and then design the most effective and successful Phase III trial. I think you're also aware that we're partnering with 2 companies on combined with novel HER2 TKIs. This is an exciting part of the field. Tucatinib has been effective in certain settings, but there's an opportunity to improve upon that. So we partnered with Boehringer. We're evaluating the combination in breast cancer. We've also partnered with Iambic, again, evaluating that combination in breast cancer. And there may be other places where that combination could make sense.

So again, in a sort of Phase Ib/II setting, learning what we can learn about might there be synergies. We talked about TKIs potentially upregulating receptor density, which might play into the mechanism of action where having receptors to cluster will trigger a stronger immune response. So we're very interested in that space.

But again, going -- so breast cancer is definitely a place where we think we can win. But now leveraging what we've learned about our ability to win head-to-head against Herceptin and the likelihood that we're going to synergize with immunotherapy, we are leaning into other areas. So take, for example, the first-line BTC trial. There's no approved HER2 therapy in frontline BTC. We know that zanidatamab works very well in BTC, and that's a setting where immunotherapy is approved. So we have an opportunity to go against no other HER2 therapy in combination with PD-L1. We think that's a high probability of success trial that will get us from second line into first line.

Now that we know we've beaten Herceptin head-to-head in metastatic breast GEA, very difficult disease to treat. I mentioned that more than half of the patients don't even make it to second line. We're now very interested in whether we could do something in the neoadjuvant, adjuvant gastric setting. Here, again, no approved HER2 therapies. After MATTERHORN, IMFINZI is approved. So we're exploring the concept of could we again go head-to-head against no other HER2 therapy, benefit from the synergy of immunotherapy in a population of patients who are in very good shape with good immune health, have a fairly low burden of disease. Is that a place where zani would really shine and looking at that kind of opportunity.

I would also -- if you want me to go a little bit further, I would say we've got really interesting data in colorectal cancer that we published, and we want to chase that down. The field of non-small cell lung cancer is now emerging. So we mentioned the partnership with Boehringer that initially is focused on breast cancer. Zongertinib is going to be frontline in non-small cell lung cancer mutants. That may be a place where adding a HER2 antibody like zani could be effective.

But I'm also impressed -- impressed is the right word but have taken notice that the population of non-small cell lung cancer patients who are overexpressing HER2, based on the literature that I read could be as large or larger than the mutant population, yet there's not as much development activity there. And we know we're working essentially anywhere we've tested zani, where there's overexpression seems to be working. So in our pan-tumor trial, we'll be enrolling colorectal cancer patients. We'll be enrolling non-small cell lung cancer patients who are overexpressing HER2, in addition to a number of other rare tumors where we might even get a broad indication depending on the results.

Got it. Zanidatamab is obviously critical to Jazz but it's not the only part of the company. So I wanted to touch on a few other important parts. And maybe starting with the sleep franchise. And there's going to be a lot of developments this year in sleep. We've got a new class of agents launching, some more drugs coming on the market as well for the cataplexy side of things. I guess -- maybe for you, I guess, how do you think about how the market is evolving, how physicians might think about what's the appropriate way to treat some of these patients with hypersomnia? And then obviously, the commercial question embedded in there of how do you see the durability of the oxybate side of the business?

Sure. Yes. No, it's a very interesting field. And as you know, we were really built around our hypersomnia franchise. So we have deep expertise here. I think the field is evolving pretty much the way we've been predicting and have been talking about it. Orexins represent a new class of alerting agents that seem to be as or more effective than other alerting agents that have come along. We also -- and what we anticipate here is that the data in NT1 will lead to an approval. So far, we don't have meaningful data in NT2 or IH, and that may be somewhat different. But what we're seeing from the emerging data are that it's clearly not addressing the root cause in any of the hypersomnias. The root cause in hypersomnias, NT1, NT2, IH is severely disrupted nighttime sleep. And until you address that root cause, I don't think you can completely treat the disease.

And so I continue to think that Xywav as the only low sodium option with flexibility around dosing will continue to be the backbone for a substantial proportion of patients with hypersomnias. Those who are on therapy now and benefiting from it, I think, will continue. We certainly are interested in orexins. We're bringing another one forward, and we think that there will be an opportunity for these to be complementary.

I see that we have just about 1.5 minutes left. Could I extend that to our epilepsy franchise as well? So we've become a leader in epilepsy through our acquisition of GW. And I think you've probably followed the success of Epidiolex, which I think is doing very well commercially because it's a terrific drug for multiple different types of seizures. And so it's being used broadly. It's very well tolerated and easy to combine. And so you see polypharmacy where Epidiolex continues to be a backbone even when other therapies are laid onto that.

We've leveraged that expertise to really want to focus more broadly in epilepsies. I kind of -- so I could have easily spent this whole time as an oncologist talking about the cancer franchise. But I'm really impressed with how genomics are now transforming the field of epilepsy in the way that genomics transformed oncology 20 years ago. We now understand, in many cases, the genetic causes of epilepsy and can not only target them, but sometimes reverse the underlying disease. And so we brought forward several new -- we said we have a new agent for absence epilepsy. I haven't said the mechanism of action yet. We've partnered to in-license a Kv7 inhibitor from Saniona, we have a Kv4 inhibitor in-house, as you know. We actually have a few other things in play.

So we see epilepsy as a really good opportunity to fit into our overall, let's say, refined strategy around rare disease, so rare epilepsy, rare oncology. And we're out of time without having an opportunity to talk about Modeyso, which is a super exciting drug. Maybe if I could steal 20 minutes to go over. We've said the ACTION trial will have an opportunity for an interim OS by end of year or early part of next year. That's an interim, we would have a second bite at that apple. I'm excited about that because that launch has gone very well because there's such an incredible high unmet need. As a pediatric oncologist, trained 25 years ago, the field didn't change much before Modeyso.

And so now there's an opportunity to treat these patients with a novel targeted agent. The approval is in second line, but I think everyone knows that these patients have a very poor prognosis and the best way to use any new agent is in frontline immediately following their radiation therapy. And so ACTION will allow us to formally have a label in that frontline setting.

Well, I think the fact that we went over time just speaks to how much there is to the story and how exciting it is. And thanks again for being here.

Pleasure.

Thanks so much, Leo.

Good day, and thank you for standing by. Welcome to the Jazz Pharmaceuticals 2026 First Quarter Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to turn the conference over to your speaker for today, John Bluth, Head of Investor Relations. Please go ahead.

Thank you, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its first quarter 2026 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website, along with the press release and quarterly report on Form 10-Q for the first quarter ended March 31, 2026. On the call today are Renee Gala, President and Chief Executive Officer; Sam Pearce, Chief Commercial Officer; Robbie Iannone, Global Head of R&D and Chief Medical Officer; and Phil Johnson, Chief Financial Officer.

On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements such as those related to our future financial and operating results, growth potential and anticipated development, regulatory and commercial milestones, which involve risks and uncertainties that could cause actual events, performance, and results to differ materially from those contained in these forward-looking statements. We encourage you to review these risks and uncertainties described in today's press release and under the caption Risk Factors in our annual report on Form 10-K for the fiscal year ended December 31, 2025. We undertake no duty or obligation to update our forward-looking statements.

As noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website.

I'll now turn the call over to Renee.

Thanks, John. Good afternoon, everyone, and thank you for joining today's conference call. Building on our record year in 2025, we are pleased to share our results from an exceptionally strong first quarter, led by commercial execution across our highly differentiated products for sleep, epilepsies, and cancers. This resulted in our highest ever first quarter total revenues of $1.1 billion, reflecting more than 19% year-over-year growth, driven by the outstanding performance of Xywav, Epidiolex, Modeyso, and Zepzelca. Our commercial teams generated double-digit growth across all our promoted brands and saw strong contributions from our ongoing launches. This performance reflects the discipline and consistent efforts of our teams working with clarity and purpose to support the physicians and patients we serve.

In addition to our impressive commercial performance to start the year, we are urgently advancing the development of zanidatamab for patients with HER2-positive first-line locally advanced or metastatic GEA where the unmet medical need remains significant. The FDA recently accepted our sBLA for Ziihera under real-time oncology review and granted priority review with a PDUFA date of August 25, 2026. We are ready to launch Ziihera in GEA as soon as we receive FDA approval, and we expect Ziihera will become the HER2-targeted therapy of choice for HER2-positive first-line GEA patients given the magnitude of benefits seen across both experimental arms when compared to the trastuzumab control arm.

In R&D, we continue to make progress across our pipeline with multiple ongoing registrational zanidatamab trials, early-stage trials evaluating oncology assets, and the early development of neuroscience and epilepsy assets. The year is also off to an excellent operational start with cash flow of over $400 million in the first quarter and non-GAAP adjusted EPS of $6.34. Our financial strength and disciplined capital allocation enable us to invest in the continued growth of our commercial portfolio and pipeline while also positioning us to execute on business development opportunities that fit our strategic focus in rare disease.

With that, I'll turn the call over to Sam to share more details on our commercial performance.

Thank you, Renee. Our commercial team delivered strong results across Jazz's portfolio with momentum from our 2025 launches and coordinated execution continuing into 2026.

I'll begin on Slide 7 with sleep. Xywav's net product sales increased 18% to $408 million in the first quarter of 2026 compared to the same period in 2025. As expected, HCPs and patients continue to drive demand for safer, low-sodium Xywav, and we saw strong new patient growth with approximately 425 net patient adds. There are now approximately 16,600 active patients taking Xywav, which remains the #1 branded treatment for narcolepsy based on product revenues and the only FDA-approved treatment for idiopathic hypersomnia.

Our field teams continue to expand both the IH and narcolepsy markets by educating HCPs on the importance of addressing the full spectrum of daytime and nighttime symptoms. These efforts are complemented by digital and media campaigns to increase disease awareness and support patient education. Our Jazz care support services, including field-based nurse educators, support patients from initiation through titration and across the long-term treatment journey. These services remain important differentiators for Jazz.

Moving to Slide 8 and Epidiolex. Epidiolex net product sales increased 15% to $250 million in the first quarter of 2026, driven by strong underlying demand and 16% volume growth during the quarter. Expanding our reach in the adult patient population and specifically in the long-term care setting remains a key focus and an important near-term growth opportunity. Our Nurse Navigator program continues to have a meaningful impact on improving patient persistency and expanding utilization of this resource remains a priority for 2026. Finally, as part of our commitment to bring Epidiolex to appropriate patients in Japan, we have partnered with Nippon Zoki, a Japanese company with deep expertise in CNS disorders. Jazz remains the sponsor of the clinical trial, and Nippon Zoki will lead regulatory, distribution, and commercial activities in Japan.

Turning to our oncology portfolio, starting with Ziihera on Slide 9. In the first quarter of 2026, Ziihera generated net product sales of $13 million. Feedback from biliary tract cancer physicians continues to be positive with real-world experience consistent with the clinical profile observed in our trials. We are also continuing to expand into new community-based accounts beyond academic centers, increasing awareness of Ziihera in BTC and building readiness ahead of a potential launch in GEA.

As a reminder, there is a substantial customer overlap across our solid tumor footprint, including approximately 90% overlap between BTC and GEA accounts. We believe this positions us well to accelerate uptake in GEA following its anticipated approval and launch on or before the August 25 PDUFA date. Once approved, our existing cross-functional team will be positioned to reach target customers and support rapid adoption of this practice-changing regimen for GEA patients.

Turning to Slide 10 and our GEA launch preparations. Physicians are expressing excitement and interest in the potential use of Ziihera in GEA. It has been more than 15 years since a new first-line HER2-targeted agent became available for patients with metastatic gastric cancer. Given the unprecedented median overall survival data of more than 2 years, we believe Ziihera has the potential to become the preferred HER2-directed therapy and foundational backbone for treating HER2-positive first-line metastatic GEA.

The addition of tislelizumab further improved survival outcomes in both PD-L1 positive and PD-L1 negative patients, consistent with Ziihera's unique mechanism of action that generates an innate immune response in the tumor. Ziihera already benefits from an established permanent J-code through its FDA approval in second-line HER2-positive BTC, which we expect will simplify reimbursement in GEA and reduce the administrative burden for providers. In addition, the compelling outcomes from the HERIZON-GEA trial supports our expectations for favorable payer access.

Finally, our comprehensive Jazz care support services, together with Ziihera's established availability across customers' preferred distribution channels position us to enable seamless patient access at launch.

Turning to Slide 11 and Modeyso. Modeyso generated $41 million in net product sales in the first quarter of 2026. This strong early performance following its launch in August 2025 reflects the significant unmet need in H3 K27M-mutant diffuse midline glioma, high awareness driven by advocacy groups and the value physicians see for patients. Approximately 500 patients have been treated with Modeyso since launch through the end of the first quarter.

Our highly experienced neuro-oncology field teams, including medical and access colleagues continue to support the launch. The teams remain focused on expanding reach in community settings, whilst maintaining a well-supported presence in academic centers of excellence. Robust patient-centric support services and payer coverage continue to underpin launch momentum and support appropriate access for patients.

Moving to Slide 12 and Zepzelca. In the first quarter of 2026, Zepzelca net product sales increased 60% to $101 million compared to the same period in 2025. Growth in the first quarter was primarily driven by strong uptake in the frontline maintenance setting following FDA approval of Zepzelca in combination with Tecentriq in October of last year. Given the strength of the IMforte clinical data and the opportunity to improve both progression-free survival and overall survival for patients with extensive stage small cell lung cancer, health care providers are rapidly adopting the Zepzelca combination in the first-line maintenance setting.

As a result, this new indication is driving the product's strong performance. Our commercial initiatives will continue to be focused on first-line maintenance, reflecting our ongoing commitment to this priority. For the rest of 2026, first-line maintenance adoption is expected to grow with second-line use decreasing due to competition and fewer Zepzelca naive patients available for treatment. Overall, we are satisfied with the impressive commercial performance achieved across our portfolio in the first quarter and remain focused on maintaining this momentum throughout the year.

With that, I'll now turn the call over to Rob to provide an update on our pipeline. Rob?

Thanks, Sam.

I'll start on Slide 14. This is an exciting time at Jazz. In addition to our outstanding commercial execution, we are also preparing to bring zanidatamab to HER2-positive first-line metastatic GEA patients. The data from the HERIZON-GEA trial definitively demonstrated that zanidatamab offers improved outcomes on all efficacy measures compared to trastuzumab and should be the new HER2-targeted agent of choice. The data also showed tislelizumab further improved survival outcomes in both PD-L1 positive and PD-L1 negative patients.

The benefit regardless of PD-L1 status may be driven by zanidatamab's unique mechanism of action known as biparatopic binding. This enables zanidatamab to cross-link neighboring HER2 receptors, leading to receptor clustering, which blocks HER2 growth signaling and also triggers the complement cascade. Zanidatamab's ability to uniquely and broadly activate the innate immune system may in part explain the additional efficacy observed when tislelizumab was added to zanidatamab even in PD-L1 negative tumors.

The triplet arm of zanidatamab, tislelizumab, and chemotherapy demonstrated improved overall survival with a remarkable median OS of 26.4 months, representing a meaningful improvement of more than 6 months median OS compared to prior studies in HER2-positive patients who have a poor prognosis in the metastatic setting. Among patients who had an objective response, the median duration of response was 20.7 months. Again, this benefit was observed irrespective of tumor PD-L1 status.

To put this into context, in the KEYNOTE-811 trial, the duration of response for trastuzumab and pembrolizumab plus chemotherapy was 11.3 months. We are moving quickly to bring zanidatamab to HER2-positive first-line metastatic GEA patients. Following the oral presentation at ASCO GI in January, we submitted the data for potential inclusion in NCCN guidelines.

We're pleased that the manuscript has been accepted for publication by a top-tier medical journal and plan to submit the peer-reviewed manuscript to NCCN once it has been published. Our supplemental BLA for zanidatamab has received priority review with a PDUFA date of August 25, 2026. We are actively engaged with the FDA in the review process, and we expect potential approval and launch of zanidatamab in GEA on or before the PDUFA date.

Turning to Slide 15 and our pipeline. We have multiple clinical trials across our pipeline from early stage to registrational trials. We look forward to sharing data from some of these ongoing trials at the upcoming ASCO meeting in early June with a number of presentations on lurbinectedin and zanidatamab. The second planned interim analysis for overall survival of the zanidatamab and chemotherapy arm of the HERIZON-GEA trial is still expected midyear. At the time of top line readout, this arm showed a clinically meaningful effect on overall survival with a strong trend towards statistical significance compared to the control arm.

The next pivotal Phase III trial for zanidatamab is in metastatic breast cancer patients who have progressed on or are intolerant to in HER2, and trial enrollment is progressing well. We continue to expect to complete enrollment in the EmpowHER trial in the first half of 2027, with top line data anticipated in late 2027 or early 2028. Other earlier-stage trials continue to progress across new indications, including a potentially registrational pan-tumor basket trial and a neoadjuvant adjuvant breast cancer trial.

Looking ahead to later this year or early 2027, we anticipate the ongoing Phase III ACTION trial will have an interim overall survival readout. This trial is designed to confirm the benefit of Modeyso and support regulatory approval as frontline therapy directly following radiation instead of waiting for signs of tumor progression before treating with Modeyso. We are working with dedicated focus to both realize the full potential of our near-term opportunities and to rapidly progress our pipeline. Our in-house research and development efforts are underway, and we look forward to sharing updates on those and further pipeline progress in the future.

Now I will turn the call over to Phil for a financial update. Phil?

Thanks, Rob. I'll start with high-level comments on our non-GAAP adjusted P&L, as shown on Slide 17. Please note that our full financial results are available in today's press release and 10-Q.

The outstanding execution of our field-based teams was reflected in record first quarter revenue of $1.07 billion, driven by 45% growth in our oncology portfolio, 18% growth in Xywav, and 15% growth in Epidiolex. Strong underlying performance drove the vast majority of our revenue growth. I do want to point out 2 smaller items that also contributed to growth this quarter. First, we had the normal 13 shipping weeks for our U.S. oncology product this quarter, while in last year's quarter, we had 12 shipping weeks. This contributed about 2 percentage points to our worldwide revenue growth rate. Second, the significant devaluation of the U.S. dollar led foreign exchange to contribute about 1.5 percentage points to our worldwide revenue growth.

Moving down to P&L. Our non-GAAP adjusted gross margin declined slightly year-on-year, primarily due to higher sales of products carrying royalties, namely Zepzelca and Modeyso. Non-GAAP adjusted SG&A expense decreased by about $164 million. You may recall that in last year's quarter, we recognized litigation settlement expenses of $172 million. Excluding these expenses, SG&A increased by $8 million, driven by the inclusion of Modeyso expenses. Non-GAAP adjusted R&D expenses increased by $13 million, primarily due to the inclusion of Modeyso clinical trial expenses and higher compensation-related expenses.

Our non-GAAP adjusted effective tax rate this quarter was slightly lower than our full year 2026 guidance due to excess tax benefits from share-based compensation, while our shares outstanding for the quarter reflect the accounting effect of our higher share price on our convertible notes and employee stock plans. At the bottom line, we posted very robust non-GAAP adjusted EPS of $6.34.

Supported by our strong start to the year, we are reaffirming our full year 2026 revenue and expense guidance, including total revenue guidance of $4.25 billion to $4.5 billion.

Total revenue guidance for 2026 includes the assumptions you see on Slide 18. As a reminder, we assume competitive dynamics in our sleep business will increase in the second half of the year, including high-sodium generics gaining volume and one or more daytime weight-promoting agents potentially entering the narcolepsy market. We also expect to see a decline in Xyrem and high sodium authorized generic revenues as generic high sodium oxybates build their volumes over the course of 2026. And as Sam mentioned earlier, we expect a decline in second-line use of Zepzelca. Our Q1 performance and focus on disciplined capital allocation position us well to achieve our 2026 guidance.

Moving to Slide 19. Our balance sheet remains strong. We continue to generate significant cash from our business, recording $408 million of cash from operations in the first quarter of the year, and we ended the first quarter with $2.9 billion in cash and investments. Our overall financial position and robust operating cash flow provides significant flexibility to invest in value-driving commercial and R&D programs as well as in promising corporate development opportunities to support our rare disease strategy.

I will now turn the call back to Renee for closing remarks.

Thank you, Phil.

I'll conclude our prepared remarks on Slide 21. The first quarter of 2026 builds on the successes we achieved in 2025. Our focused commercial execution led to more than 19% growth in the first quarter. And based on these results, we are on track to achieve our 2026 financial guidance. We look forward to several upcoming catalysts, including the second interim analysis of overall survival from the HERIZON-GEA trial midyear. Top line readout for overall survival for the confirmatory ACTION trial for Modeyso is expected at the end of this year or early next year. And the top line readout from the trial evaluating zanidatamab in late-stage breast cancer post in HER2 treatment is expected in late '27 or early 2028.

We continue to build upon our proven scientific expertise and capabilities to make a meaningful impact for patients. Supported by our strong financial position, you should expect to see us invest in our commercial brands and pipeline and business development to broaden our portfolio in key strategic focus areas of sleep, epilepsy, and oncology in addition to other areas of rare disease.

I'd like to thank all our Jazz colleagues for their efforts and dedication to making a difference in the patients' lives that led to an exceptional first quarter. We are relentlessly focused on continuing to execute and deliver life-changing medicines to patients.

That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Our first question today will be coming from the line of Jess Fye of JPMorgan.

Question on zanidatamab for breast cancer. So if we assume zani beats Herceptin in breast cancer and gets approved one day for use in the post in HER2 setting, how do you expect physicians to make decisions about how to sequence agents in the context of a lack of data for other products post in HER2, among other things?

I'm happy to address that, Jess. This is Rob Iannone. We became very interested in this space based on good advice from many key experts in the field. And the fundamental issue is that once HER2 moves to frontline, there's very little data about which HER2 agent to select as subsequent therapy. So the trial that we're running 303 will be the first time that we definitively in a randomized setting, evaluate zanidatamab versus what would be considered a standard of care. So we expect to be out ahead with important data that will inform decisions about whether to use zanidatamab or other HER2 agents in that space.

And the next question is coming from the line of Joseph Thome of TD Cowen.

Congrats on the quarter. Maybe one on Modeyso. Do you have any updated thoughts on sort of the size of this patient population? I think historically, it was thought that it was maybe 2,000 or 3,000, but it sounds like it sounds like already hitting 500 patients. So any thoughts on that total opportunity just given the strength of that launch? And maybe a follow-up, if I can, on M&A. Kind of what's your latest thinking in terms of where you'd like to go? Obviously, we've seen a lot of activity in the past few weeks in different areas. Kind of what's the sweet spot in terms of size and area of focus for Jazz going forward?

Yes. Hello, Sam here. I'm happy to take the question on Modeyso to start with. Yes, we're extremely pleased with the launch so far, $41 million in Q1 really gives us a lot of confidence around achieving that $500 million peak opportunity in the U.S. And as you mentioned, we've had 500 patients treated since launch. And I think that just reflects the very high unmet need that we see in this space. Overall survival from diagnosis is just 1 year. So this product has had a meaningful impact, and it's supported by high awareness from physicians and, obviously, very strong patient advocacy support as well.

In terms of the size of the patient population, I think our best estimates are aligned to what you mentioned there. And over time, of course, we'll continue to evaluate that. But we do see potential upsides in duration of treatment as well as the size of the population. What we've seen so far is that patients are staying on treatment for longer than we initially anticipated. We'll have to wait for this cohort of patients to really mature before we get a really good handle on whether the duration of treatment exceeds that, that we saw in the trial, which is around about 10 months. But extremely happy with the start. I think our teams have done an excellent job really executing this launch well in such an important area of medical need.

And Joe, this is Renee. I'll jump in on BD. So we are highly engaged on the BD front, and I do expect us to have deals announced over the course of this year. We do have a clear strategy that is focused on expanding our presence in rare disease, in particular, where we believe there's a significant unmet need. So strengthening our current areas of epilepsy, sleep, and rare oncology, also expanding into new areas of rare disease, areas where we think we can leverage our capabilities and our footprint to continue to scale our business while driving further growth and profitability.

In terms of the deal types, we -- it really depends on the asset and the transaction at hand, but we are looking at licensing structured deals, also outright M&A. I think the key here to being successful in BD is identifying value or risk that others don't see and then staying myopically focused on execution as we did with the Chimerix launch, the Chimerix acquisition and subsequent Modeyso launch. And we have very strong momentum now with the new CBO, Chief Business Officer, on board as of January 1.

Importantly, we are well positioned to execute. Phil mentioned, we have a strong financial position, $2.9 billion in cash and cash equivalents on the balance sheet, strong cash flow. And while M&A has picked up, we do believe there is still a lot of substrate that is actionable and well aligned with our strategic priorities.

Our next question will be coming from the line of Leo Timashev of RBC.

I wanted to stay with, you mentioned epilepsy. I just wanted to touch on that. You've been making a lot of investments in that area, both with Epidiolex, [ Cenobamate ] asset, you also have JZP-047, and now you mentioned potentially looking at BD there as well. So I guess I'm just curious how you're thinking about that area, to what extent it's a continued focus and how you think about either synergies or risk of cannibalization across sort of many different assets there?

Yes. Thanks for the question. This is Renee. I would say this is definitely an area of focus for us. There continues to be significant unmet need across the epilepsy space. You see a strong amount of polypharmacy here with respect to multiple -- sorry, multiple medications generally on board, in particular, when we're looking at serious refractory epilepsies. We think with the position that we have with Epidiolex being the #1 branded product and having the very long durability out to the very late 2030s, it gives us greater opportunity to continue to build around that franchise to build scale. I'm thrilled to see additional opportunities for patients with the strong data that we've been seeing come out with a number of companies in whether that's on the proof-of-concept side, starting to go into registrational studies or work that's happening early in pipelines.

As we think about ourselves, we think there is plenty of room and need -- unmet need for patients to continue to see new mechanisms explored and new options for patients. So we do think there's still plenty of substrate, a great opportunity for us as a leader in epilepsy. You will note, last quarter, we said we were advancing the first molecule coming out of our labs that was not just a formulation play, but an innovative target novel mechanism coming out of our lab that went into patients in the epilepsy space. So we will continue to invest here, and we're excited about the opportunities.

Our next question is coming from the line of Annabel Samimy of Stifel.

Just want to circle up on Modeyso again. Obviously, it's been exceedingly promising since the outset, and you have a potential to move into first-line treatment. I guess my question is, how should we think about the potential move into first-line treatment? Does this significantly expand the market? Should we think about this like we think about Zepzelca moving into first line and how it significantly inflected growth? I guess I'm trying to understand the magnitude given that most patients are in first line, progress to second line. Is it only about duration? Or is there a population opportunity there?

Yes. Hello, Annabel, happy to take that. Yes, I think there's 2 factors when we consider the ACTION study and what that will do for Modeyso and for improving the treatment to patients. Some patients don't make it to second line. So of course, there are more patients available to be treated. But having the opportunity to get Modeyso to patients before they progress will mean that the duration of treatment should be longer if they can use it straight after radiation. So those 2 things, I think, do -- will contribute to us achieving the $500 million peak potential, which does incorporate an assumption that we will have that first-line label. Rob, anything more to add on that?

I mean you covered it well. I'd just point out that sometimes it's hard to judge progression in these patients. And then as you point out, once it's clinically apparent in addition to imaging, patients may rapidly progress and not benefit from second-line therapy. So the opportunity to start Modeyso right after the radiation therapy really does potentially add a significant benefit to patients and, ultimately, duration of therapy.

And our next question is coming from the line of Marc Goodman of Leerink.

Sam, can you talk about Epidiolex OUS? I heard Phil talk about the FX impact, but those numbers couldn't have just been FX, something is doing pretty well there. So maybe just talk, was there any particular country? Was there any buy-in? Anything unusual there? And maybe you could just comment on Rylaze as well, which happened to have a really good quarter and what was happening there?

Yes. Thanks for the question, Marc. Yes, it's great to see the performance outside of the U.S. for Epidiolex, very strong growth indeed. Around about 2/3 of that, I believe, was volume, and there was about 1/3 due to FX and some gross to net benefits from places like the U.K. with a VPAG adjustment that happened there. And I think really, this is just down to terrific execution by our teams. As you know, Epidiolex was launched a little bit later in Europe. So there's still quite some opportunity to continue to penetrate in the pediatric segment, but of course, also in the adult segment, which is a focus for both the U.S. and the ex-U.S. business.

And then your other question around Rylaze. Yes, Rylaze, yes. Rylaze delivered a strong quarter, $104 million, which was 10% revenue growth. But that was comparing to quite a low Q1 '25. So I think the performance that we've seen in this quarter is in line with the prior quarters that we've seen other than the Q1, which is a low point. What we've seen with Rylaze is the COGS impact that started in '24 has been fully realized now. And our focus continues to be on making sure that patients -- appropriate patients can receive Rylaze that they're switched at the first sign of a hypersensitivity reaction and the opportunity to continue growth in AYA. But I think that $100 million per quarter for Rylaze is a good kind of stable base for us currently.

And the next question is coming from the line of Etzer Darout of Barclays.

This is Jordan Becker on for Etzer Darout. Congrats on the impressive quarter. Maybe just one, if we could expand on any second half dynamics for oxybates now with a full quarter in the rearview. Maybe if you could provide some more color on any potential competitive pressure from LUMRYZ specifically? And then on that, maybe any perceived pressure to IH growth down the line if LUMRYZ is approved in IH?

Yes, I'm happy to take that question on Xywav. Yes, we're very pleased with the continued momentum for Xywav, $408 million this quarter, 18% revenue growth, and a really healthy 12% volume growth. We continue to see really good patient adds, 425 net patient adds in the quarter, most of them continuing to come from IH, 300 net patient adds for IH, which is consistent with what we've seen in prior quarters. So we finished the quarter with 16,600 active patients. And when we look ahead to the outlook for Xywav for the remainder of the year, obviously, we're very pleased with the momentum that we're taking into the second quarter. We still have continued strong payer coverage, more than 90% commercial lives covered. Nothing has changed around the nature of our Xywav business in the first quarter of this year.

And our 2026 full year guidance does include assumptions that generics will build volumes in the second half of the year as well as the potential for the entry of new wake-promoting agents entering the market in the second half of the year in the NT1 narcolepsy segment. But we believe Xywav will continue to have a really important place in therapy. We've invested in some really meaningful evidence generation, XYLO and the DUET studies, which show the importance of having a low-sodium option. And as you mentioned, it's the only option approved for IH and the DUET study, which shows just how effective Xywav is as a nighttime agent. And we believe those 2 benefits will continue to resonate strongly with physicians and patients, of course.

Our next question is coming from the line of Brian Skorney of Baird.

This is [ Charlie ] on for Brian. I was just wondering if you could give us a sense of the size of the opportunity for Epidiolex in the adult and long-term care setting. And maybe some more color on the initiatives you're taking there with the new formulation? As well as would be curious to hear, will you be sharing any data from the Phase Ib in focal onset when you get that? And do you have any idea in terms of timing there as well as what your expectations are for the setting for Epidiolex?

I'm happy to take the first part of your question in relation to the adult segment, and then I'll hand over to Rob to talk about the study. Yes, we're very happy with the performance of Epidiolex in the first quarter of this year, $250 million, 15% revenue growth and 16% volume growth. As you probably recall, Epidiolex was launched initially very much as a pediatric drug, and we've seen really good penetration in that segment, a leading agent, obviously, for pediatric patients. One area that we do continue to see opportunities in is in that adult segment, particularly in long-term care facilities. So we've made some specific investments there with a dedicated team focusing on those facilities. And we've also invested in a diagnostic tool, REST-LGS tool because we know that adult patients with LGS often go undiagnosed. So we've supported physicians to help ensure that those patients can get a definitive diagnosis and benefit from Epidiolex.

In addition to that, one of the hallmarks of Epidiolex is the very long persistency that we see, but we do see an opportunity to drive that even further. We know that patients that are enrolled onto our JazzCares program, which also gets the support of a Nurse Navigator, they do stay on treatment longer. So we've got a particularly focused effort now on ensuring that as many patients as possible can benefit from our JazzCares suite of services, and we believe that will drive even longer durations of treatment for Epidiolex. In addition to that, we're making quite significant investments in evidence generation. We have the EpiCom study in TSC and the BECOME survey, which has been focused on adults, which really just underlines the benefit that Epidiolex has not just for the control of seizures, but also for controlling some of the non-seizure symptoms that these patients experience as well. And that's one of the very significant differentiating benefits of Epidiolex.

So overall, we're very encouraged by the momentum that we have with Epidiolex, but also really see a lot of long-term potential to continue to grow Epidiolex into the future, particularly in that adult segment.

Thanks for the question on the focal onset seizure study. We're super excited about it. There's a lot of interest from epileptologists to more formally evaluate Epidiolex in this setting. As you know, doctors and treaters think about epilepsy in terms of types of seizures. And we have lots of data showing activity of Epidiolex across really every type of seizure with some preliminary evidence in focal onset seizures as well. This is an evidence generation study to go deeper into this particular population, and we would intend to publish this as soon as we have data available to do so. We haven't given any specifics on that yet. After a little more time lapses and we get a good sense of the enrollment rate, we may be able to update further.

Our next question is coming from the line of David Amsellem of Piper Sandler.

I had a long-term competitive landscape question on your oxybate business. So your competitor has Valiloxybate, the sodium once-nightly or potential no sodium once-nightly product that's in development. To the extent that reaches the market, can you talk about how that could impact your Xywav business, both in terms of narcolepsy and the IH setting? And just in general, how are you planning to respond competitively to overall a more crowded landscape? The obvious is, of course, of orexin, but also next-generation oxybate products as well?

Maybe I can step in on that, and then I'll ask Rob to comment on how we're viewing orexin. So I would first point to the fact that Xywav has been competing for the last 2 years with a number of high-sodium options on the market. And over that time, we have not only built a strong group of patients that are relatively persistent in terms of their use of oxybate, the specific relief and flexibility that they receive from Xywav and also being the only option available for IH. We've done a lot of work in the market in terms of disease awareness.

One of the areas that we've invested quite a lot in that Sam has spoken to earlier is the patient support services. I think that is highly differentiating for Jazz in terms of the extent of our services and the way that we have deployed those. And so we will continue to ensure that the unique differentiating benefits of Xywav as well as our various support services are well understood in the market. I would also note that we do, from a patent perspective, have a lot of confidence in our overall patent estate.

So when you're thinking about the various programs that are out there that may be looking for a 505(b)(2) sort of path. From that perspective, we do have robust patents that include many Orange Book listed patents out to 2033 and '37 and then an Orange Book listed IH patent out to 2041. But maybe I'll also invite Rob to comment with respect to orexins coming into the market and our view there.

Yes. We've been following orexins carefully and our conclusion is that it's likely to be complementary to Xywav. As Sam mentioned, alluding to the DUET study, we have significant data showing that the root cause in hypersomnia, such as narcolepsy type 1 and 2 as well as IH is really disrupted nighttime sleep. And oxybates are the only therapy that can address the disrupted nighttime sleep directly. And Xywav, of course, the only low sodium formulation that we believe is safest for patients who are at a high risk for cardiovascular outcomes.

Certainly, orexins are showing to be potent daytime alerting agents. There's some preliminary data showing though that you can have insomnia, especially with the longer half-life formulations. And the limited PSC data that are out there suggests that certainly not improving disruptive nighttime sleep and may actually on the first half of the night, be impacting it negatively with the reports of insomnia. So we continue to think that this important space to follow. We have an orexin in development still. And -- but we think ultimately, this is going to be complementary to Xywav.

Our next question is coming from the line of Mohit Bansal of Wells Fargo.

Congrats on all the progress. Just want to ask about Zepzelca IP here. I see a few new Orange Book listed patents here in 2025. So they go all the way to 2040. So how should we think about the life of Zepzelca beyond 2029, that's the comp of matter patent at this point?

Yes. Thanks, Mohit. This is Renee. So we do have a strong patent estate for Zepzelca. And as you noted, we do have multiple patents that extend out to 2040. We're also pursuing multiple new patents with the patent office that would also extend out to that time frame with additional applications, whether that be combo therapies, formulations, or methods of treatment. We have also stepping back and speaking to the ANDA filers that we've disclosed, we have filed suit against all 5 ANDA filers. And as a result of filing that suit, a stay of approval is in effect for up to the 30 months as is imposed by the FDA. And so while we're not going to speak broadly to active litigation, we do feel that we have a strong patent estate. And as we have more clarity and information on that, we will be certain to share that.

Our next question is coming from the line of Jason Gerberry of Bank of America Securities.

Just one, Phil, on Xywav, I apologies if I missed this, but at the beginning of the year, I think you guided to flat to mid-single-digit growth for Xywav, given the growth of nearly 20% in 1Q. Just wondering if we should be assuming that we're coming in towards closer to the high end of that number? Or were there some onetime dynamics in the 1Q number to call out? And how should we think about zanidatamab pricing OUS and any MFN-related considerations?

Sure. Thanks for the question, Jason. On Xywav, in the U.S., really pleased, as Sam mentioned, with the great execution of our field-based team. In terms of sort of underlying growth, we had volume growth of about 12% here in the first quarter. There was a bit of additional pickup coming from net price, primarily gross to net favorability with both mix of business and then patients successfully transitioning more quickly than in the past back on to their insurance in that first quarter reauthorization period. So that is something that is more of a first quarter phenomenon. We wouldn't expect to see that kind of net price pickup quarter-on-quarter as we get into Qs 2 through 4, but definitely pleased with Xywav performance in the first quarter sets us up nicely. We're achieving the full year guidance. I think that also applies to this total revenue guidance as well, not just Xywav.

And then for the MFN zani, right now, the MFN considerations, as you know, are a bit uncertain. You've got some sort of conflicting input out there, certainly GLOBE and GUARD are as proposed to use a basket of ex-U.S. countries to provide reference pricing for the U.S. So we'll certainly be taking that into account as we look at the strategy for getting Ziihera to patients outside of the U.S., which is certainly a priority of ours, but one that we will need to take account of the current situation here in the U.S. as we move forward. I'm not sure, Sam, if you'd like to add any your thoughts from a commercial perspective or Renee more from a corporate strategic perspective.

I think you've covered it nicely, Phil.

And our next question will come from the line of Ami Fadia of Needham & Company.

I had a follow-up on the comments related to the oxybate franchise, particularly Xywav. I think at the beginning of the year, you talked about anticipating the potential for some additional headwinds either on pricing side or just in terms of access with the entry of generics. Maybe if you could sort of talk about some of the dynamics around whether you're seeing any pushback on the use of Xywav, particularly in narcolepsy? And how do you see the utilization in narcolepsy evolve with more generics kind of on the market? And then just on the Modeyso ACTION trial, can you sort of talk about what -- which interim OS analysis will be done by the time you have the data readout in late 2026, early 2027, and just sort of your confidence around the time line of that readout?

I'm happy to take the question relating to Xywav. Yes, of course, we've seen 2 multisource generics enter the market in Q1. As yet, we haven't seen any impact on Xywav business so far. As I mentioned previously, we continue to have a strong payer coverage supporting the use of Xywav. So nothing really has changed in the nature of our business for Xywav. But of course, it is still early days for the generics in the market. We do anticipate that as their volume grows through the course of the year, then we may start to see some actions taken by payers. That may include utilization management. We don't know yet.

But we're very confident that Xywav offers a really important and differentiating option for patients, being the only low-sodium option, the only product approved for IH. And of course, it has already demonstrated how effective it is as a nighttime agent and the impact that has on daytime symptoms. So we've obviously carried strong momentum throughout the last 12 months and into this year, and we're in a strong position as we go into Q2.

Maybe I'll hand over to Rob for the question on Modeyso.

I'll go ahead, Sam, just add one thing real quickly as we think about what we're seeing with Xywav before we go on to Rob for Modeyso. Certainly, the dynamics are a bit unusual in the first quarter given reauthorization. But I do think we're seeing continued support by patients and physicians of the unique benefit that Xywav offers from looking at the net patient adds. I think LUMRYZ net patient adds were announced roughly 100 adds this quarter, like the 100 last quarter. Our numbers just in narcolepsy have been larger than that in each of those 2 quarters. Again, I think underscoring this unique benefit that only Xywav can offer and the safety advantage it confers being valued by patients as well as physicians. So we're in a great position from that perspective as well as we think about the back part of the year and how things could play out. Rob?

Yes. So Ami, the ACTION trial is an OS-based endpoint, and there's one interim analysis and then a final analysis. The projections we gave are based on our current understanding of the events because it is an event-driven trial. And certainly, if the events slow over time, that could change, but we'll update as appropriate as time goes on.

And our next question is coming from the line of David Hoang of Deutsche Bank.

I first wanted to ask on the timing of a potential NCCN guideline incorporation for zani in GEA. Do you have any sense of relatively when that might occur versus the PDUFA date and how important is a Category 1 recommendation to drive uptake? And then in breast cancer, for zani, I wanted to get a sense of how you're thinking about the opportunity size in the different settings. So obviously, you're looking at post HER2, but I think you're also looking at neoadjuvant and adjuvant. And so I was just curious as to your thoughts on size of the opportunity in those various things.

Great. On the NCCN guidelines, we proactively submitted the abstract data because it was available. We will certainly update NCCN with the full manuscript as soon as that's available, and we hope that gives them everything they need to make a prompt decision on that and adoption, which we expect. Certainly, we think the data speak for itself. I mean head-to-head against Herceptin, zanidatamab definitively wins. Clear that tislelizumab is adding and there's likely to be a synergy between zani and tislelizumab as demonstrated by the activity in the PD-L1 negative subset, supporting its use upfront with tislelizumab. And so we think those data speak for themselves, and that should be reflected in NCCN.

Sorry, just to finish off the remainder of that question there. Yes, I mean, NCCN guidelines inclusion, obviously important. We think that the data supports a Category 1 inclusion. If it comes before the launch, then that will open up access ahead of regulatory approval. Of course, we don't promote that ahead of regulatory approval, but certainly, that will make it easier for physicians to provide access to their patients. And yes, the breast cancer opportunity, obviously, very significant, significantly larger than either the BTC opportunity or the GEA opportunity with many more patients that can potentially benefit from zanidatamab. So we're excited, obviously, about that for the long-term potential for HER.

And that does conclude today's Q&A session. I would like to turn the call over to Renee Gala, CEO, for closing remarks. Please go ahead.

Thanks, operator. I'd like to close today's call by thanking all our partners and stakeholders for their continued confidence and support. We look forward to sharing further updates on the potential approval of zanidatamab in GEA and additional meaningful progress with you over the remainder of the year. So thank you for joining us, and have a great day.

This concludes today's program. Thank you all for joining. You may now disconnect.

Good morning, everyone, again. Thanks for joining us for this next session with Jazz Pharmaceuticals. I've got Phil Johnson, who's the CFO of the company, along with John Bluth and Jack Spinks from the IR team.

Phil, thank you so much for taking the time to be with us today. What I'd like to do is maybe turn it over to you for some opening remarks, and then we can dive into a Q&A.

No, definitely appreciate it, Ami. Thank you very much for hosting us today. Looking forward to the opportunity to answer questions that are of interest to you and have already enjoyed some of the interactions we've had with investors through virtual conference, looking forward to further sessions later today.

Before I get started, please do note that we'll be making forward-looking statements today. Those are all subject to risks. Actual results could differ materially from what we're describing. Please do consult our SEC filings for a more fulsome disclosure of the risk factors affecting our business.

And then if we do refer to guidance today, which I'm sure we will, we're referring to the guidance that we gave on our fourth quarter 2025 earnings call on February 24. So maybe just starting with a high-level overview of where the company is at. 2025 was an exceptional year for Jazz. It was our 21st consecutive year of top line revenue growth. Strong commercial execution across our diversified portfolio delivered record total revenues of $4.3 billion.

For our largest product, Xywav, we start 2026 with a really strong position, roughly 16,000 patients at the end of last year, taking that particular product, excellent payer contracts in place to begin the year. And our position is the only low sodium oxybate, something that's really, I think, resonating well with physicians and patients, places us in a position of strength as we enter a year with some more uncertainties, in particular, the introduction of generic high sodium oxybate and the introduction of some daytime wake-promoting agents in the back half of the year as well.

We're focused on sustaining the really strong execution and launch mode for Modeyso as well as that first-line maintenance indication for Zepzelca and reinforcing those differentiated profiles that we have for both Epidiolex and Xywav, our 2 largest products.

2026 total revenue is expected to be $4.25 billion to $4.5 billion. That -- we're gunning for our 22nd consecutive year of revenue growth, expect double-digit growth across our epilepsy and oncology franchises driven by Epidiolex, Modeyso and Ziihera. And then as we talked, expect Xywav to be flat relative to 2025 to up mid-single digits.

We're excited on the pipeline side as well, some progress that we've made, presented practice-changing datamab for both zanidatamab in HER2-positive first-line metastatic GEA at ASCO GI and also the data we presented last year for Zepzelca in the first-line maintenance setting for extensive stage small cell lung cancer, completed the sBLA submission to the FDA under also the real-time oncology review program for zani in first-line GEA -- that could result in our expectation is we will get an approval and launch in the second half of this year. And also at our last call, we did notice that -- or did note that the FDA granted breakthrough designation for zani in this particular setting as well.

We did submit the abstract from the ASCO GI presentation to NCCN for their consideration for inclusion in guidelines. And as soon as we have presentation -- or sorry, publication, I should say, in a top-tier journal, which we expect in the near term, we'll submit those data as well to NCCN to support potential guideline inclusion there.

And then lastly, I'd say on Zani first-line GEA, we do expect, as stated before, that second interim overall survival readout for Arm B, the doublet to occur mid this year. More broadly on the Zani development program, we're seeing continued strong enrollment of patients into EMPOWER, the metastatic breast cancer study underway where we'll be the first to generate really important data in patients, who either progressed on or are intolerant to Enhertu.

We're confident that Zani can play a really meaningful role in this setting, aim to complete enrollment in the study in the first half of next year with top line data late in 2027, early in 2028. And then the PAN-tumor trial also is enrolling well. On dordaviprone, we do expect by year-end this year or early 2027, the first interim overall survival analysis from the ACTION study that studying dordaviprone in that first-line setting of H3K27M mutant diffuse glioma.

On the business development front, we made some great progress last year, both with the Chimerix acquisition as well as the licensing deal with Saniona in the epilepsy space. We do expect to have more deals this year to announce, and we're in a great position financially to transact with that's with licensing or M&A, having finished last year with $2.4 billion in cash and investments and strong cash flows.

So looking forward to further bolstering our future growth outlook as well as building out, as Renee had talked about earlier this year, our refined corporate strategy focusing on rare disease. So great momentum. We just had a recent, I think, all-time closing stock price high the other day as well. So lots of great momentum in the company and looking forward to a great year in '26 and beyond. With that [indiscernible] the questions.

Yes. No, first of all, congratulations on all the momentum that we are seeing with the progress as well as it's being reflected in the stock price. Maybe I wanted to kick us off with the comment that you made around sort of Renee talking about the shift in focus and strategy of the company to rare diseases.

Could you elaborate on what that truly means in terms of your prioritization across the different segments of the business, whether it's CNS, oncology and some of the assets in both CNS and oncology could be viewed as rare diseases as well. So what does that really mean in terms of how you prioritize investments in your portfolio, but also how you think about business development?

Yes. I think in reality, Jazz is and has been a rare disease company, even though we've talked about our business, as oncology and neuroscience, in effect, all of our currently marketed products and all of our successes have been in places where they're effectively rare diseases. And we have divested some opportunities that had broader application, thinking of Sunosi back in the day, for example.

So I do think it's a refinement of the strategy, not necessarily a revolution of the strategy. It is also the case that we have been looking in select cases at some investment opportunities that would have been more broad. And those are ones that we're saying de novo, we're not going to do that anymore. We will focus on those things that are rare disease within areas that are existing strengths of ours like epilepsy, oncology and sleep, but also look to get into new areas of rare disease as well.

Should something that is either internally developed or licensed or acquired lead us into something that is a broad disease, we'll certainly want to look at how we maximize value. We're certainly doing that, I think, effectively with Zanidatamab as we initially brought that in, thinking of its potential in biliary tract cancer and gastric cancer and now see some great potential in breast cancer, which is a larger tumor type.

So we won't turn away those opportunities, but that won't be the focus. We'll be really looking to build in rare disease where we've got some demonstrated capabilities that we think allow us to be very successful getting those molecules to patients and also creating positive return for shareholders. There's an important differentiation that Renee pointed out in the strategy that I think would be welcome news for investors as well.

We recognize that in areas that we have strong pre-existing expertise, including in-house expertise, that we can and should be in a position to invest across the broad spectrum of opportunities from marketed products all the way back into preclinical, like we did with Saniona last year in the epilepsy space.

We do expect to get into one or more additional rare disease areas. We want to take more measured risks as we make those entries. So we'd be looking probably at things that are post proof of concept. So post Phase II [indiscernible] are on market as our initial entry. I could see us doing something that is maybe not post proof of concept for that molecule, but that concept has already been proved out by another molecule, and we think we have the best-in-class. But we wouldn't go earlier than that.

Once we've then established greater expertise and have a more solid foundation upon which to make those investment decisions, then you would expect to see us going into Phase I or even preclinical in those areas.

Maybe I want to sort of layer on, on top of that and try and understand how you're thinking about business development, and it's always been very core to Jazz's strategy. And Renee, as you've gone in new role, reemphasized that, that continues to be one of the pillars of the strategy. But I think over the years, Jazz has done a wide variety of deals.

For example, the GW transaction, Zani, Modeyso, I think they are all different in scale at the time when you made those acquisitions. But they've all sort of ended up helping you achieve the direction that has set out -- has been set out for the company. But given that you are about to launch or expand the indication for zani, you have maybe a line of sight into breast cancer data, you'll continue to grow some of your other end market products. What is the priority in terms of bringing on either a mid-stage asset versus a much more transformational deal that can add another big pillar even if it's in rare disease, another big pillar to the company?

Yes. No, great question. We -- before I actually get to answer your question, I do want to just give a quick aside. The company is, and I think, a longer arc of time in a really important transformation from more traditional spec pharma into more biotech biopharma. And we announced on the fourth quarter call, we had the first actually Jazz invented molecule move into the clinic.

So while corporate development, I think, will always be an important part of how we source molecules to benefit patients and benefit shareholders, our expectation is that over time, you'll see some portion of those assets that we're bringing to market coming from our own research efforts.

We, through the GW acquisition, got some really good capabilities in the chemistry side of things, actually with Chimerix recently, some great capabilities in biology that we'll continue to build upon. But I would say, again, longer arc of time, many of the investors we know maybe have a shorter time frame they're thinking of. But as you think about Jazz overall, please do keep in mind this transformation that we have front and center that we're driving toward as well.

In terms of the types of deals, I would say Zani and Chimerix are more representative of both what we're focused on and what's available to us realistically. We looked last year as we're revising and refining the strategy what were the opportunities in each of the areas we're currently in and then more broadly in rare disease areas that we could move into. But there really was significant substrate in those areas, probably the one exception actually of sleep, where currently sort of orexins and not much else.

But I do think the Zani licensing deal has been a really important transaction for us and one that can be significant not only for patients, but for shareholders in terms of their return. Chimerix equally, I think what it was an acquisition and not a licensing deal, much later stage, pre-market asset is shaping up to be a really great asset, both for patients and for shareholders.

So we'll look to do both licensing and acquisitions. Those -- I think people should expect are more likely more bolt-on than transformational. And you can never say never -- facts and circumstances will dictate what makes a ton of sense for us. But most of the things we're seeing in rare disease on the acquisition side are probably in that $500 million to $2.5 billion kind of a range, mass balance.

And then licensing, obviously, is more measured investment, less upfront with the shared economics downstream. But looking to be very active. We have upped the amount of management time and attention we place on this. We had the press release out earlier this year with Tom Regan, who came to us with the Chimerix acquisition, stepping into that Chief Business Officer role, and he's added great energy and excitement to that area and really pleased to have him working with the Executive Committee and the Board on our future corp dev activities.

Okay. Fantastic. So I'd like to move on to Zani for our next segment of the discussion. You've recently announced that you've submitted the sBLA. You've made the submissions for the NCCN guideline changes, what is your expectations with regards to the time line around the NCCN guideline change?

And maybe given all the data and the excitement around it, it would be helpful to get your latest thoughts on the target addressable market and the peak revenue potential for the product. I was earlier talking with Zymeworks and they're certainly a lot more optimistic and wanted to get your view as well.

Yes, I appreciate it. Jack, do you want to take this one?

Yes, happy to, Phil. And thanks, Ami, for the question. I think I'll start with how fast we've gone to date. We presented top line data here on the HERIZON-GEA-01 trial in November. We were able to submit that data, presented at ASCO GI. And ultimately, as you mentioned, Ami, submit that sBLA towards the end of February. So the team has gone really quick.

I think, in ensuring that we can get this data to market. We've already submitted the NCCN data. So this puts us in a really great spot when we think about launch. If you think about the time line, again, assuming a priority review here, we would hear about the PDUFA 60 days after that submission in late February, assuming a priority review, that would give us 6 months late August PDUFA date.

So we'll be hearing about that soon. But that keeps us square in that second half of this year launch time line for GEA. So we're quite excited. Again, we have RTOR. We have breakthrough therapy designation. So I think a lot of positives here, and we hope to hear about that PDUFA date soon. No updates on the NCCN guideline timing, Ami. We have submitted that. It's a bit out of our control. But when we think about when the regularly scheduled meetings are, we know there's one in August.

Again, we hope to have an off-cycle review. But I would note, it becomes less relevant if you have an earlier launch. So I think those are things we're paying attention to and thinking about as we look to launch later this year. And maybe I'll just address the last piece of your question when we're thinking about the addressable market for GEA.

Certainly, we think it's quite exciting. We are approved and indicated in second-line BTC. That's a very small patient population. When we think about broader HER2-positive BTC in the U.S., you can call it 3,000 patients. Again, we're talking about just second line, where we're approved today. We have the ongoing registrational trial in first line, but that second-line indication is very small. So when we think about GEA broadly, this data we've submitted would indicate us for first-line GEA.

That's potentially -- you're looking at an addressable patient population, who are HER2-positive around 8,000. So it's a substantially larger patient population relative to our currently indicated. Globally, it's much larger, around 63,000. So certainly excited for the launch.

We think the data themselves -- the data speaks for themselves. They're quite exciting. When you think about that launch, that uptake, having strong data here is very helpful, and it's something we certainly think we have. So looking forward to getting the PDUFA date, looking forward to launch potential NCCN listing, all exciting coming this year.

I want to move to the breast cancer programs. Obviously, you've demonstrated that Zani can be beneficial for patients post-Enhertu in GEA. How does that sort of increase your level of excitement around the potential in breast cancer? Is there any -- maybe sort of size up for us what are the pros and cons for its applicability in breast cancer? What is different about breast cancer as an indication and the competitive space there that may make a different or give you more confidence based on the data that you've seen in GEA in breast cancer?

Jack, why don't you start off and then I may complement.

Sure. Yes, Phil. I think that's a great question, Ami. Breast cancer is on the whole, I would say a more competitive space, but I do think there's an interesting space where Zani can play here. When we think about the trial we have ongoing, the Phase III EMPOWER breast cancer trial, this is a patient population that's looking at patients who have progressed on Enhertu or are intolerant to Enhertu.

So that space is really wide open. There is not a HER2 targeted agent that's generating data there, and we can be the first to do that. Again, that -- as Phil mentioned earlier, that data is reading out late next year, early '28. And I think having that data really helped inform treatment decisions post Enhertu, which today, there's not a good guideline and precedent set for what should you receive in terms of HER2-targeted agents post Enhertu.

We certainly do have data that is being generated to date that's already been generated in post-Enhertu patients. And I think, Zani's MOA really leads itself to having a positive trial here. I would note importantly here, and you mentioned some of the gives and takes. I think it's really important to think about what this trial is looking at addressing.

What's the experiment being run here. Our GEA data was, is zanidatamab a better HER2-targeted agent than Herceptin. At the end of the day, that's what we were testing. Our Phase III EMPOWER trial, the comparison is Herceptin chemo. So we -- yes, different indications. So we will certainly need to see that data. We want to have the Phase III data to inform those decisions. But when we think about what we're testing against, is zanidatamab a better HER2-targeted agent than Herceptin in breast cancer? We know the answer is GEA. It's definitively, yes.

So I think when we look to this breast cancer trial, I think we're quite excited given we have that GEA data, given we have data in patients who have progressed on T-DXd. So we need to generate the data. Ultimately, we need to read that data out. But I think what we have to date is really promising in terms of what this trial has potential for.

And we have this late-line trial. We also have an ongoing EMPOWER breast cancer trial in neo-adjuvant patients, which I think is equally exciting. And that's a little bit longer dated. But again, when we think about where zanidatamab can play, and I do want to take a step back briefly because it's not that we have to say we need to beat Enhertu. We can say zanidatamab can play in these areas, can look at novel combinations across the HER2-positive space in breast cancer and beyond and say, we can own these spaces.

We can generate data that are practice changing. So I think we've got a lot to be excited for certainly in this, call it, second-line setting with Enhertu, but also broadly. Phil, I don't know, if you have anything to add there.

Well said. Your first point was one I wanted to make sure I got out. So we're good.

Excellent. You've also generated some promising data for Zani in combination with docetaxel in first-line in HER2-positive breast cancer and the data was presented at ESMO last year. What are your plans for developing further in this patient population?

Yes, it's a great question, Ami. And that data, I think, do serve as proof of concept. When we think about the response rate we saw the progression-free survival, that wasn't a fully mature trial. And our partners, B1 presented that data. And I think it's -- again, when we think about what zanidatamab can do in breast cancer patients, that data is certainly very supportive.

I think I'll lean a little bit on my prior commentary because I don't think we have to go head-to-head against Enhertu. I think the data that they've presented in first line are extremely good. you could argue practice changing. And I think they're set to move and be the first-line standard of care.

And I think with zanidatamab, we don't have to say we need to target beating Enhertu in first line. I think having that data later line post progression is a huge white space, having data in neoadjuvant -- adjuvant where we can decrease overall toxicity for patients with early-stage breast cancer. I think those are all areas where we can play.

Can we look at novel combinations. We've had data with HR-positive breast cancer patients. We've had data in combination with CD47. So we've had a lot of interesting data and interesting spaces, where we can look at that are all still very meaningful without necessarily saying we need to go head-to-head against Enhertu run a very long study. We can instead look at areas, where I think we can effectively commercialize where we can effectively compete and do so with a high probability of success.

Okay. I'd like to move to Modeyso next, but maybe is there a plug that you want to highlight anything that might be presented at the AACR meeting this weekend on Zani, particularly? Or when you feel the pipeline maybe?

You gave me the most up to speed. I'm also going to give an advance notice. I'm not sure, if my computer is going to force a restart here. I thought I had said this and not do this until this evening. But if you lose me, that may be what happens. So Jack, do you want to -- anything you got to say on the upcoming medical meeting?

Yes, I can briefly touch on AACR. I mean there's, I think, some exciting early data. We have data being presented the NeoZanHER trial, which is an early neoadjuvant study of zanidatamab in breast cancer. I think that data is certainly exciting, build on data that's been presented. When we think about some of the early MOA work, I know we're presenting a poster on Zani's MOA and specifically looking at models, preclinical models in activity post-TDXd.

So again, speaking to this breast cancer opportunity, I think that's, again, incrementally helpful. And then we are looking at also presenting some data across JZP-3507 and/or down from Modeyso. So I think there's some exciting early data there, Ami. So we're looking forward to presenting that and also obviously looking forward to later in the year with upcoming medical meetings. We have, obviously, our second interim analysis of Zanidatamab later this year, launch for Zani and GEA. So a lot of exciting milestones, I think, upcoming.

Yes. Okay. Let's talk about Modeyso. It's sort of been a promising launch at the outset. Maybe if you could talk about your sort of initiatives to continue to tap into the market and your latest thoughts around the peak revenue potential? What it will take to get there? And what is the possibility of achieving above those peak revenue expectations that you put out there?

John, how about I put you in the mix here?

Sure. Happy to. So Phil mentioned Ami, why the Chimerix acquisition of Modeyso was such a good strategic fit for us from a business development strategy standpoint. One of the other reasons is because it represented such an advance for patient care. This product is the first advance for patients with this horrible form of glioma in about 50 years. So there's great hope and excitement among the physician and patient community for the product.

And so we're really excited that we were able to get it approved and onto the market so quickly, and we're very excited about the launch as it's progressed so far with all that patient and physician excitement. And I think there are a couple of variables which will help sort of determine what the slope of that launch curve looks like.

One of them is duration of therapy and what that duration of therapy is going to look like, I think will emerge with more visibility as we go through the next several quarters. And then the other piece is related to -- sorry, I just had a breakout.

Yes. Therapy.

Yes, therapy. Thank you, Phil. It's related to how many patients there are. And so we think there are about 2,000 patients. And we might be right or we might be wrong about that. There could be more, there could be less. And I think that with a lot of rare diseases, you see when there is a new therapy that comes online, you see patients kind of come out of the woodwork because there's a new option for patients. So I think those are the 2 pieces that are going to really dictate what the slope of the launch curve looks like.

And I think it's also the peak revenue potential that you asked about, Ami, as well. So this is one that's going to take a while for that first element that Sean had mentioned to become more apparent to us of how many months of treatment are we seeing in actual clinical treatment.

Again, this is a product that depending on how you measure it, has somewhere in that 22% to 28%, if I'm recalling the numbers correctly, response and some pretty long responses. So with the launch having just occurred in August of last...

My computer or is it Phil's computer? Okay, there you go.

There we are.

Sorry, we lost you for a second there, Phil. But you're back.

Okay. So it will take until end of this year, year-end and into next year for us to really know how many patients are persisting for much, much longer than the 10 months average that we're assuming. So that will take a bit of time for it to play out. We're quite hopeful with that. But again, it will take probably into next year for us to really have a good read for the average thinking mean, not median duration of response and duration on treatment.

And maybe one last point is that we've got the ACTION trial ongoing. And so that trial will get some initial data from, we think, late this year, beginning of next year. And while we do think there is some first-line use going on right now with physicians, that's a trial that could bring that into the label as well.

Yes. Okay. I'd like to switch gears to the sleep franchise or maybe Xywav. You've talked about IH being the continued sort of growth driver for this drug. Of course, we have the dynamic with generic Xyrem impacting the market a little bit. But could you elaborate on what is it that you're focused on in terms of continuing to drive growth for Xywav this year, particularly in IH?

And talk about the backdrop of the competitive landscape potentially that's likely to change with the LUMRYZ IH data that's expected soon. And then stepping back, we are seeing an evolution in the face with the orexin data. Of course, we've seen less data in IH, but I think that is going to come around the corner. So how are you thinking about the drug sort of trajectory over the next couple of years?

Yes. So I would say on the overall oxybate front, clearly, for us, Xywav is the product that offers unique benefits in the marketplace right now with the only approved low sodium oxybate. And as reflected in our guidance for this year, we expect to be a really important piece of our business moving forward through this year. And while we haven't commented on the future, we still see a really strong role for Xywav beyond '26, largely in IH, as you're pointing out.

So within IH, this is a market that we're still building and raising awareness and education, including in the physician community. So we have significant efforts that continue there in terms of just disease state awareness, patient identification. The overall market is large. This is one that has seemed to be -- if you look at some of the stated data, maybe half the size of the narcolepsy market, 37,000 patients relative to 75,000 or so in narcolepsy.

We continue to have many of our prescribing physicians state that they think they have a similar number of IH patients as they would narcolepsy patients. So there is a lot of growth we see in this market. It's possible that having more than one company eventually out marketing could help with that awareness and penetration of the category of oxybate into the IH market.

I would say we will continue to have a unique benefit, which is low sodium. This is resonating with patients and physicians currently, even in a scenario within the narcolepsy market, we're now for close to 3 years, we've had a branded high sodium competitor. We've had an AG for the last couple of years with high sodium.

We've continued to be adding patients net each quarter, I think speaks volumes to the health benefits that physicians see with low sodium. This is a patient population where you're talking patients with narcolepsy or idiopathic hypersomnia that do have a 2 to 3x increased risk for cardiovascular events. We and others have generated data that shows increasing sodium intake leads to clinically meaningful increases in blood pressure, which is a negative prognostic factor for cardiovascular events.

So that benefit will continue to be something that Xywav will offer that at least the current products would not. Also in IH, while data may be coming soon, my understanding is they can't actually market in IH until March of 2028. And in fact, any significant revenues that are generated in non-narcolepsy indications prior to that time, there's a very significant royalty that's paid to Jazz on this.

So we will look for sort of continued evolution to see what that data looks like. On other products coming into whether it's in the narcolepsy space or in IH, orexins in particular, as you know, for a long time, we said we view these as being complementary, not competitive products. I do think over time, others in this space, whether those are companies acquiring assets that are in the oxybate space and they already have an orexin or KOLs, increasingly, I think, are seeing that these will likely be complementary therapies and not substituted.

Data so far looks strongest with orexins in NT1 patients, narcolepsy type 1 patients. Expect, frankly, to have that first approval coming here later in the year. It's a bit more mixed. I think when we see NT2 data and then still jury out sort of on IH of what the data will look like there. But initial data, I'd say, doesn't look to be as strong in something like NT2 as an NT1 and I think a pretty big question mark in IH.

But certainly, we welcome if there are daytime weight-promoting agents that are helping these patients, whether those are narcolepsy patients or IH patients to experience better outcomes, phenomenal. But we do see a continued really strong role for oxybate to play and a strong role for low sodium oxybate like...

I think, you're on mute Ami.

I'm trying to read your lips.

I thought you could. So maybe just a quick follow-up on that. We've heard from almost every expert that we've spoken with or some of the other companies in the space that they view the oxybate as complementary. And I think there's an effort to generate more data on sort of sleep architecture with the orexins.

So I'm curious if from your perspective, you're thinking about generating any additional data on Xywav to further sort of elucidate the impact on nighttime sleep architecture. So Phil, I think we lost you for a second there. I'm happy to repeat the question.

I may need you to go ahead and have Jack and John tag team on this because I'm getting a multiple cycling of this coming on. I need to rejoin. Sorry, I really apologize.

No worries.

Yes, happy to jump in here, Ami. I think our team is continuously looking at what additional data we can generate. I think it will be helpful. Once an Orexin is approved, it makes it a little bit easier to run these kind of studies. But I think when we think about overall sleep architecture, we certainly see the benefit of having an oxybate and particularly Xywav.

And I think it would be helpful as we think about the landscape and it's evolving to have the data. So I think that's something Rob will certainly be thinking about going forward is where and when can we generate that kind of additional data. So nothing to speak to today, but I think we're continuously looking at where else can we generate this data to benefit patients.

Yes. Yes. I wanted to switch gears to Epidiolex. The performance has continued to exceed expectations. What are some of the measures that are being employed to ensure consistent growth in 2026?

And you've also talked about assessing Epidiolex in focal-onset seizures. The focal-onset seizures space is evolving with a lot of data that has recently been generated and more to come. So maybe if you can just speak to how you see its position evolving in that market.

Sure, sure. Maybe I'll start with the first part of it and what we're doing with Epidiolex to continue the robust growth that we saw last year to continue that going forward. One of the programs that we've got is a Nurse Navigator program that really helps patients manage through dosing and compliance with the polypharmacy that exists in the epilepsy space.

And that's been a very successful program. So we're going to keep leaning into that and expand it and try and get that program to more and more patients and awareness among providers. And then when you look at the additional growth opportunities in the space, the adult population is really another area for us to focus on. So I think those are 2 growth areas that from an execution standpoint, the team is looking to continue to execute around.

And then with regard to focal onset seizures, yes, we did just start a study at the end of last year in focal onset. And looking at the impact Epidiolex has had in other seizure types, we're very excited about seeing that data, but the study is just getting off the ground right now. But we think it has the potential to be a good fit in the polypharmacy approach to focal onset seizures also.

Okay. I know we are coming up on time, but maybe if I could squeeze in one last question on JZP-047, which you've identified for absent epilepsy. What gets you excited about the mechanism? And maybe just talk to us about the opportunity in...

Sure. So we haven't disclosed the mechanism. We're going to keep that close to our vest for now. But I think what's especially exciting about it for us is that it's a Jazz-developed molecule. And so we've talked a lot about how corporate development is going to be part of this ongoing shift and transition from a specialty pharma company to an innovative biotech company.

Our pipeline, our R&D pipeline, we want to fill with our own programs, and we're starting to do that now with JZP-047. So we think there's a need in [indiscernible], and we've got that expertise in epilepsy. And so we're excited to move that program forward and share more with you.

Okay. All right. Looks like we are at the end of our time. Thank you both and to Phil as well for taking the time to have this conversation and participating in our conference.

Thanks for having us, Ami. Appreciate it.

Thank you.

Hello, everyone. My name is Etzer Darout, senior biotech analyst at Barclays. My pleasure to have Jazz Pharmaceuticals with us today. On stage with me, I have Phil Johnson, Chief Financial Officer; and John Bluth, Head of Investor Relations. Thank you so much for joining us today. Phil, I'm sure folks are relatively familiar with Jazz, but maybe just to kick us off, just provide some introductory remarks, and then we'll go into our Q&A.

Yes, I'd be happy to. Thanks, Etzer, for hosting us here. And this is a great location to be in and a great time of year to be done here in Miami Beach. Just a disclaimer, please do as we're going through the discussion. If there's things you're interested in learning more about, including risks that can affect our business, please refer to our recently filed 10-K if we do refer to guidance during the discussion today, that will be the guidance we provided on our recent Q4 earnings call.

So 2025 was a great year for the company and really sets us up extremely well for 2026. And I think had important advancements in commercial, the pipeline as well as in corporate and development. I'll touch just briefly on each of those. So on the commercial side, in 2025, we had record revenue for the company growing 5%, driven by 12% growth in Xywav, 9% in Epidiolex and initial uptake of Modeyso that was quite strong. That was our 21st consecutive year of growth. This is a pretty outstanding achievement for any company. We're really proud of that accomplishment.

On the pipeline side, had a couple of really incredible pieces of data come out, practice-changing data in first-line maintenance, small cell lung cancer with our products, Zepzelca in combination with atezolizumab. And then probably most importantly, for the company, the first-line GEA readout as any data map, where we should unprecedented overall survival results extending beyond 2 years.

On the corp dev side, had a really interesting acquisition, both from a patient perspective, acquiring Chimerix with their drug dordaviprone shortly after the acquisition, we're able to get that approved and launched off to a great start. And also from a financial perspective, I think it's shaping to be a phenomenal return for Jazz and Jazz shareholders as we acquired deferred tax assets that will reduce our cash taxes over time by over $200 million.

We also received a priority review voucher with the approval of Modeyso and sold that, I think, for at least a 10-year high of $200 million. So really pleased with that deployment of capital. As we come into 2026, we provided guidance that was $4.25 billion to $4.5 billion in revenue for the year that would be 2.5% growth at the midpoint, meaning we are aiming for our 22nd consecutive year of revenue growth as a company as well. On the pipeline side, one of the biggest events people are looking for is approval and launch for zanidatamab in that first-line GEA setting. Initially, we've been targeting a submission to the FDA in the first half of 2026.

On our fourth quarter earnings call, we said that would be in the first quarter. And then at the recent conference, I won't mention the name. We had confirmed we actually already have submitted to the FDA. Post the data being available, the FDA had included us in the RTOR program, the real-time oncology review program and then more recently assigned breakthrough designation for zanidatamab in first-line GEA as well. So we're optimistic that we'll receive a priority review and look forward to approval and the launch of the product later this year.

And on corporate development side, we're really well positioned, I think, understanding the substrate that's out there in rare diseases of interest to us and with great financial resources to be able to act $2.5 billion roughly in cash investments, strong ability to leverage if we need it for attractive opportunities and additional focus that we place on corporate development with the hiring of a Chief Business Officer, Tom Riga, dedicating additional management time and focus to those efforts. So confident we'll be able to find really good opportunities for us to deploy capital, improve outcomes for patients and drive greater returns for shareholders as well.

Great. And maybe just internally, when you think about investments in the business, obviously, new franchise, epilepsy franchise, huge components of the company today, but then you have this growing oncology business with Ziihera hopefully coming -- continuing to grow as we get more and more clinical updates. How are you thinking about sort of resourcing CNS relative to oncology just internally and how you kind of think about that business over the next couple of years?

Yes. So we've got great opportunities sort of in that nonsleep portion of our business. As part of the guidance, we did say that revenue, which is over half of the company's total revenue in 2025, we expect to grow double digits here in 2026, continued growth of Epidiolex and then obviously ramping for Modeyso and growth in Ziihera as well. So we are extremely focused in terms of capital allocation on investing behind the existing marketed products and making sure that we're getting those to patients who can benefit from them in driving revenue there. That is what pays the bills and gives us the resources to invest.

Secondarily, really making sure that we're investing behind the existing pipeline. It's in-house now. We've got some great opportunities, first and foremost, probably to build out indications for Ziihera and then certainly, high priorities as I mentioned earlier, for us to go ahead and increase the company's future growth profile through additional corp dev. As we think about the areas where we're currently operating in, sleep, epilepsy and oncology, as you look at the substrate there, there is the most interesting innovative science, probably in the epilepsy space in the oncology space in sleep, which I'm sure we'll talk about going forward. Orexins are currently the only sort of real innovation coming forward. That may change over time, and we'll continue to look for opportunities to grow that franchise as well. But then definitely beyond the areas that we're currently in, we see some really good opportunities in rare disease to go ahead and expand our presence, use our capabilities to drive great outcomes for patients as well as for investors there as well.

We haven't yet done that. So I know we've been saying this for a few years, but I wouldn't be surprised if in the coming quarters or years you're seeing us expand into one or more new rare disease areas beyond those that we're currently in.

And people which tend to have short memories. So we think about the Modeyso transaction is sort of being a recent one. And just maybe looking forward, is that maybe a framework in terms of what we could see from Jazz and just in terms of sort of the deal type deal size?

Definitely love if we could find some more Chimerix is to acquire. I would say that if you think about where we'll be investing in the areas we've got existing deep expertise knowledge and relationships, we'll invest across that full spectrum from marketed products all the way to preclinical. So the Saniona licensing deal that we did last year in the epilepsy space is an example of that. If we're going into new areas of rare disease, which I mentioned, I expect that we will do going forward, those initial investments would likely be targeted to things that are post proof of concept or at least proof of mechanism with an improved compound going after that mechanism.

And as we build that expertise, knowledge and relationships begin to invest earlier in clinical or even preclinical development.

Great. And maybe on to the sleep franchise, obviously, on Xywav, a great performance the last couple of years. But we have Lumryz other generic oxybate potentially coming online as well. Orexin agonists being talked about sort of your view on the durability, if you will, of the sleep franchise.

Yes. So we're really pleased over the years with how Xywav has performed not only in building out the idiopathic hypersomnia indication where we're the only approved drug, and I think we've been quite successful in building awareness of the utility of an oxybate for patients with idiopathic hypersomnia, but honestly, also in narcolepsy as well, where I think many on the street, potentially even some internally expected something different to happen than what really happened. So we've been continuing to build quarter after quarter the number of patients on Xywav with narcolepsy, even with the emergence of a branded competitor and the AG. We had, I think, even more net patient adds in the fourth quarter than the branded competitor did.

I think it speaks to the unique benefit that Xywav offers, which is a safety benefit of having low sodium using the patient population, whether that's those with narcolepsy or idiopathic hypersomnia that have a 2x to 3x higher incidence of a risk for cardiovascular events. We've got data that shows, for example, if you go from a high sodium oxybate to a low sodium oxybate, you see clinically meaningful reductions in blood pressure. This kind of benefit, we think, is resonating with physicians and patients. It's part of the reason why we're not only building the market in idiopathic hypersomnia but having probably more durability in narcolepsy than many would have thought.

I mentioned on our fourth quarter call, there were some accounts last year that had a step through the AG before you can get to one of the branded options and we still have the highest share there. So this benefit, which is a safety benefit does resonate with physicians, with patients, and we'd expect to resonate with many payers as well.

Great. And we've had conversations with different KOLs and their views on orexin agonist in general seems to be varied. In your conversations with key opinion leaders around the potential impact of orexin agonist. What are you hearing from them about what that impact could be on?

There's great excitement for the orexins, not only hypersomnias where we're operating potentially in patients with ADHD or Alzheimer's, Parkinson's, et cetera. We don't follow that portion of as much. So I'll limit my comments maybe to talking about the role in hypersomnias. Certainly, orexins appear to be the most potent weight-promoting agents that we've seen today, particularly in narcolepsy type 1 patients, which is where we'd expect to see the first application and approval of Takeda's product especially getting approved and launched yet this year. I think the role in NT2, the role in IH is still to be played out, and still uncertain. Jazz for quite a number of years, has been saying that we view orexins and oxybate as being complementary and expected there to be concomitant use, not that orexin would actually cure patients and obviate the need for oxybate.

I think for many years, people looked at that as a maybe Jazz self-serving comment. There is hope, I think that these orexin products might go ahead and be the cure, if you will, functional cure for patients with narcolepsy, particularly narcolepsy type 1. That does not seem from our view to be the way the data is playing out and I think other whether it's KOLs or other corporates, I think, are also adopting the view that these will be complementary therapies. My expectation is that if the company is going to spend a couple of billion dollars to get a company that has an oxybate and they already have an orexin, they're probably not viewing them as being competitive, either of being complementary. So hopefully, good news for patients with narcolepsy that this could be a more effective daytime treatment to use alongside an oxybate to help treat their symptoms and get better outcomes.

Great. And maybe a couple of questions on epilepsy. Epidiolex settlement looks to have a really nice IP runway. But when you think about sort of maybe the growth profile or the growth outlook for Epidiolex, how are you thinking about that?

Yes. So really pleased to have the ANDA settlement with the 10 ANDA filers that we announced last year in the early part of the year, giving us runway out to the very late 2030s. And the product last year grew nicely, past that $1 billion mark. And we see opportunities for continued growth of Epidiolex going forward. A number of places where we're focused. One I would highlight is in the adult patient population. Many of these are in long-term care settings. We've been expanding our outreach efforts there. Many of these patients also have LGS, a condition that takes over a dozen years often to be diagnosed. So we've helped with the rest LGS tool to help physicians identify these patients at times, there can be difficulties as someone goes on to therapy of getting up to and titrating to an efficacious dose and then staying on therapy.

We have a really effective nurse navigator program that's been rolled out to a minority of patients so far that we're looking to expand because we do see better experiences on products, including greater persistency when they're having that additional support. We're also looking for ways to improve the product profile for those adult patients. We haven't been specific about the exact formulation, but we have some working on a formulation that could make the product more attractive to adult patients and looking for additional ways that we can generate data to inform clinicians on uses of Epidiolex, including the Phase I study that we recently mentioned, we're starting in focal onset seizures as well.

And then beyond Epidiolex itself, with that long runway to the very late 2030s, this certainly is a franchise we'd like to build out with additional products to have in the bag and build on our existing relationships to benefit patients.

Yes. And how much of the safety tolerability observed with Epidiolex? How much of a differentiator is that in epilepsy?

Most of these patients are on polypharmacy. They're typically taking 3 or more antiseizure medications. And Epidiolex seems to combine very well and is often one of those medications that they're on. You even see this as some of the newer products coming through clinical development or in a number of these cases, you've had probably 1/3 or more of patients that have been on Epidiolex in those studies as well. So we do expect going forward, there will be additional innovative therapies that will help improve patients' reductions in seizures, but there will be a continued need for additional add-on therapies and Epidiolex is well positioned to be one of those.

Great. And maybe a few questions on the oncology franchise. Let me first, maybe Modeyso sort of encouraging a launch maybe you can kind of speak to that, what's sort of driving that? And maybe how you see that evolving in the next few years?

Yes. So we've been really pleased with the uptake of Modeyso -- really been nothing for these patients since the advent of radiotherapy 0 years ago. We saw strong initial conversion of patients that were on the expanded access program over. But of the 360-plus patients treated in 2025, the vast majority of those were new patients. So really pleased with that adoption and uptake, including in those new patients, not just the conversion from the EAP program. This is a product we said we see having $500 million peak sales potential just here in the U.S. This early uptake is very encouraging. We're still reserving judgment on whether that $500 million should change or not. We're monitoring 2 things over time to understand if that should be moved up. One is do we get the Epi right, roughly 2,000 patients? Are there actually more out there that can benefit from Modeyso.

And then secondarily, duration of treatment. We've been in the market since mid-August. So it's still early to know how long patients will stay on. Our first patients will get out to a year, obviously, therefore, are going to be those that would have been out in August of this year. So by end of this year, I think we have a much better view on average duration of treatment, that is median and be able to understand does that also influence the peak sales potential.

And maybe you could comment on how much -- how important is that front line update on sort of that $500 million peak number in the U.S.? And I guess, maybe how we should think about -- could it be potentially more if that...

No, great question. The first-line use was included in that $500 million estimate when we had provided it. When we acquired Chimerix, we did make some adjustments to the ACTION study. We increased the number of patients by about 100. We changed the primary endpoint to the overall survival that we think is more appropriate and that readout is expected in late this year or early in 2027. So look forward to that readout as well. We are approved in that recurrent setting. That's where we promote to, but we do know that given the unmet need there and the physicians see this as a very well-tolerated drug, some of that early uptake is occurring and physicians using this in earlier line patients in first-line patients.

Great. And with -- we talked about the Horizon update in gastric cancer, obviously, great results. How are you preparing for that launch in that frontline population and again, extending that beyond? And I guess you also have to kind of think ahead and potentially breast coming on in a couple of years. So how are you thinking about that initial launch? And then how are you setting up hopefully for success beyond gastric?

Yes. So really excited to be bringing this to market in the not-too-distant future given the kind of practice-changing results that we generated. The current indication is in second-line biliary tract cancer, and these are effectively the same physicians, probably just 90-plus percent overlap of the prescribing physicians for first-line GEA. So these physicians are getting initial experience with the drug in those BTC patients. We think that initial experience will be very helpful as we come to market later this year in first-line GEA. And then yes, the next thing sort of up would be breast cancer. There, we're studying in metastatic breast cancer, basically in patients who have progressed after Enhertu therapy or intolerant to Enhertu therapy.

We're really the first one into generating data in that space, which right now is sort of a third line plus but with Enhertu moving into the first line, that would become more of a second line plus kind of indication. And we're almost going quite well. We currently expect enrollment to complete in the first half of 2027 and then trying to use our best estimate of what we're seeing in event rates currently, that would be late '27 or late '28 for the initial readout there, that would be the final PFS and then the first interim OS.

Great. And again, beyond this initial data set, with this profile, there are various ways you can go. You can go into earlier line breast cancer. There's also the tumor-agnostic approach around HER2 therapies. How are you thinking about that beyond the initial indications that you're currently executing on?

So we do feel like the data that we generated in that first-line GEA study are pretty definitive proof that at least in that setting, we have a vastly superior targeted HER2 agent compared to Herceptin. So clearly, we're looking where Herceptin was approved and successful, which is breast cancer and gastric cancer, looking for ways to expand there. That could be both early breast cancer, like you mentioned, adjuvant, neoadjuvant, also early gastric. And then we're looking at some places where maybe Herceptin didn't get approved, didn't quite meet the bar, but with a much more potent HER2 agent, we could have success. So we're looking in non-small cell lung cancer. We have some really outstanding early results in colorectal as well that we're looking at.

And then even within the existing areas that we're in, trying to figure out what are ways we can go ahead and improve the data that's available for physicians over time to inform use. So striking up partnerships with companies that have novel could be best-in-class for 2 targeted TKIs, for example, in breast cancer. So we've got a recently announced collaboration with Boehringer Ingelheim, zongertinib, and then you'll probably expect to see more of that from us over time as we build out zani. There's the ongoing pan-tumor trial that you had mentioned that could also lead to an additional indications. That's a registrational quality and size of the study as well.

And within oncology, there's other areas as well, you mentioned the frontline maintenance, small cell lung cancer study. When you think about, again, optionality around the oncology portfolio and in the pipeline. How should we think about sort of the rest of the oncology business for Jazz?

Yes. So with Zepzelca in that first-line maintenance setting in combination with atezolizumab really excited about those results, strong overall survival benefit and very clinically meaningful benefit there. We would expect to see that become standard of care in that first-line maintenance setting. As far as how the overall product revenue progresses, that will depend on the dynamics in the current second line, which is the majority of use, where there is a competitor that has overall survival benefit that we would expect to become standard of care over time, and our use in second line decline.

And also, there's not data that we would point to that would indicate that we expect if you're getting Zepzelca in that first-line maintenance setting, that you'd be rechallenged in second line. So again, really pleased with the benefit we can bring for patients in that first-line maintenance setting. That's where we've been focused for quite some time. We'll continue to be focused there, but recognize that, that second line business will decline overtime.

Great. And then early on in the pipeline, you have, again, a few different assets across different therapeutic areas of interest, one of which is the KRAS and G12D and pan-RAS programs. Just how are you looking at that space as it evolves and where you think ultimately Jazz could play a role in that space, again, given how much interest there is overall in the RAS space?

Yes. So we've got a couple of Phase I assets ongoing and RAS that you mentioned, the sort of in expansion cohorts now. So pleased we're moving into that. We've got the conditionally activated interferon alpha is moving into some cohort expansions as well. So pleased that we're sort of passing some of those initial Phase 1 hurdles moving into those either dose escalation, dose expansion or cohort expansion studies that have strong interest in solid tumors for each of those assets. We also -- as Jazz has been transitioning over the last 6, 7 years, into a more fully integrated biopharma company, including not just early development, but actually preclinical development, our own research. We're pleased to have moved our first Jazz generated asset into the clinic. This is in the epilepsy space, still holding off on disclosing mechanism of action. We expect to see more assets coming from those efforts as well.

While [ corp dev ] will continue to be the primary source for us of getting new innovation into the company, assets like as I hear, like Modeyso, we're really pleased we're beginning to see sort of the fruits of the labor over many years to build the research capability that can generate interesting assets as well.

Great. And we mentioned focal onset seizures as a potential long-term opportunity for Epidiolex. Maybe the basis, if you will, for a bit, for that is maybe some preliminary data that you've seen internally maybe preclinically physician feedback on maybe anecdotal evidence. What's driving that?

That as well just clinical data you've seen. So we're basically in specific diseases, if you will, as opposed to the seizure type, and we've seen benefits in focal onset. I do think we want to make sure that we're thinking about how to best direct that development to be consistent with our focus on rare disease and also the kind of pricing profile at Epidiolex has as well. So trying to find a patient population where you've got a significant benefit that you can feel good about both the incremental outcomes that you're driving for patients as well as then the kind of pricing that you have for the product.

Great. Bill, John, thank you so much for your time. Enjoy the rest of the conference. Thank you for our listeners, and we'll be back to our next session shortly.

Thanks, appreciate it.

Alrighty. Hello, everyone. I think we'll go ahead and get started. Thank you for joining us on day 2 of TD Cowen's 46th Annual Health Care Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. And it is my pleasure to have with me today several members of the Jazz Pharmaceuticals management team. We have CFO, Phil Johnson. We have the Head of Oncology Clinical Development, Amal Melhem-Bertrandt; and we have Head of Investor Relations, John Bluth, down there at the end.

So thank you for joining us. Maybe before we dive into the individual programs, it'd be great to start with just a brief overview of the company's recent progress and maybe your outline goals for 2026. I know we had recent year-end financials. So if you want to kick it off and then we'll dive in.

Well, first, thank you very much for having us. A great conference, great to be in Boston, a great lineup of investors here to meet with and really pleased with the progress we've been making at Jazz. I appreciate your interest in the company.

We will be making statements today that are forward-looking. Please do refer to our SEC filings, including the recent 10-K for the factors that may affect our business going forward. If we do refer to guidance, we're referring to the guidance that was provided on our most recent fourth quarter earnings call.

So 2025 was an outstanding year for the company and one that sets us up really well for 2026. And I think shows significant progress in the commercial part of our business with the pipeline as well as in corporate development. So 2025 was a record year for us with our highest revenue ever, highest revenue quarter in the fourth quarter, 21st consecutive year of growth in revenue as a company, a pretty outstanding achievement.

Really headlined with 12% growth in Xywav, 9% in Epidiolex and extremely strong start to Modeyso. Our oxybate franchise went over $2 billion for the first time. Epidiolex passed the $1 billion mark and our oncology franchise, again, above $1 billion. So really strong performance across each of our verticals.

On the pipeline side, I'd highlight really practice-changing data that was presented on first-line maintenance use in small cell lung cancer in Zepzelca in combination with atezolizumab and then probably most notably the first-line GEA data of zanidatamab that really showed unprecedented results, including more than 2 years of overall survival.

On the corporate development side, made some really good progress with the acquisition of Chimerix that brought Modeyso, again off to a really phenomenal start. Really great to have this option for patients that have had no drug alternative, basically, to help them with this really aggressive and rare form of brain cancer. That acquisition also brought some significant financial assets including a deferred tax asset that will reduce our future cash taxes by over $200 million, and then we did receive a priority review voucher, which we sold for $200 million. I think it's a high watermark in terms of sales price in the last 10 years, half of that then flowing to Jazz.

So shaping to be a really great transaction, not only for the benefit that Modeyso can bring to patients, but the financial return it can provide to Jazz and our shareholders. Also complemented our presence in epilepsy with early-stage asset, clinical asset from Saniona that we have high hopes for.

And I think on the back of the ANDA filings or ANDA settlements we had last year in Epidiolex that give us visibility to the very late 2030s in terms of the duration of that franchise, you should expect to see us continue to invest not only in Epidiolex, but in other assets to build out our epilepsy presence.

If we think about sort of more broadly, apart from commercial pipeline and corporate development, we also had, I think, a very successful CEO transition last year from Bruce Cozadd, our long time CEO and Founder, to Renee Gala. I think it was well received both internally and with the Street. Also refined strategy that Renee rolled out at JPMorgan, sorry, for the commercial-free competitor earlier this year, really highlighting the company's continuing focus on establishing ourselves as a leading rare disease company.

So if we think about 2026, again, great momentum coming into the year. On the financial side, provided our guidance, $4.25 billion to $4.5 billion in total revenue for the year. 2.5% growth at the midpoint. So hopefully, we'll have our 22nd consecutive year of revenue growth in 2026, really driven by strong growth in our combined epilepsy and oncology portfolio. We expect those products to grow in total double digits this year, again, buoyed by Epidiolex, Modeyso and Ziihera as well.

On the pipeline side of things, last year, I think we took one of your top picks for the year off the board. The morning we were having this fireside chat last year with the announcement we were going to be acquiring Chimerix. We don't have that kind of an announcement to help you with. But we do have a little new nugget. So when we get into the pipeline side of things for 2026 on our most recent earnings call, we have said that rather than submitting zanidatamab to the FDA in the first half of the year, that would occur in the first quarter of this year.

We've got a really great momentum with the agency, having gotten real-time oncology review, the breakthrough designation that we had disclosed on the earnings call, maybe, Amal, you can give the most recent update to where things stand.

Yes, happy to state that we've now completed the filing for the sBLA for GEA. So PDUFA clock starts. And yes, excited to see what comes next.

Yes. So the next step that you hear from us will be when we get a PDUFA date from the agency, but really pleased. The team has done a phenomenal job. If you think about this data in mid-November to have a completed submission by this point in the year is a phenomenal achievement by the team. I think shows Jazz's prowess in terms of being able to turn around these kinds of large complex studies quickly and also the agency's interest in these data as they see them also being really transformational for patients with first-line GEA.

We also, on the pipeline side, late this year, early next year, could have the readout from the first-line study of dordaviprone that continues to be ongoing, the ACTION study where things are progressing well.

And then on the corporate development side, we have very active efforts ongoing. And as Renee said, earlier in the year and on our call, a few weeks ago, you should expect to see us do one or more transactions this year, see great substrate, particularly, I'd say, in epilepsy, oncology and some other of the rare diseases and really are focused on dedicating additional management time and effort to ensure we're uncovering the really great opportunities and acting on those.

Really pleased. We've got a new colleague on our Executive Committee, Tom Riga, as Chief Business Officer, bringing in additional senior management time and attention to these efforts and quite confident you'll see activity from us this year that will give you a really good idea of the direction we want to be taking the company going forward. But again, great momentum that we've got coming into the year, just recently hit an all-time company high on the stock price as well. So really feeling that this is sort of the start of another chapter for Jazz. It could be a really promising one. So looking forward to it.

Awesome. Great. Well, a lot to dive in on. Maybe we'll start with some aspects of the base business. And obviously, you mentioned the 2026 revenue guidance of $4.25 billion to $4.5 billion. Maybe if you could drill down a little bit as much as you can on sort of how you expect the individual components of that to look, whether it's broad neurology versus broad oncology? And obviously, there's been some focus on Xywav just given the increased potential for Xyrem generics and obviously, we might have a new Takeda compound this year. So how do you see that franchise evolving throughout the year?

Yes. So over half our revenue in 2025 came from the oncology and epilepsy part of our business, and again, see really good growth there, again, double-digit growth expected in 2026, driven by Epidiolex, Modeyso and Ziihera. Again, with the first quarter and now already in submission, if we get priority review from the FDA, which we would certainly hope for, you should expect to see revenue in 2026 from the GEA indication.

We also have the possibility of NCCN guideline inclusion that absent the approval could also lead to potential utilization. Again, we will not promote for that indication until we have the FDA approval. But NCCN guideline inclusion would open up avenue for prescribers to get reimbursement for use in that first-line GEA setting. So we feel really good about that part of the business.

On the oxybate, this has been probably the biggest question mark that both we and investors had coming into the year. I would say the way things are shaping up are certainly, I think, in a very positive trajectory. So we've got an agreement with Hikma on the authorized generic that allows that to go as late as the end of 2029.

And then currently have 2 generics, Ascent and Amneal, who've expressed their intent and talked about some of their list pricing in the true generic portion of the market. But again, we could have had generics as early as 12/31/2025, and there could have been more than 2. So I would say the way things are shaping up at this point in time are pretty positive.

We've also done a lot of work over the last couple of years to establish the unique benefit that Xywav offers that the authorized generic can't offer, the true generics can't offer, nor can the other branded competitor, which is low sodium. These are patient populations, patients with narcolepsy or idiopathic hypersomnia that are at an elevated risk relative to the general population for cardiovascular events and increased sodium content, including in data that we've generated has been shown to increase blood pressure, not something you want to do in a patient population that already has increased risk for cardiovascular events.

We see this benefit being valued by physicians and patients already. I mentioned on our first -- our fourth quarter call, we've had accounts last year, for example, that put the authorized generic in the first position, you had to step through the AG to get to either LUMRYZ or to Xywav. In that particular account, we still have the leading share by quite a margin. So again, that unique benefit is offered by Xywav, we think does resonate.

The other parts of our business that are high-sodium oxybate. So the authorized generic royalties that we get as well as our high-sodium oxybate product, Xyrem, we do expect a pretty significant decline in revenue this year, particularly in the remaining Xyrem revenue now that there will be generics to Xyrem available.

And then maybe can you talk a little bit about the progress in idiopathic hypersomnia and kind of how much growth remains for Xywav in the IH market? Obviously, making some good progress quarter-over-quarter, you can watch the patient adds. How penetrated into IH do you think you are and how much of a growth driver is this going to be going forward?

Yes, we definitely see this as a growth driver for a number of patients on Xywav moving forward, over 5,000 patients with idiopathic hypersomnia on Xywav at the end of 2025. The numbers we've seen and talked about in the past are roughly 37,000 IH patients sort of diagnosed and seeking treatment. Although we hear from many physicians that they have as many IH patients in their practice as narcolepsy patients. Those patient numbers of narcolepsy are probably more in that 70,000 range.

So we certainly see there being opportunity for there to be upside beyond that 37,000 based on sort of what we're hearing in the marketplace. And we are having really consistent growth in IH. We do continue our efforts, both with consumer campaigns and physicians to drive awareness of the disease and the role that oxybate can play in helping patients manage their symptoms there.

And then if we do have an orexin compound maybe enter later this year, do you see this as something that patients would pick one or the other? Do you see combination use potential? Obviously, you have some experience with your own internal orexin pipeline. But I guess how do you see that kind of panning out?

We definitely see this as great news for patients with narcolepsy, in this case, in the near term NT1 patients. It does appear that orexins are probably the most potent wake-promoting agents that we've seen to date. What we've seen to date is wake-promoting agents being used in combination with oxybate. You've heard from Rob and others over the years, our view has always been that oxybates and orexins will be complementary and used together, that orexins would not replace oxybates. I know there's quite a bit of debate around that across the years.

It does seem that the consensus is sort of converging on concomitant use of the 2 to help patients with narcolepsy and not one substituting the other. It is typically the case and has been for quite some time that newly diagnosed narcolepsy patients will get one or more wake-promoting agents first before they go on to oxybate. So that could delay compared to what we would have had in the past.

The time it takes for a newly diagnosed patient to get to oxybate, but we do expect that many of them will have a need for that nighttime treatment, kind of benefits it can give in terms of restoring sleep and then the benefits that confer in the daytime as well. But yes, augmented with a more potent, more effective daytime waking agent in the orexins.

And maybe can you talk -- maybe shifting to Epidiolex. I think this is one of the most maybe underappreciated opportunities in the pipeline, especially after last year when you provided the update on sort of exclusivity. Can you remind us, I guess, where you sit with exclusivity on Epidiolex. As you mentioned, it's already a $1 billion drug. And where do you see the opportunities for growth in the current business and then maybe we'll get into some of the expansion opportunities that you mentioned?

Yes, certainly. So the ANDA settlements give us visibility to exclusivity to the very late 2030s. We haven't gotten more specific than that, but we did add the modifier very to late to try to convey sort of our confidence in going pretty deep into that decade with exclusivity. We do see additional ability to build that brand. There's a lot of opportunity still in adults. A number of these patients, particularly they have LGS, for example, don't get diagnosed until very late. It can take over a decade for them to get diagnosed.

So we've been doing things to work with the community, including LGS, REST-LGS tool that helps to be able to understand if these patients, in fact, are suffering from this disease and could benefit from treatment with Epidiolex. We talked about initiating a Phase Ib study also in focal onset seizures and some work that we're doing. We haven't been exactly specific on the formulation, but formulation enhancement that could improve usability, particularly in adult patients.

So we see additional opportunities to drive Epidiolex growth and also, as I mentioned earlier, to build on that franchise with additional corporate development, be that licensing or acquisition.

And maybe can you give us an update on the -- you obviously did in-license the Saniona compound. Kv7 is obviously a very interesting target for seizure disorders. Where do you think you would like to study this Kv7 and kind of when could that enter the clinic?

So we haven't given timing quite yet or specific seizure types that we would go after. This is a molecule we do think could be best-in-class, given the selectivity it has for Kv7.2 and 7.3 relative to 4 and 5, that allows us, hopefully, to drive up the dose, get the intended efficacy benefits and not some of the side effect liabilities, again, to be proven out, but that's the promise that we saw in the Saniona molecule and the reason for doing the licensing.

Great. Maybe we'll flip over to zanidatamab. Maybe on the currently approved indication since launch, kind of what are you seeing in the BTC market that gives you at least confidence that everything is going well from a marketing perspective and kind of laying the groundwork for GEA? Obviously, it's a smaller market, but kind of what are you seeing so far?

Do you want me to start...

Yes.

So I think really pleased with the initial feedback we're getting from physicians who are treating patients with BTC using zani. We estimate the overlap in the prescribing physician population between BTC and GEA to be about 90% or more. So clearly, this is a really important initial experience for physicians to be getting with the product. so that when they're able to go ahead and prescribe it for GEA, they know how to use zani, feel comfortable using it and then give it to appropriate patients with first-line GEA.

But maybe, Amal, you want to comment on this one?

And definitely, the data that we've seen with our frontline trial support and even validate that zanidatamab is a best-in-class HER2 agent. So really excited, and we're hearing great feedback from oncologists. So...

And maybe jumping over to GEA. Can you just hit the high points of the recent data presentation, maybe both from the doublet and the triplet perspective. What have you seen that you find encouraging, if anything surprised you? Obviously, with the triplet, didn't see a huge difference on PFS, but obviously, you're seeing a great benefit on OS. So how do you kind of bring that all together?

Yes. So just to remind everyone of what the experiment was, right? It's a 3-arm trial. And in 2 of the arms, we're comparing zanidatamab to Herceptin. And based on that comparison, the zanidatamab containing arm beat Herceptin. So that was the fundamental experiment. We have now shown that we can -- we've decisively shown that we beat Herceptin in a registrational, large, randomized trial.

The surprising part was what we were aiming for was to hit on PFS, but we also hit on OS as well for the triplet, and we saw a trend towards the benefit for the doublet. In addition, what we also saw is that in several subgroups that we looked at specifically the PD-L1 subgroup, we saw a benefit for zanidatamab across not only PD-L1 negative, but PD-L1 positive, so effectively beating Herceptin on all these parameters, which is really exciting.

I may just add, as you think about looking at the space, we're working with many sell-side analysts, talking to many investors beforehand, how can we understand how your trial results might compare to other results that have been posted in this space.

One of the things that was, I think, heartening when we looked at was the PFS in our control arm, which was 8.1 months. Coincidentally in KEYNOTE-811, that same control arm also had a PFS of 8.1 months. And if you look at the time course of those events, those curves effectively overlap at all time points. So it does give you a comfort that this is a similar patient population that had similar benefit on the same regimen in PFS, which is unaffected by subsequent treatments.

So then you go on to what the subsequent treatments provide? And let's focus on PFS first. We saw 12.4 months of PFS in both our doublet and triplet compared to the 10 months on KEYNOTE-811. Again, cross-trial comparisons, all the caveats that you're well aware of. When you get to overall survival, it was 20 months in KEYNOTE-811, 24.4 on our doublet, 26.4 on our triplet. And if you missed it, we did specify that, that 26.4 months was effectively the same whether those patients on the triplet were PD-L1 positive or negative.

So any way you slice it, these results, we definitely view as practice changing to get to past 2 years of overall survival and to have that benefit, for example, with the PD-1 be independent of PD-L1 status. This sort of speaks to the mechanism of action that Rob Iannone, our Chief Scientific Officer, can speak to much more eloquently than I can on why it is we think that effectively, this mechanism of zani is unique and is turning cold tumors hot and allow them to benefit -- these patients to benefit from the treatment.

And then obviously, you mentioned you finished the submission for GEA, so that's great. Can you kind of walk us through outside of that, when could we start seeing some revenues flow through? Obviously, the NCCN guideline updates could also be important, where do you stand on that process?

Do you have anything on NCCN?

Yes. So we've submitted the data to the NCCN right at the time that we presented the ASCO GI data. What we're going to follow that with is as well a publication that hopefully should be upcoming in a top-tier journal. And typically, the NCCN would be meeting around the summer time frame. But since -- because of the data and how compelling they are, we are hoping that there could be an off-cycle decision.

Great. And when you think about a combination partner in the triplet regimen, obviously, KEYTRUDA is used pretty heavily in the U.S. I guess, do you think you're going to get sort of an agnostic combination partner label and you'll be able to use zanidatamab with KEYTRUDA or any PD-1 that's available? Yes or no? And maybe why is that maybe not important if it's not?

Yes. I mean I can't comment on the label because that's negotiation. But in practice, those anti-PD-1s are viewed as equivalent and interchangeable. So we potentially expect that based on physician preference, what they have on formulary that they could potentially use it with any other anti-PD-1 if they so choose to do so.

And how large of an opportunity do you think GEA is for Jazz?

So it's definitely a larger opportunity than BTC. We have not given specific revenue numbers by indication. We've given a broad view of what peak revenue could be based on the 4 indications that we had ongoing at that point in time, which were our pan-tumor trial, first and second line for BTC, GEA and then breast cancer. And that was the $2 billion-plus peak revenue potential and that we have given patient numbers.

So in the geographies that we have access to, effective was about 12,000 for second-line BTC patients, about 3,000 of those here in the U.S. There were about 63,000 GEA patients, about 8,000 of those here in the U.S. and then about 150,000 breast cancer patients. So I think it's safe to assume that the revenue potential probably does scale by those larger patient populations. We haven't been specific on the exact numbers for each.

And then once the drug hopefully does get approved, how are you thinking about providing metrics to the Street on how each of the individual components of the launch are going? Are you going to be able -- obviously, with narcolepsy, you can see narcolepsy in IAH, is it going to be as clear with zanidatamab to show how the patients are growing between BTC and GEA as well or how are you thinking about splitting that up?

Great question and one that we surely have interest in. It can be difficult at times to really understand what's the indication that a patient is getting a drug for and you have multiple indications. Right now, it's easy for us to say the number of patients that got Modeyso because they're just a number that got the drug. When we get into then zani and having to break it out by indication, we have to figure out how we can help the Street understand where we're seeing utilization. But you're right, it's not as clean a data set to be able to opine definitively.

And maybe jumping over to breast cancer because it is going to be the next expansion opportunity for zanidatamab. Maybe what have you seen so far in the data that gave you excitement that zanidatamab could potentially be differentiated here? And that supported moving into the EmpowHER study?

Yes. I mean it's accumulation of data over the years. A lot of it is preclinical as well, where we've shown that zanidatamab is a superior anti-HER2 agent compared to Herceptin. We've also seen data from our studies that are open label that we can do some cross-trial comparison versus Herceptin where zanidatamab is superior. And now we have a definite experiment, a randomized trial is showing that zanidatamab is superior to Herceptin. So definitely bolstering that confidence in our ability to win for the 303 trial.

Again, in that trial, we are again comparing to Herceptin. Herceptin -- the patients could have been exposed to Herceptin in the past, either in neoadjuvant, adjuvant setting, even metastatic setting. So we also have a bit of a leg up there. So yes, really excited hopefully when those trial results come out.

And can you remind us on timing for the trial results, what we'll see and what's fileable based off the EmpowHER data? I think maybe the reason was they could come as early as maybe the end of 2027, but can you kind of walk us through what we're looking for there?

Yes. So what we've seen is robust enrollment ahead of what we've projected. We anticipate to complete enrollment in the first half of 2027, hopefully earlier. And then it will be a matter of when the events come. What we are projecting so far is that they could come out late 2027, early 2028, but again, it's an event-driven trial, so we'll have to see.

And then outside of these 3 indications, I guess, where else are you excited for zanidatamab? I know you have a basket study ongoing as well and potentially that's towards sort of more tumor-agnostic label expansion opportunity. But what are the other opportunities that we should be paying attention to?

Yes, we're looking at several opportunities. So first, the expansion of what we can combine zanidatamab with. So we've recently disclosed partnership with BI to study zanidatamab in combination with their TKI that's directed towards HER2. Definitely -- so definitely exploring other combinations where we can use zanidatamab.

And data that we have from before from studies that were done in the Phase I where zanidatamab showed real potential, such as in colorectal cancer and non-small cell lung cancer, where we're looking for expanding. For colorectal cancer, we've also disclosed at ESMO some really compelling frontline data with zanidatamab plus chemotherapy where we've seen 100% response rate. So lots of exciting potential for zanidatamab.

Great. And maybe jumping over to Modeyso. You mentioned, obviously, we loved Chimerix and dordaviprone. The launch is going really, really well. So far, I guess, is it surpassing your expectations? And when we look into the next year, I guess, how much of that Q4 great early launch do you expect to kind of persist and expand this year?

So it's definitely off to a phenomenal start, probably is exceeding our high expectations for the product. And that speaks to both the unmet need in this tumor type as well as the strong advocacy work that had been done by our Chimerix colleagues prior really giving great visibility to the physician community of this potential new treatment.

One of the things we've been focused on is increasing testing rates. Really pleased with the direction we're seeing there. I think prelaunch, we're estimating that to be maybe in the 60% range. Now seeing that getting north of 70%, 75%. So that would be a continued focus for us as well.

It's unclear right now if what we're seeing in the strong uptake reflects a greater peak sales potential, which we said is over $500 million here in the U.S. or if we're something maybe getting to that peak sales potential more quickly. I would say the 2 main variables probably and whether that peak sales potential is confirmed or revised moving forward is going to be on the epi.

I mean we've made estimates of how many patients are out there. It's really tough when you have these small patient populations to nail that. 500 patients more or less can make a meaningful difference there. And then also, it's early yet to know on duration of therapy in the real world relative to what we would have seen in clinical trials. So again, still very pleased with the way those things are trending. But I'd say, really pleased with the progress, but it is early to know if that $500 million is still valid if we might need to move that up.

And how important is the frontline study maybe in the overall expansion of Modeyso? And do you feel that study is pretty reasonably de-risked?

We did announce earlier that we were going to increase the trial size and change the primary endpoint to have it focused on OS. So we had another 100 patients or so. We do expect that study probably to read out late this year, early next year. And I would view that as important. It's going to be helpful if that does show a benefit, confirms the benefit we've seen so far. We've gotten questions at times, hey, if you don't show a benefit if you narrowly missed, is that the end of the world? I don't know if that's necessarily the case either. I think the existing data and unmet need here, there's probably a role for dordaviprone even if that were to occur.

But again, our base case and expectation is we show a benefit in the first line, formally expand the indication into that and continue to get even more use in that setting.

Great. And maybe last question, just going back to the BD component because that has come up quite frequently. Any additional details on where you think you want to expand the business? And obviously, with the GW acquisition, you levered up quite highly and you've been able to delever pretty efficiently. What's the appetite to do sort of a larger deal versus maybe a smaller licensing kind of transaction?

I would say we're looking to build each of our existing verticals and as Renee, I think, really well laid out at JPMorgan, we're going to look to get into other areas of rare disease, where we can apply some of our same skills and expertise. In those areas, we have existing deep expertise. You should expect to see us transact preclinical all the way through to market assets. In the areas that we're going to be stepping into that are new, we will do that probably with a derisked asset post proof of concept or at least the mechanism has already had proof of concept.

In terms of leverage, GW went up roughly to 5x. We could certainly get up to that again. If we did that, we'd want to have a really clear plan for how we quickly delever, not only to, I think, assuage any fears that our debt and equity holders might have, but also from a practical perspective so that we could be back in the position again to do more corporate development to add to the growth profile of the company going forward.

Awesome. Thank you very much for the great discussion.

Thanks for having us. Appreciate it.

Good day, and thank you for standing by. Welcome to the Jazz Pharmaceuticals Fourth Quarter 2025 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to turn the conference over to your speaker today, John Bluth, Head of Investor Relations. Please go ahead.

Thank you, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its fourth quarter and full year 2025 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. along with the press release and annual report on Form 10-K for the fiscal year ended December 31, 2025.

On the call today are Renee Gala, President and Chief Executive Officer; Sam Pearce, Chief Commercial Officer; Rob Iannone, Global Head of R&D and Chief Medical Officer; and Phil Johnson, Chief Financial Officer.

On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential and anticipated development, regulatory and commercial milestones which involve risks and uncertainties that could cause actual events, performance and results to differ materially from those contained in these forward-looking statements.

We encourage you to review these risks and uncertainties described in today's press release and under the caption of Risk Factors in our annual report on Form 10-K for the fiscal year ended December 31, 2025, and our subsequent filings with the SEC. We undertake no duty or obligation to update our forward-looking statements.

As noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website.

I'll now turn the call over to Renee.

Thanks, John. Good afternoon, everyone, and thank you for joining us to discuss Jazz's fourth quarter and full year 2025 results, as well as our outlook for 2026.

I'll begin on Slide 5. Jazz had an exceptional year in 2025, representing our 21st consecutive year of top line revenue growth and underscoring our commitment to operational excellence as we deliver meaningful innovation for patients. We achieved record total revenue in 2025 of $4.3 billion. This included fourth quarter revenue of $1.2 billion, reflecting 10% year-over-year growth and our highest revenue quarter ever. We expanded our portfolio through multiple approvals and launches.

Following our acquisition of Chimerix in April, we rapidly received approval of and launched Modeyso bringing this new therapy to patients who previously had no approved drug options. From its launch in August, Modeyso generated $48 million in 2025 revenue. In October, we received approval of Zepzelca in combination with atezolizumab in the first-line maintenance setting following the strong overall survival data presented at ASCO in June. Our most significant R&D progress came with the presentation of practice-changing data from our first randomized Phase III clinical trial of zanidatamab supporting the opportunity for [ Zanin ] to become the HER2-targeted agent of choice across a number of tumor types. Zanidatamab in combination with tizoluzimab in chemotherapy demonstrated more than 2 years of median overall survival in first-line HER2-positive metastatic GEA, an unprecedented survival benefit for these patients whose 5-year survival rates remain below 10%.

In addition to our outstanding execution on the commercial and regulatory front, we resolved nearly all major litigation for the company. We settled outstanding ANDA litigation for Epidiolex, increasing the runway into the very late 2030s, and we resolved the majority of litigation in our rare sweet franchise. These achievements are all underpinned by our strong financial position and performance, which Phil will cover later in the call.

As we look ahead to the next decade and beyond, we are sharpening our strategic focus on rare disease. Our rare disease strategy is centered on strengthening our current franchises and expanding into new areas of rare disease supported by multiple dynamics that make this space attractive for Jazz as outlined on Slide 6.

[ Bill ] on the capabilities we have developed over many years and our long-standing commitment to delivering life-changing medicines we believe Jazz is particularly well suited to have a meaningful impact for patients with rare disease. We look forward to announcing future pipeline advancements and new business development transactions.

Our proven track record in corporate development, as outlined on Slide 7 includes a number of successful value-creating transactions in rare disease. For example, we acquired zanidatamab through a licensing agreement with a modest upfront payment. Since then, we've made significant progress with an approval in second-line BTC, practice-changing data in GEA and what is now an extensive development program across breast and other HER2-expressing cancers.

With the Chimerix acquisition, in addition to securing Modeyso, we generated significant financial value by recognizing a deferred tax asset that will reduce our future cash taxes by over $200 million. And as announced in January, we sold our priority review voucher for $200 million in gross proceeds, half of which will flow to Jazz. In fact, each of the deals outlined here has added new areas of strength and expertise, which we intend to leverage to continue building a more valuable company.

2025 was an outstanding year for Jazz. One that we're proud of and one that provides us with immense confidence in the future. We are building upon this momentum in 2026 as we prepare for the potential launch of Zanidatamab in GEA and sustain the launch execution for Modeyso and Zepzelca. We also remain focused on reinforcing the differentiated profiles of Epidiolex and [ Niwa ] as the leading branded treatments for epilepsy and narcolepsy, respectively.

In parallel, we continue to advance our R&D pipeline and pursue a business development strategy that is aligned with our rare disease focus, aiming to deliver durable growth and long-term value creation for patients and shareholders.

I'll now turn the call over to Sam to discuss our commercial performance.

Thanks, Renee. I'm pleased to share the strong commercial execution we delivered across our diversified portfolio in 2025. Starting on Slide 9 with our rare sleep therapeutic area, which includes Xywav, Xyrem anti-sodium oxybate authorized generic royalties. We delivered more than $2 billion in total revenue in 2025, including $559 million in the fourth quarter. Xywav revenue grew 12% to approximately $1.7 billion for the year. In the fourth quarter, Xywav generated $465 million, representing 16% growth compared to the same period in 2024. Our sleep team delivered exceptional performance in 2025, and we remain committed to providing a safer, low-sodium option for patients with narcolepsy and IH.

As designated by the FDA, Xywav is superior to high sodium oxybate based on the greater safety provided by a low-sodium medicine. These benefits continue to resonate with physicians and patients, driving approximately 500 net patient adds in the fourth quarter and more than 2,000 net patient adds in 2025, including a 34% increase in net active IH patients.

Xywav remains the #1 branded treatment for narcolepsy and the only FDA-approved treatment for IH. Field execution continues to be supported by our disease awareness digital campaigns across both narcolepsy and IH. These efforts are increasing awareness of these distinct disease states, the availability of Xywav and encouraging patients to engage in treatment discussions with their health care providers. We enter 2026 in a position of strength with more than 16,000 patients taking Xywav.

Two generic versions of high sodium Xyrem are entering the market and are expected to negatively impact high-sodium Xyrem revenues. There is also a modest step down in the royalty rate from 2025 to 2026 to the Hikma authorized generic, or AG, with significant economics still flowing to Jazz.

Given that Xywav is not AB rated to high sodium oxybate, we do not anticipate a material impact on low sodium Xywav revenue in the first half of 2026. Whilst we expect the competitive sleep landscape will evolve in the second half of the year, it's important to note in an increasingly competitive environment, Xywav remains clearly differentiated, offering a safer, low-sodium profile and continues to be the only FDA-approved treatment for IH. As a separate and unique indication for Xywav, we see the most opportunity for patient growth coming from IH.

Moving to Slide 10 and Epidiolex. Epidiolex reached a significant milestone in 2025, achieving blockbuster status we have $1.1 billion in revenue, up 9% year-over-year with strong underlying demand, driving 7% volume growth in 2025. Fourth quarter 2025 revenue was $287 million, representing 4% growth compared to the fourth quarter of 2024. I'll note that year-on-year growth was negatively impacted by higher-than-normal inventory levels at the end of fourth quarter '24.

Looking ahead, we see our greatest growth opportunity in the adult patient population, particularly through expanded reaching long-term care settings. In addition, on the Navigator program, continues to meaningfully improve patient persistency, and we're focused on increasing utilization of this [ resort ] in 2026. Given the long runway for Epidiolex, we will continue to invest in additional development opportunities, including new formulations with a clear focus on driving growth in adult patients. We believe Epidiolex is well positioned to remain an important antiseizure medicine for patients over the long term.

Moving to our Rare Oncology portfolio. I'll start with Ziihera on Slide 11. Ziihera is a highly differentiated [ HER2 ] targeted therapy that represents a key pillar of Jazz's future growth. We are focused on maximizing [ Biver's ] potential across HER2-positive cancers, supported by the strong Phase III Horizon GEA results, which exceeded existing standards of [ can ]. Beyond GEA, zanidatamab had demonstrated an encouraging activity across additional [ Hereressing ] tumor positioning it as a meaningful multi-indication commercial opportunity. Our largest near-term opportunity is in third-line metastatic GEA, where we have the potential to launch zanidatamab in this indication in the second half of 2026. Awareness and experiences Ziihera continue to build particularly across academic centers and large community networks with additional opportunity to expand familiarity as we move into GEA and other [ China ] plants.

From an access standpoint, Ziihera benefits from an established permanent J code through its FDA approval in second-line [ percolate ] tract cancers simplifying reimbursement and reducing administrative burden. This is complemented by our comprehensive gas care support services, along with flexible ordering and fulfillment options. Our existing commercial footprint, capabilities and experienced teams position us well to execute effectively in GEA and to support broader development across additional HER2-expressing achievements.

Turning to Slide 12 and Modeyso. Product launched in August to the end of 2025, Modeyso generated $48 million in revenue. This strong early performance reflects the significant unmet need, high [ are ] driven by [ advice ] groups and the value physician fee for patients with H3K27 mutant diffuse midline [ done ].

Early uptake has been driven by new patient start, largely within academic centers of excellence. As the launch progresses, we are focused on expanding [ use ] in the community setting and gaining further insights into real-world treatment patterns, including duration of treatment. Based on what we see today, we believe Modeyso recommends a compelling per opportunity of greater than $500 million in the U.S. In 2025, more than 360 patients received Modeyso, offering new hope for patients and their families facing this devastating disease which have a median survival of approximately [ banner ] from diagnosis and less than 6 months following progression from frontline radiotherapy.

The launch is supported by highly experienced uro-oncology focused steel sales, medical and access teams appropriately timed to deliver targeted engagement to both personal and nonpersonal channels. In addition, our exclusive distribution partnership with Onco360, provides robust patient-centric support services, and we are encouraged by strong payer coverage and continued positive launch momentum.

Moving to Slide 13 and Zepzelca. In October, we received FDA approval for the combination of Zepzelca and Tecentriq, expanding Zepzelca into the first-line maintenance setting for extensive stage small cell lung cancer. This approval broadens Zepzelca's addressable market and represents an important milestone for the brand. In 2025, Zepzelca generated $307 million in revenue. In the fourth quarter, revenue was approximately $90 million, representing 15% year-over-year growth compared to fourth quarter '24. We believe the growth in the fourth quarter was primarily driven by initial demand in the frontline setting.

Given the strength of the clinical data and the opportunity to improve outcomes for patients with extensive stage small cell lung cancer, we are prioritizing our commercial efforts on the first-line maintenance setting going forward. As we look to 2026, we expect a shift in utilization with declining second line yet and increased adoption in the first-line maintenance setting.

I'll now turn the call over to Rob to review the development program that is underway to zanidatamab and provide an update on our pipeline. Rob?

Thank you, Sam. 2025 was a transformative year across our R&D pipeline, and we look to build on this momentum in 2026. Starting with the practice-changing data we presented at ASCO GI on Slide 15. The zanidatamab plus tizolizumab and chemotherapy arm demonstrated a clinically meaningful and statistically significant improvement in OS with more than 7 months improvement and a 28% reduction in the risk of death versus the trastuzumab control arm.

The benefit was observed in PD-L1 positive and PD-L1 negative patient subgroups. Zanidatamab plus chemotherapy showed a clinically meaningful survival benefit with the median OS of over 2 years with a strong trend to our statistical significance at the time of this first interim analysis for OS. An additional planned interim OS analysis for this comparison is currently expected mid this year.

For PFS, there was a clinically meaningful and statistically significant benefit in the zami plus chemo arm compared to the control arm as represented by a greater than 4-month median difference. We are moving quickly to bring zanidatamab to HER2-positive first-line metastatic GEA patients. As we previously noted, we submitted the Horizon GEA data to NCCN and for inclusion in the oncology guidelines. On the regulatory front, we expect to complete the submission for our supplemental biologics license application for zanidatamab under real-time oncology review in the first quarter of this year.

I'm also pleased to share that the FDA has granted breakthrough designation for zanidatamab in GEA. We expect these designations will allow us an even closer interaction with FDA and potentially greater speed to approval. Based on this, there is the potential to launch zanidatamab in GEA in the second half of this year. Our data firmly positions zanidatamab as the HER2-targeted agent of choice in first-line GEA replacing trastuzumab as the standard of care, offering unprecedented durability and survival benefits. We believe zanidatamab's role as the new standard of care will extend across multiple tumor types.

And on Slide 16, you can see the robust development program that is underway for zanidatamab, which we believe has been meaningfully derisked by the strength of the GEA data. The next pivotal Phase III trial for zanidatamab is in metastatic breast cancer patients who have progressed on or are intolerant to in HER2. The treatment landscape is evolving as we anticipated, within HER2 moving into frontline metastatic breast cancer, laying the groundwork for zanidatamab potential move into the second-line plus metastatic breast cancer setting.

Our EmpowHER trial represents the first clinical trial to evaluate a HER2-targeted agent after treatment within HER2. Based on early data generated to date, zanidatamab has shown clinical activity after trastuzumab-based regimens, including HER2, which is an antibody drug conjugate of the monoclonal antibody trastuzumab. We believe zanidatamab will be able to fill an unmet need in the breast cancer space and believe the compelling first-line GEA data helped to derisk the ongoing metastatic breast cancer trial.

We are incredibly excited about this opportunity in breast cancer, and we are also hearing similar excitement from physicians and sites that continue to enroll patients to this trial. We expect to complete enrollment in the EmpowHER trial in the first half of 2027 with top line data anticipated in late 2027 or early 2028.

As we continue to evaluate the potential for zanidatamab to be used in multiple HER2-expressing solid tumors, we're pursuing collaborations with partners to combine zani with novel therapies. For example, a Phase I trial in combination with Boehringer Ingelheim's onungertinib was recently initiated to explore the combination in metastatic HER2-positive breast cancer, along with other potential tumor types. Other earlier-stage trials continue to progress across new indications, including a potentially registrational pan-tumor basket trial and a neoadjuvant adjuvant breast cancer trial.

We're also exploring other areas like non-small cell lung cancer and colorectal gazer. We have great confidence in zanidatamab and intend to fully maximize the value it may offer to HER2-positive cancer patients. Beyond zanidatamab, we have a number of promising development opportunities across our diversified pipeline, which are outlined on Slide 17.

We have strengthened our early-stage pipeline with two recently initiated clinical trials. As we refine our strategy to focus on rare disease, in areas where we have deep expertise. We will continue to build on our research and early development capabilities. A great example of this is JZP047 which was developed in-house at Jazz, and I'm pleased to share was cleared to proceed into a Phase I study under a new IND. We initiated a Phase I healthy volunteer trial in January to evaluate JZP047 for the treatment of apsonse epilepsy.

Building on our expertise in epilepsy and as we explore areas of growth for Epidiolex, we also initiated a Phase Ib trial of Epidiolex in focal onset seizures. Looking ahead to later this year or early 2027, we anticipate the ongoing Phase III ACTION trial will have an interim overall survival readout. This trial is designed to confirm the benefit of Modeyso and support regulatory approval as frontline therapy directly following radiation instead of waiting for signs of tumor progression before treating with Modeyso.

Before I turn over the call, I will share an update on JZP441 and orexin we brought into the clinic with our partner, Sumitomo. Based on our continued assessment of this molecule, we have made the decision to stop the development of JZP441 and end the partnership with Sumitomo. As leaders in sleep, we see promise in the orexin receptor agonist mechanism of action as complementary to oxybate and Xywav as the only low sodium oxybate, and we are continuing to investigate our backup Orexin program.

Overall, we have a number of exciting clinical trials that are advancing across our pipeline from early stage to registrational trials, and we're looking forward to sharing further updates this year.

Now I will turn the call over to Phil for a financial update. Phil?

Thanks, Rob. I'll start with our top line results on Slide 19. Please note that our full financial results are available in today's press release and 10-K.

In the fourth quarter of 2025, we achieved a record total revenues of $1.2 billion, with Xywav, Zepzelca, and Rylaze all posting their highest ever revenue quarter. Total revenue growth of 10% was driven primarily by 16% growth in Xywav and strong initial uptake of Modeyso. For the full year of 2025, we recorded $4.3 billion in total revenues, also a record, representing 5% growth over 2024. Full year revenue growth was driven by Xywav, Epidiolex and Modeyso partially offset by Xyrem.

Turning to Slide 20. Our full year 2025 non-GAAP adjusted net income was approximately $522 million, and we reported non-GAAP adjusted EPS of $8.38.

Moving to Slide 21. We're pleased to share our full year financial guidance for 2026. Our 2026 total revenue guidance range of $4.25 billion to $4.50 billion equates to growth of about 2.5% at the midpoint compared to 2025. We have strong momentum in our rare oncology and epilepsy revenues. Sales of these products totaled $2.2 billion in 2025 and in 2026, we expect double-digit growth in this part of our business, driven primarily by Epidiolex, Modeyso and Ziihera revenue from our rare sleep franchise on the other hand, which totaled $2.01 billion in 2025 may decline due to the evolving sleep market that Sam mentioned, including the introduction of multiple generic high sodium oxybate products.

We expect total were [ sleep ] revenue of $1.8 billion to $1.9 billion, which represents a modest decrease in 2025, primarily driven by Xyrem and [ SIFMA ] AG revenue. Specifically with two generic high sodium oxybate products on the market, we expect a further reduction in sales of Xyrem, which generated $146 million in revenue in 2025.

For the Hikma AG, there is a modest step down in the royalty rate from 2025 to 2026 with significant economics still [ flowing ] Jazz. For branded low sodium, Xywav, we expect revenue to be flat to up mid-single digits. Moving to the rest of our guidance line items. Our non-GAAP adjusted gross margin percent guidance is 90% to 91%. This is a slight decline from 2025, primarily due to higher sales of products like Modeyso and Ziihera, driving higher royalties and to a lesser extent, the potential for higher tariffs on products imported into the U.S.

Our non-GAAP adjusted SG&A guidance range is $1.26 billion to $1.32 billion. Excluding the Xyrem and Avida litigation settlement expenses from 2025, this means we expect SG&A expenses to be relatively unchanged in 2026 as increased launch expenses from Modeyso and Ziihera in the first-line GEA setting as well as increased investment in key commercial capabilities and AI are offset by productivity efforts across our global commercial organization lower facilities expenses and lower legal fees.

Our non-GAAP adjusted R&D guidance range is $725 million to $775 million. This represents an increase over 2025, driven by increased spend for Zanidatamab, both for ongoing and new studies across multiple potential indications, including breast cancer, higher expenses for [indiscernible] as we recognize a full year's worth of activity, higher spend on preclinical and early clinical programs, including JZP898, JZP-815, JZP-3507, formerly ONC206 and JZP-053, Saniona molecule and higher spend on advanced analytics and AI. We expect our non-GAAP adjusted effective tax rate to be between 11.5% and 13.5%.

Finally, our guidance range for fully diluted shares outstanding of $65 million to $66 million. The increase from 2025 is driven by normal factors like shares issued for employee compensation and those purchased by employees via our stock purchase program as well as by accounting for our 2026 and 2030 convertible notes now that our stock price exceeds the conversion price of those notes. We've included an Excel worksheet in the Investors section of our website to help you model this impact. You'll note that we're not guiding to adjusted net income or EPS this year. This reflects both a review of questions we've received and not received from investors and analysts as well as a review of peer guidance practices.

Moving to Slide 22. Our balance sheet remains strong. We continue to generate significant cash from our business, recording approximately $1.4 billion of cash from operations for the full year 2025 and we ended the year with $2.4 billion in cash and investments. Our overall financial position and robust operating cash flows provide significant flexibility to invest in value driving commercial and R&D programs as well as in promising corporate development opportunities to support our refined strategy on rare disease.

I'll now turn the call back to Renee for closing remarks.

Thank you, Phil. I'll conclude our prepared remarks on Slide 24. 2025 represented a truly transformational year for Jazz. We delivered record financial performance, achieved multiple regulatory approvals successfully launched innovative therapies and generated practice-changing clinical data that positions us for significant future growth.

Our refined strategic focus on rare disease leverages our proven capabilities and positions us to compete and win in areas where we can make the greatest impact for patients. We have the opportunity to invest in our pipeline, the growth of our commercial products and also in corporate development where we think there is a solid foundation for us to transact in our existing areas of sleep epilepsy in oncology, as well as in other areas of rare disease.

With our strong financial position, diversified commercial portfolio and robust pipeline, we are well positioned to drive durable growth and create long-term shareholder value. That concludes our prepared remarks.

I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Our first question comes from the line of Jason Gerberry with Bank of America.

I just wanted to follow up, Phil, on just, I guess, the guidance around Xywav for 2026. So I believe it's flat, potentially growing mid-single digit. So is the right way to think about the dynamics there? That in a flat scenario, IH is growing and maybe the conservatism to a guidance of flat is just payer contracting concessions that may need to occur?

And there was some commentary about limited generic impact in the first half, but second half, I'm just wondering, I know there was like not total clarity earlier in the year on when you'd have a full line of sight on what the generic Xyrem impact is. So is there something that you're kind of reserving in the guidance conservatism wise in terms of like what the second half impact could be?

Yes, Jason, thank you for the question. So as we think about the evolution over 2026 of Xywav, we come into the year really well positioned, both from a contracting perspective. Kind of net patient adds we had throughout the year, including in the fourth quarter and the recognition that patients and physicians have for the unique safety benefit that's offered by Xywav is the only low sodium oxybate.

We also now have better line of sight into the timing of entry for generic high sodium oxybate products where it appears that now we've got two as we speak, that are in the process of having their launch that could have occurred as early as December 31 of last year, but is occurring now. It will probably just given the dynamics in this marketplace with the need to register physicians and patients into the REMS program take some time for those generics to build their volumes over time.

That's one of the dynamics that could lead to maybe different effect on branded Xywav in the first half versus the second half. And we also have an evolving landscape more broadly in sleep where there is the potential for a couple of weight-promoting agents to be entering the market in the second half of the year.

And often, we do see with new patients in narcolepsy, for example, they'll typically go on to wake-promoting agent first. They may even go through one or more of those before they would then progress on to oxybate to give them some of the nighttime benefits that oxybate can offer that the daytime waking agents cannot. So those some of the dynamics that are factoring into our thinking. We're really pleased with where we're at and the outlook we have for the year.

I'll just ask Sam, is there anything that she would want to complement to my answer from her commercial perspective.

I think it was a great answer, Phil. Yes, I think you mentioned we're carrying really fabulous momentum into 2026, and we have payer contracts in place for this year. We're very happy with the patient adds that we saw in 2026, 2,000 additional patients at the end of the year. And most of that is coming from IH.

We actually had 34% growth in the numbers of active IH patients by the end of the year. So you mentioned around that, and we do feel as though the IH business is probably going to be the major driver of continued growth for Xywav being the only approved medication in that space. So yes, we entered the year with some confidence. We also know that what we've seen through the course of 2025 is really significant support from health care physicians and also from patients.

We know patients with narcolepsy and IH, the vast majority of them have some kind of cardiovascular or cardio metabolic issue. And therefore, the low sodium option is one that is -- resonates extremely well for this particular patient type. And even with any payer action that may be taken, we do believe a strong commitment from HCPs to ensure that those patients can access a low sodium option.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

This is Mike Riad on for Sean. Are you able to provide any more color on the level of that modest step down on the Hikma royalty rate relative to last year? And then any commentary on the overall impact to the AG volume with two more generics coming on market?

Yes, Mike, this is Phil. Maybe I'll handle that, the first part. We're not able to disclose the specific royalty percentages. We had said in the past that the prior royalty rate that we had for the latter part of '24 and through '25 was quite high. So I think that sort of links that there is a step down coming into 2026, but we do still have significant economics flowing to Jazz, but I can't be more specific than that.

Sam, do you want to comment maybe on the AG?

Nothing too much more to add, Phil, with -- the AG has obviously been in the market for some time. And we -- nothing much more to add to what you said, Phil, in terms of our expectations there.

Our next question comes from the line of Marc Goodman with Leerink.

Rob, can you talk a little bit more about JZP047, the background of the asset? Is this cannabidiol from GW deal? Or what kind of preclinical data do you have? I mean, what's the proof of concept, the mechanism? Why absent seizures? Anything you're willing to give us.

Yes. Thanks for the question, Marc. So we haven't yet disclosed the specific mechanism of action for competitive reasons. But I can say that it's not in the cannabinoid space. It's a novel chemical entity that we developed -- discovered and developed at Jazz.

We have strong preclinical data, we believe in absence epilepsy and that will be our initial focus of development. The development starts in healthy volunteers where we think we'll get meaningful information around safety and exposures that we expect would be efficacious to derisk the asset before going into a patient population.

Our next question comes from the line of Akash Tewari with Jefferies.

This is [ Anna Sagon ] for Akash. Can you give us a little more context on that post in-HER2 breast cancer population, potential uptake? Like how big is the population what kind of treatments to patients typically take postin HER2? Any kind of context on like potential penetration, whether you consider dropping price to enhance access and the like.

So I can -- Renee, would you like me to start with regard to the clinical treatment landscape there and how we're viewing that?

Yes. Why don't you go ahead and start with that, Rob?

Yes. So we see this landscape, I think, is evolving just as we had predicted within HER2 moving to front line potentially with pertuzumab. And HER2 being an ADC that is developed on top of herceptin and possibly given with pertuzumab, it really disrupts the subsequent therapies. And so it becomes unclear what therapies to use after and HER2 after patients have had in HER2. That's the opportunity for zanidatamab where we have prior data showing activity. So we're positioning this post in-HER2. We said there are about 150,000 patients with HER2-positive breast cancer in the markets that we serve.

And we think it would be the first to have data in this post in-HER2 setting. The study is being conducted essentially in third line plus because currently, patients get the Cleopatra regimen, which is chemo accepting [ Perjeta ] and in [ HER2 ] is approved in the second line. But if that moves forward, you can imagine use in the second line as setting to -- just to wrap up the second part of that question. Yes, we're obviously very excited about the opportunity to bring Ziihera into the breast cancer setting. -- too early for us to comment at the moment on the pricing strategy there.

And just to add there that, that study currently is expected to read out at the end of next year or early the following year. So we should complete enrollment next year, and we will have some time to continue to consider price, as Sam mentioned.

Our next question comes from the line of Mohit Bansal with Wells Fargo.

Just wanted to double click on your Xywav comments regarding first half being mostly unaffected versus second half. Can you just talk a little bit more about that? So what are you expecting the competitive pressure on Xywav to be like in the second half in your guidance? And

then as you get into like next year, like how do you see this franchise evolving in the face of low sodium competition?

Yes. We're obviously very pleased with the momentum that we've generated through 2025 way of delivering $1.7 billion, 12% growth year-over-year, and that momentum was carried into the fourth quarter with 16% growth in the fourth quarter. I've already mentioned the numbers of patient adds that we saw throughout the year. So the messages that we've been conveying to the market are really resonating Xywav is highly differentiated in the market, the only low sodium option, the only oxybate with an IH indication.

So that gives us enormous confidence. We have good payer contracts in place as we go into the year. But of course, the landscape -- the sleep landscape is evolving. From where we sit today, knowing what we know, we know that there are two generics coming into the market to multisource generics plus we have Hikma in the market as well. We don't expect significant -- we really expect minimal impact on the sideways business in the first half of 2026.

In the second half of the year, obviously, we've got that increasing competitive dynamics Phil mentioned that generics are likely to build their volumes throughout the year. We could see also the entry of at least one new promoting agent in the market as well. So given all of those things, we may see more a different dynamic emerging in the second half of the year. But we will continue to focus on conveying the significant differentiation of Xywav, which is clearly resonating with prescribers and patients.

And we'll be continuing to convey those messages to those customers. And we expect to continue to see the product being highly appreciated in the market.

Our next question comes from the line of David Hoang with Deutsche Bank.

So maybe a follow-up to some of the questions here on the Sweet-Wake franchise. Just in terms of your payer contracts, you mentioned that you feel confident about the ones you have in place. Is there any possibility for the payers to ask you to come back to the table to maybe negotiate over the course of the year? And could you envision any step edits or other restrictions being put into place by payers that might favor the multisource generics?

Yes. Whilst we do have good contracts in place as we enter the year, there's always the possibility that the payers may want to approach us if there's a significant event in the market with multiple generics.

But one thing that is worth considering is that the rebates that the payers have for products as significant as Xywav are quite material and very significant. So of course, they'll be wanting to consider coming back to us to renegotiate and walking away from those rebates. So in order for them to have confidence to do that, of course, they want to be confident that the generics are built enough volume and support in the market. And also another consideration there is that even if step edits were put in place, and certainly, that is an option. We know that physicians and patients really value the low sodium option.

I mentioned before that well over half, about 70% of patients with narcolepsy and IH have a cardiovascular or a cardiometabolic comorbidity. And so really, the last thing is one to be giving those patients is a heavy salt dose every single day for a chronic condition. So even with a step edit, we believe that there will be a strong commitment from health care providers to move through those step edits to get to low sodium, eye way. So all of these things are possible. But I think the strength of our differentiation it doesn't change. We're still the only low sodium option in the market and that will, I believe, will resonate with some prescribers and patients.

I'll add something really quickly. We have had a small number of accounts, for example, in 2025, where AG was put in more privileged position and basically have to step through that to get to Xywav. And we saw physicians very motivated to do that for their patients given the unique safety advantage as Xywav conveys, as Sam has mentioned, and we had leading share effectively in that account.

So -- we've seen this happen at least on a small scale already. And again, it reinforces our belief that Xywav has a unique value proposition in the marketplace that neither the AG in the past or the emergence of the high sodium generics can replace.

Our next question comes from the line of Brian Skorney with Baird.

Maybe for Sam, the Modeyso launch, which really off to a much better start than I think a lot of us expected. I'm just wondering -- how do you think about these initial launch metrics? And I understand that they're early and conventionalized the greater than $500 million U.S. sales guidance? And how the ACTION study may come into play there? Do you think you need to hit in that study to achieve that guidance? Or can you get there given the current label and if action were to hit you envision that would change the peak guidance?

Yes. Thanks for the question. Yes, we're clearly delighted with the early phase of the launch of Modeyso at $48 million in 2025, which was just 4.5 months of launch is really terrific. We -- obviously, this market is a market which has seen very little development over the last 6 years.

So the launch of Modeyso was one that was highly anticipated by physicians and by patients. We had very high awareness and really strong advocacy support from patient organizations. And obviously, a very high unmet need for this treatment. So we've seen really strong uptake I think in relation to the peak sales opportunity, we obviously, as we see the uptake and the way this product has been accepted into the market increasingly confident about the $500 million peak sales opportunity.

That does assume that we hit on the first-line action study to achieve that because what that means is that the product will get used earlier, immediately after radiotherapy as opposed to waiting for progression, which is the label that we currently have. There's still quite a lot that we need to understand about this market. for example, what really is the real-world duration of treatment. That's going to be quite an important factor in the overall size of the opportunity.

And also, what is the true epidemiology in this market as well. We've used the best available data to do that. But obviously, the longer on market more confidence we're going to get around these areas. Testing rates is also something that we've been working on. We've seen that steadily increasing as well. So all the launch metrics are very positive, and we are increasingly confident about that $500 million sales opportunity.

Our next question comes from the line of David Amsellem with Piper Sandler.

So maybe a bigger picture question about the Sleep-Wake franchise. So Obviously, you mentioned 441. You are looking at other orexin agonist. But absent that, would you consider making a significant acquisition, in other words, an inorganic way of trying to extend the life of your sleep wake franchise bearing in mind that eventually Xywav will go off patent? And maybe taking a step back, strategically, do you just simply toggle over to oncology and neuroscience, neurology more completely and look at sleep wake as sort of a more mature franchise that you manage for cash. How are you thinking about that?

Yes, I'll jump in on that one. So as we look at our strategy going forward and where we're investing, we are investing in the growth of each of these current franchises, sleep and epilepsy and oncology. And we think there are multiple opportunities there, both within our current portfolio and opportunities to invest in licensing and M&A to augment those opportunities.

Would be specific on particular opportunities we're interested in probably isn't that helpful. I would say from a medical perspective, we're excited to see the new innovations coming from orexins. And as Rob mentioned, we continue to be active in this area in terms of early programs, but we also see there's still opportunity there in terms of really understanding is there a benefit for nighttime disrupted sleep.

We seem to see right now data that points to orexins being complementary with oxybate, and we have yet to see any PSG data or otherwise on orexins that will tell us that we'll have therapies that can be fully treated without being augmented with a therapy like an oxybate that can address the nighttime symptoms, but if we just step back and look at our business and the growth drivers, we believe we have a highly differentiated product in Xywav, as Sam has described, we're in a strong position as we go into this year.

We have a highly differentiated franchise in Epidiolex with multiple early-stage programs that we're advancing. A lot of opportunity across oncology whether that's Modeyso or the Zepzelca first-line approval and a really meaningful growth driver with zanidatamab that we're investing in heavily. So that's how we're thinking more broadly about our investments and where we're headed and how we think about investing across the franchises.

Our next question comes from the line of Joseph Thome with TD Cowen.

Maybe one on the -- it looks like another trial from the Chimerix acquisition was launched in PCPG. Can you just talk a little bit about the size of that market maybe as it relates to the market for [indiscernible] for H3K27M? And then maybe a bit of a follow-on to the last question. Obviously, with Epidiolex, you levered up the balance sheet and you work to kind of delever that over the years. You just mentioned BD several times through the call. I guess how comfortable are you to lever up the balance sheet again? Is that something that you're considering and kind of the size of the transactions, that would be helpful.

Rob, can you cover PCG in terms of what we're aiming to achieve there with that study? And then maybe, Phil, do you want to jump in on the balance sheet?

Sure. Happy to. So just to remind the group that 206 asset is a follow-on to Modeyso hitting the same [ clip ] and dopamine receptors but potentially with greater potency. And we have an opportunity based on preclinical data that we have to evaluate that in geochromocytoma and paraganglich are rare neuroendocrine tumors. And so this will serve as a proof of concept, at least in that tumor type, which we prioritized to demonstrate the activity of that next-generation molecule.

And John, your question regarding leverage, we certainly have deleveraged substantially on a net basis, down to about 1.5 turns of EBITDA at the end of 2025. And we do have the ability to go ahead and lever up for a transaction or a series of transactions. If we find ones that are particularly compelling in terms of benefit they can bring to patients and our conviction that we can create significant value for Jazz shareholders as well.

I would say over a longer arc of time, I think the expectation is that you will see debt to be less and less of the capitalization of the company over time, but I would encourage you to think of that as probably a sawtooth with some peaks as we do transactions, particularly if they're M&A, but over the long term, we'd expect that overall capitalization be [ more ] weighted towards equity and less towards debt as we move forward.

Our next question comes from the line of Leonid Timashev with RBC.

I wanted to ask on Epidiolex. You mentioned both the fact that patent settlements extending the cliff out to the late 2030s, and interesting continuing to grow that franchise. So I guess I'm curious how you're seeing or what you need to do to continue to grow the adult side of that business? And maybe what you're seeing currently with adult uptick, maybe where education, additional education is needed and sort of how you think about the size of that opportunity relative to the pediatric side?

Yes. Thanks for the question. Yes, we were delighted in 2025 to achieve $1.1 billion blockbuster status for Epidiolex, delivering 9% growth year-over-year. I think we've continued to drive really strong momentum behind this brand. With our current license indications, there still remains significant opportunity for us to make an impact.

We've identified the adult segment has been a key source of future growth. We have invested that in long-term care teams that are going to those long-term care facilities because what we do know is that there are a significant number of patients particularly LGS patients who reside in long-term care settings that have not had a definitive diagnosis of LGS. So we've invested with that team in particular tool, the rest LGS tool to help physicians diagnose those patients so that they can have the opportunity to benefit from Epidiolex. So that's a key source of growth.

In addition to that, we know that persistent is the key hallmark of Epidiolex patients do very, very well in Epidiolex and they can stay on treatment for a long time. But if the patients have access to our JazzCares, with the nurse team that we have supporting those patients, then they stay on treatment even longer. So we're investing a lot in making sure that more patients can benefit from our JazzCares program.

In addition to that, we've generated data that become data that really reinforces the benefit of Epidiolex in seizure and nonseizure, seizure and non-seizure benefits. So there's a number of things within our existing label indication sources of which we're very confident in that we're going to be making investments in.

And in addition to that, given the very late 2030s, durability of the brand. We're also investing in other areas as well. So for example, new formulations of Epidiolex that will be particularly beneficial for adults as well as a Phase Ib trial in focal [ onset ] as well. So we're excited about the potential of Epidiolex to continue to grow and bringing it to more patients.

Our next question comes from the line of Ami Fadia with Needham & Company.

Just on the zani breast cancer study, can you remind us if you've shared any details around the powering of the study. And ahead of the final readout, is there opportunity to see any interim data? And also maybe just remind us of the regulatory end points that we would be that all the regulatory requirements in terms of the endpoint?

Sure. Thanks for the question. It's a two-arm trial, where patients are assigned their chemotherapy backbone by the treating physician and then randomized to receive either herceptin versus zanidatamab. So a head-to-head comparison is done versus Herceptin again, but in a different setting. It's 550 patients, which is listed on clinicaltrials.gov. And we have an opportunity to look at progression-free survival along with an interim analysis of overall survival before the final readout on overall survival.

This concludes the question-and-answer session. I would now like to hand the call back over to Renee Gala for closing remarks.

Great. Thank you, operator. And just a quick reminder to our listeners. Thank you for joining in the call today. To give you a quick overview of some of our upcoming catalysts.

As we've mentioned, we're really excited about zanidatamab in the breast cancer study that Rob was just describing. We also have the opportunity, as we mentioned on the call for an approval and a launch in the second half of this year. We do plan to get our FDA submission complete this quarter. And expect an upcoming publication in a premier peer-reviewed journal with our second interim OS readout for our zani plus chemo arm B are anticipated to occur mid-year.

In addition to the broader development program, as I mentioned earlier, we have readout planned at the end of next year for metastatic breast cancer study or early in 2028, and we're excited about the opportunity there. Given the underlying backbone comparison is again zani versus herceptin. This year, we have the opportunity for our first full year of sales in [ dordavaprone ] and expect the ACTION trial supporting that Sam described to read out at the end of this year or the beginning of next year, and that will be our first OS readout of that study. So strong momentum coming into this year from 2025, and we do expect to announce one or more deals in 2026 on the corporate development front.

So I'd like to close today's call by thanking all of our Jazz colleagues for their efforts. Our partners and stakeholders for their continued confidence and support 2025 was quite an impactful year for Jazz, and I look forward to continuing our work together in 2026. So thank you all for joining.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Great. Good afternoon, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing the 44th Annual Healthcare Conference today with Jazz. First, you're going to hear a presentation from the company's CEO, and then we're going to go into some Q&A. So if you're sitting in the room and you have a question, just raise your hand and we'll bring you a microphone or you can always submit them online to me, and I can read them up here.

So with that, let me pass it over to Jazz's CEO, Renee Gala.

Great. Good morning, everyone, and thank you, Jess, and thank you, JPMorgan, for having us. I have been attending this conference for a number of years, but this is my first as Jazz's CEO. It's such an honor to be in this role and to build upon Bruce Cozadd's amazing legacy. I'm also excited to be in a position to work with our Board, our management team and our employees to boldly move Jazz forward to realize the potential that I see for us to bring life-changing medicines to patients, to drive into the most incredible work experience that our employees are able to have and to create meaningful value for our shareholders.

So today, I'll recap our accomplishments for 2025. I'll then spend the bulk of my time talking about where Jazz will compete and win in the future and why we're confident in our ability to do so with this new strategy, which you'll see has evolved to capitalize on Jazz's strengths. And then I'll close by highlighting key upcoming milestones, and then we'll turn it over to Jess for Q&A.

Before I begin, I'll direct your attention to Slide 2, I will be making forward-looking statements today. Please consult our SEC filings on our website. You can find more information there about the risks and uncertainties about our business. Our 2025 guidance today, as we make references to it, it is as of when we provided it on November 5 with the exception of total revenue guidance, which we reaffirmed yesterday.

Turning to Slide 3. 2025 was an outstanding year for Jazz, one that we're proud of and one that we think provides us immense confidence in the future. Starting with R&D and Ziihera, we released top line results in November of our HERIZON study. By the way, if I refer to Ziihera or zanidatamab, those are interchangeable. This is the Phase III registrational first-line study of zanidatamab in gastroesophageal adenocarcinoma, or GEA. The data were presented in detail last week at ASCO GI here in San Francisco, and we presented over 2 years of median overall survival. This is unprecedented in this setting and strongly position zanidatamab to become the new standard of care in HER2-positive first-line GEA.

Also at ASCO last year, we presented practice-changing results for Zepzelca in first line -- in first line -- sorry, extensive stage small cell lung cancer in the first-line maintenance setting. This data based on its compelling overall survival benefits is expected to drive Zepzelca into becoming the standard of care in this setting.

Moving on to the commercial front. Shortly after acquiring Chimerix in April, we took Modeyso forward to get rapid approval and then launch that product. The launch is now exceeding our expectations reflecting the value that physicians see in this medicine treating patients with H3 K27M-mutant DMG. I'll just note, this is the first and only drug approved in this setting. It represents a significant advancement in this field, which has seen little to no innovation in 60 years. Also last year, we received approval and then launched Zepzelca in that first-line maintenance setting. The launch is off to a great start. Epidiolex achieved $1 billion in sales last year, reaching blockbuster status for the first time and we also achieved record total revenue for the company, finishing the year towards the top end of our existing guidance range.

In Corporate Development, in addition to the Chimerix acquisition, which added Modeyso, it brought us clinical programs and also gave us significant neuro-oncology expertise, which we plan to build upon. We also in-licensed a best-in-class Kv7 activator molecule. It's at preclinical stage from Saniona, enabling us to continue to build on our epilepsy franchise.

Finally, on the Corporate front, we resolved all major litigation that we were facing. This includes all litigation with Epidiolex and the filers giving us confidence in the durability of Epidiolex. Under these settlements, we do not expect generics to come to the market before the very late 2030s. We resolved all litigation related to Xyrem antitrust as well as all litigation related to Avadel. And with these matters behind us, we can focus squarely on running our business. We also saw that our progress began to be recognized by the investment community. We increased our market value last year by over $2.8 billion. And when you look at these impressive achievements for 2025, it's simply not possible without the dedication and talented employees that we have at Jazz. It is their efforts in 2025 that enabled us to achieve record revenues to launch multiple practice-changing products or indications into the market to generate clinical data important to our future and also position the company for success in 2026 and beyond.

Now as I shift to strategy, I'll describe a refined strategy for Jazz. This is how we intend to compete and win in the future. But in doing so, it's important to understand where the company has been.

So turning to Slide 4. I'll break our history up into 2 roughly decade-long periods, one from the company's founding in 2003 to 2013 and one from 2014 to 2025. Jazz, like many companies, began as a private startup. We had no products, no pipeline, no technology, but a very clear vision on the impact that we wanted to have for patients and employees. We successfully transitioned to a small publicly traded company with aspirations to make a significant impact on the lives of patients with neurological and psychological disorders.

We then evolved into an established, highly profitable enterprise with a thriving sleep business and an emerging presence in oncology. We built substantial late-stage development capabilities, regulatory capabilities and commercial capabilities to support our business. And during that time, we created significant shareholder value, exiting that period with revenues approaching $900 million and growing heavily concentrated on Xyrem.

In the second period, the evolution continued. We greatly expanded our presence in oncology, building a $1 billion-plus revenue franchise. We acquired GW Pharmaceuticals, providing us with a presence in epilepsy, which we continued to expand, again, creating another $1 billion franchise, and this allowed us to significantly diversify our revenue.

Our business became more sustainable and scaled as we went from less than $900 million to more than $4 billion in revenue, and we continued to hone our capabilities in late-stage development, commercial. We added research. We added early clinical development capabilities, patient support services and other capabilities to support our growing business, but despite progress over that time that was significant, our value remained relatively stable, with value from new products being offset from declining value from Xyrem.

Now as we look ahead to the next decade and beyond, we'll leverage our significant capabilities built over this 20-plus year period to deepen and expand our commitment to rare disease. We'll aim to compete and win in our existing areas, but also in new areas of rare disease, strengthening our R&D along with select other capabilities with the objective of realizing the full potential of the existing assets that we have, including Ziihera and expanding our portfolio strategically, both organically, but also with disciplined corporate development, with an aim of benefiting even more patients and building a stronger and more valuable company.

Historically, we've described ourselves as being actively in neuroscience and oncology. But in terms of our strategic expertise, the products that we have supported, the markets that we've been in, they're in what most people would refer to as rare disease. And we've been highly successful in this space with 2 of the top rare disease drugs in Xywav and Epidiolex and multiple growing oncology products.

As you'll see on Slide 5, going forward, we will sharpen our focus on rare disease in these areas that we are currently in, rare sleep, rare epilepsy, rare oncology, but also expanding into new rare therapeutic areas. And we'll do this by leveraging our proven capabilities as well as our size, our agility and our footprint.

Now you may ask why focus on rare disease. Well, you'll see there are a number of dynamics on Slide 6 that make rare disease attractive for Jazz. First, many rare diseases still have very high unmet need. Patient populations are small, making the call point relatively concentrated usually serviced by relatively small and focused field teams. Patient and physician services can provide additional differentiation in the market. There can be lower competitive intensity and a lower rate of technological obsolescence. Peak revenue can be highly attractive for a company like Jazz, although it may not be large enough to attract the attention of large biopharma and regulatory and policy dynamics continue to be favorable in this area with a high level of collaboration between sponsors investigators and advocacy to bring new innovation to patients. And given the capabilities that we have built over the years and our long-standing commitment to bring life-changing medicines to persons with serious disease, we do believe Jazz is particularly well-suited to have a significant impact on patients with rare disease.

Now how will we compete in rare disease on Slide 7, we'll continue to look for areas of significant unmet need. We'll lean into innovation as we have with products like Ziihera, Modeyso and Rylaze. We'll focus on medicines that are highly differentiated and can become a new standard of care, providing clear improvements in outcomes for patients and value to the health care system.

Now we will approach opportunities in areas where we have existing capabilities differently than when we're moving into new areas of rare disease. So in areas where we have deep expertise like sleep, epilepsy and oncology, we will leverage that expertise to invest along the full spectrum of research, development and commercialization. And as a result, corporate development deals in this area could span from preclinical all the way to marketed assets.

When entering a new area of rare disease, we intend to take a more measured approach to clinical risk. So you can expect the corporate development deals in this area would focus on assets that have achieved proof of concept or later or that have the potential to provide a meaningful benefit over existing areas where we already have a validated target. Our goal ultimately is to build each rare disease area that we enter into a robust $1 billion franchise over time, like we've done with sleep and epilepsy and oncology.

And ideally, we'll do this with multiple assets to be able to efficiently leverage our capabilities, our footprint, but also to enhance our profitability and we'll continue to build on research and early development capabilities, applying them in areas where we have deep expertise to develop novel therapies with a focus on validated mechanisms and targets following the science being disciplined and data-driven.

In the near term, you should expect to see Jazz discovered molecules coming into the clinic. And over a longer arc of time, we would anticipate more of the products that we are bringing to market will come from our internal efforts to complement the innovation we're bringing in from corporate development. We also plan to bolster our customer centricity and digital AI capabilities. In fact, by the end of this year, every single Jazz employee will be trained in AI, and we have additional operational objectives for embedding more AI into our business on a day-to-day basis.

So you may ask, how is your strategic focus really changed? What is different? And there are a number of things about this strategy that are different. And I'll give you one example. In the past, we contemplated opportunities in neuroscience that were broad in terms of the number of patients and physicians, the size and scope of the programs, neuropsych indications, for example. These are areas that we won't prioritize going forward. Now with that being said, we recognize that we, very likely, may come across molecules that we're bringing into rare disease that will have a broad applicability. We have a perfect example of that in our portfolio right now with zanidatamab.

When we brought in zanidatamab, we licensed that drug for BTC and gastric cancers to rare cancers. And we now clearly have a much broader opportunity, including in breast and other lines of therapy. So we will continue to maximize the value for Jazz when we find ourselves in these cases. And that is exactly what we intend to do with zanidatamab.

Now why do we think that we can be successful in this strategy? Well, we are leveraging a strong track record of success over a number of years already operating in these areas. And as we build on this track record of success in multiple rare diseases already, we do believe we can further broaden our foundation investing further in our 3 major value pillars at Jazz, R&D, commercial and corporate development. We have recent successes in each of these and a number of proof points that I'll go through.

Starting with R&D and Ziihera on Slide 9. We have a highly differentiated HER2-targeted agent in Ziihera, and it is now meaningfully derisked, a cornerstone of our future growth that we believe has the potential to be a $2 billion-plus commercial opportunity. This represents both successful corporate development and successful R&D. We secured zanidatamab based on our strong belief in its MOA for $50 million upfront. Our initial thesis, as I've mentioned, was based on BTC and GEA and after positive BTC data, we brought this compound in, continued to advance into additional clinical studies and through our continued R&D work, we now have a high-value asset with data across a number of tumor types and the potential to be the HER2-targeted agent of choice to be able to extend life for patients.

Underlying our confidence on Slide 10 is the positive Phase III data from the HERIZON GEA study that we presented last week. These data are unprecedented with overall survival exceeding 2 years and remarkable consistency of benefit across the relevant subgroups. Our confidence in zanidatamab's potential has only increased. The hypothesis you're testing here that we were testing was what is the better HER2-targeted agent, zanidatamab or Herceptin. Zani outperformed Herceptin across all efficacy measures in this study. And last week at ASCO GI, the data were largely characterized -- sorry, widely characterized as practice-changing and supportive of Zani becoming the preferred HER2-targeted agent of choice for GEA patients.

So as we progress towards realizing the full potential of zanidatumab, we do have a number of exciting near-term milestones beginning with GEA. We plan to submit our sBLA filing in the first half of this year with potential NCCN inclusion and then approval and launch occurring later in the year. I'm also happy to disclose today that we learned earlier today that we are eligible to submit under the real-time oncology review cycle, or RTOR, which should allow us greater speed and communication interaction with the FDA.

Looking to the coming years, we expect to have multiple data readouts across indications, including in metastatic breast cancer with our first readout from EmpowHER Phase III in late next year or early the following year. And we're also studying Zani in novel combinations and looking at additional areas of unmet medical need. Alongside R&D, we've also demonstrated incredible commercial performance in rare disease, 2 existing billion-dollar products in both rare epilepsy and rare sleep, as you can see on Slide 12. In rare epilepsy since the GW acquisition in 2021, we've driven substantial growth with this product, bringing it to blockbuster status last year. We believe Epidiolex is a highly durable, long-lived asset. And with this additional durability, we have the ability to continue to do more development, including more formulation development and generate more data, we think is useful for the product.

In rare sleep, we have established market leadership in treating patients with rare hypersomnias for nearly 20 years. We've brought forward new products such as Xywav, which is differentiated as the only low sodium oxybate and the only product approved for idiopathic hypersomnia. We've established best-in-class patient support services with this program and generated meaningful data for patients and I'll note that this program generates meaningful cash flow for Jazz, allowing us to further invest in other parts of our business.

Moving to Slide 13. Corporate Development will also continue to be a meaningful focus for our company. I mentioned the acquisition of Chimerix earlier. This acquisition brought us Modeyso, which I mentioned was previously approved in August as the first medicine in this class approved ahead of its PDUFA date. Upon launching this product, we moved very quickly to ensure that patients, physicians, all centers knew about this product, but there was already such strong advocacy and familiarity that we've seen meaningful uptake with nearly $50 million in our first 4.5 months on the market.

We've also generated significant additional value with this acquisition. With this acquisition, we recognized a deferred tax asset that will reduce our future cash taxes by approximately $200 million, and we're also pleased to announce this week that we sold our priority review voucher for $200 million in gross proceeds. As we look at '26 and beyond, we have a first-line study, the Phase III ACTION study underway. Enrollment here is ongoing, and we expect our first interim OS readout at the end of this year or later next year. We expect not only would this study support our first-line indication but also ex U.S. regulatory filings.

So closing on strategy on Slide 14. We are highly confident in our ability to execute on a strategy in rare disease. We have significant capabilities, and we're building additional capabilities to strengthen our ability to support this market. We have the opportunity to invest in our pipeline and research development and the growth of our commercial products and also in corporate development where we think there is a lot of substrate for us to be able to transact in both in our existing areas of sleep, epilepsy in oncology, but also in other areas of rare disease.

Importantly, we do have a very strong financial position to support both our internal investments as well as our external corporate development. We generated nearly $1 billion in cash in the first 9 months of last year and ended the third quarter with over $2 billion of cash and investments on the balance sheet.

And so I'd now like to close by reviewing our upcoming milestones as we look to '26 and '27. Starting with research and development and Zani for GEA, as I'd mentioned, we plan our sBLA in the first half of this year. We have already submitted to NCCN guidelines, and we expect a peer-reviewed publication to be coming in the relatively near term. We also have an interim planned, our second interim plan on this HERIZON GEA study that we expect in the middle of this year with the opportunity for approval and launch before the end of the year.

We also continue to be laser-focused on the broader zanidatamab program, our EmpowHER breast cancer study is enrolling nicely. We have enrollment plan to complete in the first half of next year, which would give us the ability to read out late next year or early the following next year, our top line readout. This is also an event-driven study as was GEA. So those timelines are subject to both enrollment and events and I'll note that this patient -- sorry, this study is enrolling patients that have progressed on or are intolerant to in HER2. So it will be the first study to read out data of this nature in this setting. Importantly, our data has also been, I would say, highly derisked. This study, given that we have now seen in GEA that Zani clearly outperformed Herceptin. In this breast cancer study, the underlying experiment is again, zanidatamab versus Herceptin. So it gives us additional confidence in the outcome of this study. And as I've mentioned, our Dordaviprone study, which is Modeyso, is expected to read out late this year or early 2027.

Moving on to commercial and our outlook for 2026. We do intend to provide guidance in February at our earnings call, the way we normally would do. And as we look at our overall outlook, we see the potential for robust growth in our non-oxybate revenue in that part of our portfolio, we have a number of exciting opportunities with Modeyso, Ziihera, Zepzelca in the first-line maintenance setting as well as Epidiolex. Our outlook for sleep is still somewhat dynamic given we do have generic versions of high sodium oxybate that will be coming into the market. As a reminder, Hikma, our largest authorized generic will not be launching a generic this year, but we are aware of 2 other companies that have expressed their intention to launch.

In this area in sleep, we are entering 2026 in a very strong position. We have over 16,000 patients on therapy. We are the only low sodium oxybate on the market, which is very important for patient safety, and we have excellent payer contracts in place as we enter the year. And then finally, on corporate development, we fully expect to announce 1 or 2 or more deals in 2026. We do aim to continue growing our business and optimizing our future value through corporate development.

So I'll close by thanking my Jazz colleagues for all of their efforts also thanking our shareholders for their continued confidence and support. And then I'll invite Rob and Sam and Phil up for Q&A and turn it over to Jess.

Great. Thanks. So as a reminder, if you have a question in the room, feel free to raise your hand and we can bring you a mic. But I will start. So maybe just starting with kind of the renewed strategy with a focus on rare disease. What are the operating margin implications of the updated strategy?

Well, I would say if you look at our business the way it's structured today, many of our underlying products are essentially rare disease products. So while we don't give forward-looking operating margin guidance, I would say continuing to build on our existing verticals of sleep, epilepsy and oncology will allow us to continue to get more out of those areas and work to enhance profitability. It's also our goal to do so -- to do the same when we enter into new areas and then when it comes to optimizing and getting the absolute most out of zanidatamab, we will be investing there will be increasing the breadth and depth of that development program. And so that will be also dynamic as we think about the overall profitability. Phil, would you like to comment further?

Sure. User error. Sorry about that. So no, Jess, I think the strategy is a larger continuation of what we have been doing. This is a space that in the past has been highly profitable for us. We would expect going forward that will continue to be the case. We will be focused, I think, primarily on identifying opportunities to drive long-term growth and value. So while we'll be cognizant of implications for profitability, the focus will not be on this quarter, next quarter profitability, it will be on building a very strong, fast-growing business that's highly valuable and more valuable in the future than it is today.

You mentioned Jazz discovered products entering the clinic over time. How soon could that happen? And where are the company's discovery efforts focused?

Well, without giving a specific timeline, we have actually some things that were discovered at Jazz that are pretty soon to be in the clinic. And it would really follow what Renee had outlined from a strategic point of view. We don't have a huge medicinal chemistry effort, for example, but it's a good group and in areas where we think we can compete in terms of developing novel agents and fit with our strategy. That's where we're focused, and we're already seeing some of those come forward.

And then -- we have a question.

So Amneal launched their Xyrem generic today. Just could you talk about how you think that will impact pricing for your oxybate franchise?

Yes. So thanks for that question. Well, just as a reminder, I mean, let's just be very clear that our business -- our sleep business is primarily Xywav, which is the only low sodium oxybate on the market and the only product with an idiopathic hypersomnia indication. With Amneal's launch and potentially, there may be more that enter into the market in 2026, they're obviously high sodium oxybate generics. And of course, we would expect to see that impact Xyrem, our high sodium oxybate as well.

Our focus during 2025, and you'll have seen in some of the results that we've disclosed during the course of last year, showed that our focus on differentiating Xywav in the market has been very, very impactful physicians. Quarter 3, we saw 450 net patient adds. And that momentum really has not slowed during the course of 2025 in the face of authorized generics on the market. So we feel very confident in the differentiation that is appreciated by clinicians and by patients and all of the other wraparound services that we put around Xywav such as in the nurse -- in-person nurse support programs, et cetera.

Having said all of that, of course, there's a lot that we don't know. So how many generics will enter the market what will their pricing strategy be? We're entering the year with exceptionally good payer coverage. So we couldn't be in a stronger position with Xywav. But some of these unknown factors are yet unknown. So we'll have to see how they play out in practice.

Maybe just to follow up on that, another investor question is, how do you approach given guidance this year in light of this kind of dynamic oxybate environment?

Sure. So we'll be providing guidance on our February 24, fourth quarter earnings call. We had just made a move coming into 2025 to provide total revenue guidance. You may recall that in prior periods, we had given guidance not only for total revenue, but also for neuroscience as well as oncology revenue. So we're having discussions that was the most useful for investors for 2026 certainly would give total revenue guidance. I think very likely we would give some level of uncolored commentary at a minimum of how we see the non-oxybate portion of our business growing, where there are the normal uncertainties, but not this unusual uncertainty that we have with generic Xyrem coming into the market in 2026. And then I assume we'll give some level of where we see the market currently for generic Xyrem, what it means for Xywav and based on those assumptions, sort of how that flows into the total revenue that we're expecting for the full year.

This is a dynamic that we have a lot of uncertainties on. We do expect that there will be generics. We just heard now, obviously, ones coming in and that there could be some others. But this is something that is less or more complex, I think, than other standard generic launches. This is a product that has to have REMS associated with it to be able to ensure there's not diversion of the product, et cetera. So this is something that the generics will have to build over time.

The registration of physicians into the REMS or registration of patients into the REMS, so like this would build over the course of the year and impact would likely be not seen early in the year and be seen more later in the year to the extent we're seeing an impact. So first quarter, as Sam mentioned, we're very, very strongly positioned with the payer contracts we have, with the momentum we have coming into the year, significant recognition of physicians and patients with the benefit of low sodium and Xywav was the only product that will be able to offer that benefit. Neither the generics nor branded products have that ability to offer that safety benefit that comes with Xywav that we have seen to be very, very impactful for physicians and patients. We would expect for payers as well.

Maybe coming back to the kind of the rare disease strategy. There are a number of rare disease companies that have a stated goal of acquiring other rare disease assets. So how do you position Jazz to kind of best compete for the assets that are for sale?

Yes. Well, first of all, I look to what we were able to achieve with the Chimerix acquisition, what we were able to achieve with the GW acquisition and be able to actually deliver on our goals to deliver a strong launch with Modeyso and to create significant additional value through the sale of our priority review voucher and being able to understand in this type of area, the importance of truly understanding the patient, understanding advocacy, how to connect well and collaborate well with investigators and with HCPs.

So I think that's been a long-standing strength of Jazz over time. And then in terms of how we really compete, we have a meaningful footprint that can enable us to make medicines available and in terms of how we think about where we want to compete, we're most focused in those areas that I described that have sort of the phenotype of the characteristics that will fit within our existing business.

Maybe turning to the recent Zani data. I guess two questions here. First, can you put the recent data into context with KEYNOTE-811. And second, on OS for the Zani doublet versus Herceptin doublet, where I think the upper end of the confidence there was like [ 1.01 ]. What gives you confidence that, that could be stat-sig at the next interim?

Sure. So thanks for the question. On the first one, I just want to remind everyone that, what was tested here was what I think is the most important question in the field, which is what's the best HER2 agent to be used in this setting. Gastric cancer that's HER2 amplified is highly HER2-driven. There's activity with chemotherapy. There's incremental activity with PD-1s, but the HER2-targeted therapies are what really make a difference in this disease. So the study was designed to test that head-to-head Zani versus Herceptin.

And as Renee alluded to earlier, definitively no matter how you look at that, Zani prevails and should become the standard of care for this line of patients. The study also looked at whether the addition of a PD-1 inhibitor, in this case, tislelizumab, would have incremental benefit in the context of zanidatamab, the way it has across multiple other studies to this point.

And those data were definitive, but what turned out to be very differentiating is that the effect was positive irrespective of PD-L1 status. And I think that's -- when you look at the overall intention to treat results where we're seeing almost 27 months -- 26 to 27 months median overall survival compared to KEYNOTE-811 which was about 20 months. But importantly, this drug now has data to show that it can be used irrespective of PD-L1 status.

And we think that makes sense based on the differentiated mechanism of action for zanidatamab, which is much more immune active. We know that it fixes complement, activates the complement cascade. We know the Fc fraction is highly active in terms of recruiting NK cells and macrophages. And so essentially turning a cold tumor hot in this context, allowing patients to use the Zani triplet in all comers without having to test for PD-L1. So compare very favorably in general, but specifically differentiated on the PD-L1 issue.

And then in your question about probability of succeeding at a later date, we had a relatively small amount of alpha spent at this interim analysis for overall survival. We have a second interim plant and then a final analysis. So we have 2 more bites at the apple there. We recognize that one thing that's really differentiating, Zani, is the duration of response that comes through in the presentation last week and will in the manuscript and so we think that given how differentiated is there with additional follow-up for those patients who didn't have a lot of follow-up that they'll continue to contribute to separation of those curves over time. So that next interim analysis is expected midyear, depending on how the events roll out. And we think we have a good shot there, certainly by the time of the final analysis.

Great. With the filing going in, in the interim potentially happening, like while the review is underway, is it possible if you do hit stat-sig at the next interim that, that could get in the label?

Absolutely. And again, just to remind folks that the regulatory standard here is not stat-sig OS. I mean, the FDA has been clear that a large PFS difference that was stat-sig with support of OS data, recognizing that in this trial, patients on the control arm could get subsequent KEYTRUDA, which wasn't available, of course, for KEYNOTE-811. So we were quite pleased to see, especially in RMC that we already had stat-sig and we came so close in arm B on overall survival at this first interim. So it may well be available during the review could end up in the initial label. If it's not, of course, we'll supplement the label. As Renee mentioned, very pleased to hear from FDA that they are allowing us to use the real-time oncology review. I think that shows their level of enthusiasm about the data and certainly enables us to speed the process as much as possible.

Great. We are out of time, so we'll stop there. But thank you.

Thank you.

Good morning and welcome to the zanidatamab HERIZON-GEA-01 Investor Call and Webcast. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Renee Gala, President and Chief Executive Officer of Jazz Pharmaceuticals. Thank you. Please go ahead.

Good morning, everyone. My name is Renee Gala, President and CEO of Jazz Pharmaceuticals. Thank you for joining us. Before I begin, please note that today's slide presentation accompanying this webcast and call is available on the Investors section of our website. Yesterday, we presented groundbreaking data from the Phase III HERIZON-GEA-01 clinical trial assessing zanidatamab in combination with chemotherapy with or without tislelizumab in first-line HER2-positive GEA patients at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium.

We have the privilege of being joined today by Dr. Geoff Ku, Associate attending physician on the Gastrointestinal Oncology Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center, who will discuss the HERIZON data. While today's call will be focused on GEA, it is important to note that these data also support our efforts to maximize the full value of zanidatamab across multiple potential indications. The data we will discuss today reflect our strong belief in zanidatamab's novel mechanism of action and solidify our belief in the promise of zanidatamab to transform the treatment landscape for multiple HER2-expressing cancers.

As outlined on Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, which involve risks and uncertainties that could cause actual events, performance and results to differ materially. We encourage you to review the statements contained in our latest SEC filings and reports, which identify certain factors that may cause the company's actual results to differ materially from those projected. We undertake no duty or obligation to update our forward-looking statements.

Our agenda for today is outlined on Slide 3. We're pleased to start with Dr. Ku, who will walk us through the trial results. Next, Dr. Rob Iannone, our Global Head of Research and Development and Chief Medical Officer, will provide perspectives on the shifting treatment paradigm and clinical development plans for zanidatamab. Finally, Sam Pearce, our Chief Commercial Officer, will provide a commercial perspective, and then we'll open the call for Q&A.

Turning to Slide 5. Results from the pivotal Phase III HERIZON-GEA trial represents the first global randomized data set for zanidatamab, which increases our confidence in zani's mechanism of action and adds to the proof of its clinical efficacy. In addition, this is the first Phase III trial to demonstrate the benefit of a novel HER2-targeted therapy when directly compared to Herceptin as part of a combination regimen in HER2-positive first-line GEA. We believe the combination of a truly unique MOA, along with the outstanding clinical efficacy and safety data we've generated for this molecule to date are supportive of our efforts broadly to look at zanidatamab as a potential new standard of care across HER2-positive indications.

I'm delighted to introduce Dr. Geoff Ku, a medical oncologist who specializes in the treatment of malignancies of the gastrointestinal tract at Memorial Sloan Kettering Cancer Center in New York. He is an associate attending physician and Head of the esophagogastric section of the Gastrointestinal Oncology Service and a member of the Cellular Therapy Service, both in the Department of Medicine.

His research focuses on the evaluation of novel therapies, including cellular therapies and combined modality treatments for esophagogastric cancer. In addition to being a member of the esophagogastric Task Force of the National Cancer Institute and of the Gastrointestinal non-Colorectal Cancer Committee of the NRG Cooperative Group, Dr. Ku was a contributing author to the HERIZON-GEA-01 oral presentation given at ASCO GI yesterday. Dr. Ku?

Thank you, Renee. It's my pleasure today to present the results of the HERIZON-GEA-01, and this is the same slide deck that my friend and colleague, Dr. [indiscernible] presented yesterday at GI ASCO. So I'll endeavor to do as good a job as she did. Turning to Slide 8. The key takeaway points are as such, HERIZON-GEA-01 supports zanidatamab as a new anti-HER2 therapy replacing trastuzumab as well as the use of tislelizumab in the first-line treatment of HER2-positive esophagogastric cancer. There is a 35% reduction in the risk of disease progression or death, both zani and chemo as well as zani, tisle and chemo versus trastuzumab and chemo, which translates into a more than 4-month improvement in median progression-free survival.

There was a strong trend towards a statistically significant improvement in survival -- overall survival favoring zani plus chemo versus trans plus chemo, and there was a numerical 5-month improvement in median overall survival. I would also note that this is the first of several planned interim analyses. However, there was clearly a statistically significant and clinically very meaningful 28% reduction in the risk of death for zani plus tislelizumab plus chemo versus tras and chemo, which translates into a more than 7-month improvement in median overall survival.

And both of these overall survival benefits were generally observed across all key specified subgroups, including patients with PD-L1 TAP scores of less than 1% and 1% or more. Finally, the safety profile was also consistent with the known profile of each individual treatment, but we will absolutely delve into this in more detail.

Turning to the next slide. This is the background. So as we all know, the outcomes for HER2-positive gastric cancer remain modest despite improvements in the last several years with a median progression-free survival of less than 1 year and median overall survival of less than 2 years. Zanidatamab is a bispecific or specifically biparatopic antibody that targets 2 different extracellular domains of HER2. And this unique molecular structure leads to also a unique mechanism of action that differentiates it from other anti-HER2 therapies.

Separately, tislelizumab is a high-affinity immune checkpoint inhibitor targeting PD-1. So there was promising efficacy as well as tolerability observed for zani plus chemo as well as zani, tislelizumab plus chemotherapy in two independent Phase II studies, which led to this Phase III study.

Turning now to the study design. So the eligibility criteria are as expected for a standard first-line HER2-positive global study. Stratification factors were geographic region, HER2 status as well as ECOG performance status. Patients were randomized in a 1:1:1 fashion to Arm A, which was the standard arm of trastuzumab and chemotherapy. Arm B was zanidatamab plus chemotherapy and Arm C was zanidatamab plus tislelizumab plus chemotherapy. The study had dual primary endpoints of progression-free survival for BICR to blinded independent central review as well as overall survival and an important secondary endpoint was the objective response rate.

I would note that Arm A excludes pembrolizumab, which is the current standard of care. It was also at the time, FDA approved only in the U.S. And as a result, the study did not open in the United States, but accrued in the rest of the world. Turning to the next slide, as we focus on statistical design. Again, the dual primary endpoints are PFS and overall survival. The primary PFS analysis will be triggered after a target event count was reached and patients had at least 7 months of follow-up. And the first interim overall survival analysis would be performed at the time of data cutoff for the primary PFS analysis.

You see below here also the sequence of testing. We start by testing PFS in Arm C versus Arm A. If that is positive, we then test for PFS in Arm B versus Arm A. And if that is positive, we look at overall survival in Arm C versus Arm A, followed then by overall survival in Arm B versus Arm A. Only if this is positive, do we finally compare both experimental arms C versus B, but I would note that the study was not designed to directly test both experimental arms.

We now turn to patient disposition. So overall, 914 patients were randomized, and there were approximately 300 patients in each arm. The one thing I would note is that a higher proportion of patients in Arm A have discontinued treatment versus the zanidatamab continuing arm. Specifically, 86% of patients in Arm A have discontinued treatment versus 76% in Arm B versus 70% in Arm C. In all 3 arms, the median follow-up is a little bit more than 2 years.

Turning now to baseline demographics and disease characteristics. We see that these are essentially well balanced across all 3 arms. Approximately 50% of patients were enrolled from Asia and then the rest were enrolled from EU, North America and rest of world. The study did enroll patients with esophageal tumors, which will comprise approximately 10% of the study population. 80% to 85% of tumors were HER2 IHC 3+, which is what we expect from other contemporary first-line studies. Somewhat surprisingly in terms of PD-L1 status, 40% of patients had a TAP score of less than 1%, while approximately 60% had a TAP score of 1% or more. You'll note that these numbers do not add up to 100% because there were some missing data points. This study allowed either CAPOX or 5-FU cisplatin every 3 weeks and overwhelmingly, 90% of patients received CAPOX.

Turning now to the primary endpoint of PFS, and this is the PFS in Arm B versus Arm A. And here, we see that there is a clear superiority. In Arm B, PFS is 12.4 versus 8.1 months in Arm A, hazard ratio of 0.65 and the p-value is highly statistically significant. And this translates into a 2-year progression-free survival rate of 31.5%. We next look at PFS per BICR in the Arm C versus Arm A comparison. And again, this is also highly statistically significant and clinically meaningful. The median PFS is 12.4 versus 8.1 months, hazard ratio is 0.63, p-value also highly statistically significant. And this translates into a 2-year progression-free survival rate of 38.2%, which is a little bit higher than in the Arm B versus Arm A comparison.

We now look at the PFS in key specified subgroups. And essentially, I think the take-home point is that all subgroups seem to benefit. One exception is the IHC 2+/ISH+ population. But again, this comprised only 15% of patients, and therefore, it could be confounded by small numbers as well as other factors. What's notable here is that all patients seem to benefit irrespective of PD-L1 status, both the 1% or more patients as well as the less than 1% patients benefit.

We now turn to a primary endpoint of overall survival, and this is the overall survival comparison in Arm B versus Arm A. Here, we do see a numerical improvement to 24.4 months from 19.2 months. This is a hazard ratio of 0.80, but the p-value is 0.0564, which just missed statistical significance. Again, I would emphasize this is the first of several planned interim analyses.

Now turning to overall survival in the arm C to Arm A comparison. This is statistically significant. The median overall survival here is 26.4 months versus 19.2 months in the control group, hazard ratio of 0.72, p-value now is highly statistically significant, and that translates into a 2-year overall survival rate of 54.3% or a 30-month overall survival rate of 43.8%. Focusing now on the overall survival by key specified efficacy subgroups. Again, we essentially see that most subgroups seem to benefit from treatment.

Again, the patients who seem to benefit irrespective of PD-L1 score. And here, we do see that the IHC 2+/ISH+ patients, the point estimate at least is less than 1, suggesting that they also derive benefit from zanidatamab. Again, these are small numbers, which could confound the analysis. We turn now to antitumor activity. On the left, we see the response rate. The response rate was 66% in the control group, which was only slightly improved to 70% in both zanidatamab containing arms. However, the complete response rate was nearly doubled in Arm C, 19.6% versus 11% in Arm A.

And I think what's particularly impressive here is the median duration of response. In particular, if we focus on the DOR in Arm C, it is 20.7 months compared to 8.3 months in Arm A and compared to 14.3 months in Arm D and such a long durable period of response is truly unprecedented in this disease. We turn now to safety summary. Again, a very busy slide, but I would focus on the fact that there was increase in grade 3 or more toxicities in the zanidatamab containing arm. Specifically, it was 71.8% in Arm C versus 59.6% in Arm A. It actually was comparable in Arm B versus Arm A at 59%. These toxicities did lead to an increased rate of discontinuation of zanidatamab versus trastuzumab.

In Arm C, there was an 11.9% discontinuation rate versus 8.5% in Arm B versus only 2.3% in A. In terms of adverse events of special interest, infusion-related reactions occurred in 25% of patients in both Arm B and C receiving zanidatamab, it was only 13.2% in patients receiving trastuzumab. The incidence of non-infectious pulmonary toxicities was also increased in Arm C, consistent with the known toxicities in this case of tislelizumab, but left ventricular dysfunction seems to be comparably low in all 3 arms.

We focus now on graphical representation of common toxicities seen in at least 20% of patients, and we'll see that there was a significant increase in diarrhea in the zanidatamab containing arms, potentially some slight increase in nausea and vomiting as well. There was also an increase in decreased weight and hypokalemia. We'll drill down on that in more detail in this slide on treatment-emergent diarrhea. Now diarrhea had emerged as one of the toxicities associated with this combination in the Phase II studies.

As such, moving into Phase III, there was mandatory diarrhea prophylaxis for patients in the zanidatamab containing arms consisting of loperamide twice daily for the first 7 days, subsequently, it could be discontinued at patient and physician discretion if they did not develop diarrhea or if they developed constipation. Possibly as a result of this, we actually see that the time to onset of diarrhea is at about the 1-week mark and the time to onset of grade 3 diarrhea is at approximately 2 weeks.

The incidence of grade 3 diarrhea was increased in zanidatamab containing arms. It was 20% in Arm B, 24.5% in Arm C and only 12.9% in Arm A. But irrespective of the severity of the diarrhea, the time to resolution was approximately 3 weeks. So finally, in the last slide, the discussion summarizes much of the information that I've already discussed. It is also a more lengthy explanation of the key points at the beginning of this presentation. I will leave it as is for those on the call to review, but it really is a summary of all of the salient points that I've discussed. Thank you all very much for your attention. I'm happy to take any questions following this. And I'd like to turn things back to Rob.

Thank you, Dr. Ku, for reviewing these unprecedented data, which we view as practice changing. The strength of the results reflect the rigor and precision with which this study was executed, and I'm thankful to the patients who participated in the clinical trial and all who collaborated with us to make this achievement possible.

Being here at ASCO GI the last couple of days has increased the excitement around zanidatamab. The momentum we continue to build around this program is invigorating as we move quickly to engage the FDA and plan to submit a supplemental biologics license application in the first half of this year. In addition, we plan to expeditiously seek NCCN listing based on these published data.

Turning to Slide 27. I'll cover zanidatamab's unique mechanism of action, which differentiates it from other HER2-targeted antibody therapies. Zanidatamab is a dual HER2-targeted bispecific antibody that binds to 2 extracellular domains on HER2, which is distinct from the traditional HER2-targeted antibodies that bind a single epitope. The antibody is engineered to bind in [indiscernible] to 2 nonoverlapping epitopes of the HER2 receptor, which is known as biparatopic binding.

This enables zanidatamab to cross-link neighboring HER2 proteins, leading to receptor clustering. Treatment with zanidatamab has been shown to block HER2 receptor growth signaling in HER2-positive cancer cells and in doing so, can slow or stop the growth of HER2-positive cancers. In addition to zanidatamab's direct effect on tumor cells, it has been shown to exert several immune-mediated effects. In preclinical studies, zanidatamab has been shown to activate the immune system via complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

We believe that activation of the complement pathway is unique to zanidatamab within the HER2-targeted antibody class. We believe zanidatamab's mechanism of action drives the differentiated and compelling clinical profile Dr. Ku spoke of today and contributes to both the strong activity when zani's combined with standard of care chemotherapy as well as when it is combined with tislelizumab, where strong benefit has been observed irrespective of tumor PD-L1 status.

On Slide 28, I will provide context around the magnitude of clinical benefit these results demonstrated compared to the current standards of care. In the case of first-line HER2-positive GEA patients, that includes trastuzumab plus chemotherapy based on results from the TOGA trial and trastuzumab plus chemotherapy with pembrolizumab based on results from the KEYNOTE-811 trial. Both zanidatamab investigational treatment arms demonstrated a statistically significant improvement in PFS, corresponding to a median PFS exceeding 12 months, reducing the risk of disease progression or death by 35% compared to the trastuzumab control arm.

Likewise, both zani combinations exceeded 2 years of median OS, representing the longest survival outcomes ever reported in this setting. The zanidatamab plus tislelizumab and chemotherapy arm demonstrated a clinically meaningful and statistically significant improvement in OS with more than 7 months improvement and a 28% reduction in the risk of death versus the trastuzumab control arm. Zanidatamab plus chemotherapy showed a clinically meaningful survival benefit with a median OS of over 2 years compared to the control arm, with a strong trend towards statistical significance at the time of this first interim analysis for OS. An additional planned interim analysis for this comparison is currently expected in mid-2026.

Slides 29 and 30 illustrate the PFS and OS Kaplan-Meier Plots, respectively, for the HERIZON-GEA-01 trial compared to the KEYNOTE-811 trial, which was the basis for approval of KEYTRUDA in PD-L1 positive patients. As you can see from these graphs, the zanidatamab treatment arm shows a clinically meaningful improvement when compared to the KEYNOTE-811 regimen. Further differentiating the zanidatamab combination, the benefit is seen in combination with tislelizumab irrespective of PD-L1 status, which we view as practice changing. On the PFS graph, you can see how similarly the trastuzumab plus chemo control arms performed by the overlap of red and maroon lines.

On the OS graph, the HERIZON-GEA-01 trastuzumab plus chemo control arm may have benefited from more frequent crossover to subsequent therapy than Arm B. However, despite the better-than-anticipated performance of the control arm, both zanidatamab combinations outperformed the control arm with more than 2 years of median OS, representing the longest survival outcomes ever reported in this setting. Importantly, benefits were observed for both PFS and OS for the zanidatamab plus tislelizumab plus chemotherapy arm regardless of PD-L1 tumor status.

The benefit regardless of status may be driven by zanidatamab's unique mechanism of action, as I described earlier. Enhanced immune activity of zanidatamab compared to trastuzumab may in part explain the efficacy of zani and tisle irrespective of PD-L1 status. Turning to Slide 31. The secondary endpoints of confirmed ORR and DOR were supportive of the primary efficacy outcomes. For the zanidatamab plus tislelizumab and chemotherapy arm, the median DOR nearly doubled the current standard of care to 20.7 months.

These secondary endpoints demonstrated deeper and more durable responses in the zanidatamab containing arms, leading to clinically meaningful improvements for patients with HER2-positive metastatic GEA. In summary, we view the overall data as practice changing compared to the current standard of care and supportive of approvals in this clinical setting for zanidatamab and tislelizumab regardless of PD-L1 status. This is very exciting news for the field and most importantly, a significant advance for patients who are facing a devastating diagnosis with limited options in first-line HER2-positive locally advanced or metastatic GEA.

Slide 32 shows the breadth of the current development program we have ongoing for zanidatamab, including multiple registration-enabling studies focused on areas where we believe zanidatamab has the potential to emerge as the preferred HER2-targeted therapy. Results from HERIZON-GEA, the first Phase III global randomized clinical trial of zanidatamab, not only underscores zanidatamab's ability to deliver meaningful outcomes for patients with GEA, but also reinforce its promise across a number of HER2-expressing tumors.

This gives us strong conviction in the clinical utility of zanidatamab more broadly. We currently have a robust development program exploring zanidatamab in various HER2-positive solid tumors, including a Phase III trial in metastatic breast cancer patients who are intolerant to or have progressed on previous HER2 treatment. A Phase III trial in metastatic frontline biliary tract cancer, a pan-tumor trial that may be registrational and a Phase II perioperative breast cancer trial.

The compelling data and durable responses seen from previous trials of zanidatamab are already resonating with oncologists, and there is excitement around potential to combine zanidatamab with novel therapies. With these positive GEA results in hand, we are focused on unlocking the full potential of zanidatamab and are excited to share more on these plans in the near future.

Now I will turn the call over to Sam to discuss our commercial perspective. Sam?

Thanks, Rob. As Dr. Ku and Rob have outlined, these results are truly impressive and represent the kind of scientific progress that can redefine outcomes for patients. It's advances like these that really drive our purpose to innovate to transform the lives of patients and their families. Turning to Slide 34. I'll begin by highlighting the significant unmet need in GEA, which is the fifth most common cancer globally and approximately 20% of patients have HER2-positive disease.

This represents about 63,000 cases each year across the U.S., Europe and Japan, including approximately 8,000 patients in the U.S. alone. Unfortunately, HER2-positive GEA is associated with substantial morbidity and mortality. For metastatic gastric cancer, 5-year survival remains below 10%, underscoring the seriousness of this disease. And despite ongoing advances in treatment, there has not been a new HER2 targeted option in the first-line setting since the TOGA regimen was introduced in 2010. Importantly, because of the strong historical precedent of HER2-directed therapies, HER2 testing is routine with adoption rates above 80%, ensuring patients can be readily identified for treatment.

Turning to Slide 35. I'll outline how our commercial strategy, combined with strong data and commercial foundation positions us to accelerate the launch of Ziihera in GEA, if approved. The Phase III HERIZON-GEA results reinforce that HER2 is the key oncogenic driver in this tumor type. These data clearly demonstrate that zanidatamab delivers superior efficacy versus trastuzumab independent of PD-L1 expression. We believe these practice-changing outcomes position Ziihera as the preferred HER2-targeted agent of choice in first-line GEA, replacing trastuzumab as the new standard of care, offering unprecedented durability and survival benefits.

Our commercial momentum in BTC provides a strong springboard for rapid uptake in GEA. Over the last year, we have expanded our solid tumor infrastructure, drawing on deep expertise within our oncology organization. Awareness and experience with Ziihera is already high across major academic centers and large community practice networks. Importantly, the compelling BTC data are translating into real-world results that oncologists are seeing in their patients, building confidence that will support adoption in HER2-positive first-line GEA.

There is also substantial customer overlap across our solid tumor footprint. Approximately 40% of our targets are shared across Zepzelca, BTC and GEA and over 90% overlap exists between BTC and GEA prescribers. Because of this and assuming regulatory approval, we anticipate leveraging our existing field force without significant expansion. Any incremental hiring will be highly targeted and fit for purpose. On the payer access front, Ziihera already benefits from an established permanent J-code through its FDA approval in second-line HER2-positive BTC.

This simplifies reimbursement and reduces administrative burden for providers. In addition, our comprehensive Jazz care support services, along with flexible ordering and fulfillment options ensure that providers can access Ziihera efficiently and without delays. While we will share more detail on launch execution as we approach approval, our existing footprint, capabilities and experienced teams position us to move quickly and efficiently to realize the GEA opportunity.

Turning to Slide 36. I'll speak to our regulatory path and the broader opportunity ahead. Following the positive HERIZON-GEA-01 results, we are preparing to submit a supplemental biologics license application in the first half of this year. We believe that the HERIZON-GEA-01 results will support near-term inclusion of zani in NCCN guidelines. More broadly, zanidatamab represents a global multi-indication opportunity for Jazz. We remain excited about its potential to redefine outcomes across HER2-expressing tumors and to build a meaningful durable franchise that expands our presence in solid tumors.

Before I turn the call over for Q&A, I want to express my sincere thanks to all who made this progress possible, to the patients and their families who participated in the study, to all of the investigators and clinical teams across numerous sites and to our colleagues and partners at Jazz, Zymework and BeOne. The dedication and collaboration have been essential in bringing zanidatamab to this point.

And with that, I'll conclude the slide presentation and turn it over to the operator to begin Q&A.

[Operator Instructions] Our first question today comes from Marc Goodman from Leerink.

Yes. Dr. Ku, could you talk about the surprise with the PD-L1 negative subgroup having better data and your thoughts on that? And maybe you could just give us a sense of, okay, we've got this data. What percent of your HER2-positive patients now are going to be using the HERIZON versus the KEYNOTE-811 regimen?

I mean -- I think it's an interesting question. I wouldn't say that my surprise -- I mean I think if you're referring to the fact that the point estimate suggests that the less than 1% patients do minimally better than the 1% or more. I mean that's not really a take-home point for me. If you look at the confidence intervals, they clearly overlap. I think to me, the kind of slightly bigger picture is that -- I think the very pleasant surprise is that both the PD-L1 essentially negative and positive populations benefit from the addition of tislelizumab.

And I think that's in contrast to the KEYNOTE data set for 2 reasons. First, in KEYNOTE-811, only 15% of tumors were PD-L1 negative. In this study, it was up to 40%. And it's unclear why. But I think one potential explanation is that, again, the KEYNOTE-811 regimen was initially FDA approved only in the U.S. and then subsequently became approved much later on in the rest of the world, including Europe. So potentially by the end of the study, investigators may have been referring only patients with PD-L1 negative tumors.

But I think that's actually ultimately very helpful because 40% of PD-L1 negative tumors really allows for a more robust subgroup analysis. And really, my take-home point is that the -- all patients benefit irrespective of PD-L1 status. And I think actually, there's a lot of interest in investigation into why that is, and it may really refer or relate to the unique biology of zanidatamab versus trastuzumab. I think turning to the other part of your question, there honestly is not a patient that I would consider for pembrolizumab, trastuzumab and chemotherapy at this point.

I mean I think that the cleanest comparison is Arm B versus Arm A and Arm B versus Arm A clearly establishes that zanidatamab is superior to trastuzumab. And again, I mean, Arm C, the -- while the median progression-free survival is similar, 2-year PFS is improved with the addition of trastuzumab, the hazard ratio moves a little bit down. If we look at median overall survival of C versus B, I mean, clearly, there's immaturity there, but there is a suggestion, especially in the median duration of response that the immunotherapy is providing an additional boost as we would expect. And as really, we saw in KEYNOTE-811, where there was an incremental benefit for the addition of pembrolizumab to trastuzumab and chemotherapy.

So maybe coming back to your point, I mean, I think -- I mean, maybe to answer the question directly, I guess the somewhat contrive situation that will arise is if someone had -- maybe I think there's a good example, if someone had ongoing inflammatory bowel disease and actually was not eligible to receive any immunotherapy and really because of the baseline bowel issues, the additional direct toxicity of zanidatamab might make me offer trastuzumab and chemotherapy. But certainly, I think pembro, trastuzumab and chemo, I think in the next -- well, certainly, I mean, once it becomes -- once an zani, chemo with or without tislelizumab becomes an NCCN companion listing, I think the KEYNOTE-811 regimen will become a historical regimen.

Our next question comes from Mohit Bansal from Wells Fargo.

So just following up on that -- with the previous question. So Dr. Ku, do you think you would -- like if you've given a choice, would you still use tislelizumab with zani in your PD-1 high patient setting or even PD-1 low? Or could you use a KEYTRUDA in combination with zani even though the data are not there?

Yes, that's a good question. I mean I think it's probably a broader question of whether all PD-1 inhibitors are comparable. And again, I mean, tislelizumab was designed rationally to be a slightly better PD-1 inhibitor. But whether it's superior to pembrolizumab or nivolumab, I think is unclear. I think my honest appraisal is that all the PD-1 inhibitors are largely similar. So I think that -- so I think clearly -- I think the story here is zanidatamab. I think tislelizumab is an important contribution.

And I think ultimately, it will depend on the specific wording of the NCCN [indiscernible] listing and ultimately, the FDA approval. If it's specifically in combination with tislelizumab, happy to give that. I mean if it's with any IO drug, then potentially -- in fact, if anything, I would prefer nivolumab. I think pembrolizumab clinically is not a great drug because it's given every 3 weeks or every 6 weeks, and we in the U.S. typically prefer FOLFOX every 2 weeks, pembrolizumab has sequencing issues.

The -- I mean, I would say that -- I mean, I can -- maybe speaking to the Memorial experience, up to this point, tislelizumab has not been on our formulary, even though it is FDA approved as first-line treatment for HER2-negative esophagogastric cancer. But based on these data, we are planning to add it to our formulary in anticipation of the fact that it will be given in combination with zani and chemo. And while kind of pricing issues are completely opaque to us as medical oncologists, my understanding is that tislelizumab is priced 10% cheaper than pembro and nivo. And certainly, any additional health care savings to what will ultimately be an expensive regimen would be appreciated.

Our next question comes from Akash Tewari from Jefferies.

This is Manoj on for Akash. Just a few from our end. Do you see the overall survival curve suppression dynamics within the PD-1 high population consistent with the ITT population, both in doublet and triplet terms? We have seen like the PD-1 component adding a late tail effect for the survival benefits like in the KEYNOTE-811 final analysis. Is there a possibility that zani's effects could be more front-loaded and zani doublet showing less of a further overall suppression going forward? Lastly, in general, what are your expectations on the doublet hitting the overall survival endpoint in the next interim?

Yes. I'm not sure I completely got all the questions, but I think for one of the questions if I understand correctly, is whether the -- well, first of all, I have not seen any of the survival curves based on PD-L1 positive and PD-L1 negative. And I think, honestly, in my discussions with colleagues and other KOLs, I think the -- I mean, again, I think one of the things you have to be cautious about with subgroup analysis is that if you have 15 variables and if you delve deeply into them enough, you're liable to see an association or a result that you did not expect.

I think, again, the broader picture is that, I think the very pleasant surprise and I think good news for our patients is that all patients seem to benefit. But so certainly, I have not seen separate Kaplan-Meier curves based on PD-L1 cutoffs. But I think certainly in the future, I think that would be, I think, an interesting and welcome analysis. Maybe -- I think maybe the main point of your question really was whether immunotherapy offers a tail at the end of the curve as we have seen with other studies. And yes, I mean, that actually would be my expectation.

Again, I think the median duration of follow-up is right around 2 years, which is really right around the median PFS and overall survival numbers. So I'm hoping that with time -- I mean, especially when you have a median duration of response of nearly 21 months that we will begin to see a tail at the end of the curve for Arm C favoring Arm B, but we'll have to see.

And I think -- finally, I think with regards to your question about whether I expect that Arm B will eventually hit statistical significance, it is on the verge. There is a numerical superiority at this point. I certainly don't have a crystal ball, but I think, yes, I mean, the expectation is that hopefully, with the next interim analysis, Arm D will be -- have a statistically significant improvement in overall survival versus Arm A.

Thanks, Dr. Ku. This is Rob. I would love to add my perspective on some of the questions that have come so far. The place that I'd like to start is just to remind everyone that fundamentally, the study was designed to compare zanidatamab to Herceptin in this highly HER2-driven cancer. And the results, we believe show that zani is definitively better than Herceptin really on all efficacy measures and therefore, should be the new HER2 agent of choice. That's really the first decision that any practitioner needs to make.

Secondarily, we explored whether tislelizumab would improve on those outcomes. And the results we have certainly show that irrespective of PD-L1 status. And that last finding, as Dr. Ku mentioned, is really quite unique and differentiated, and we think could be related to zani's unique immune mechanism of action. And we also find the results that tisle adds to the benefit to be highly consistent with all of the other data in the literature showing that this disease is sensitive and responsive to PD-1 inhibitors.

When you look at the PFS curves by PD-L1 status, the upper bound of the 95% confidence interval is below 1 for both positive and negative subgroups. And then when you look at the overall survival curves, these results are also consistent regardless of PD-L1 positive status with the upper bound of the confidence interval slightly crossing 1 in the PD-L1 positive subgroup. But I do want to call out some limitations that -- and to ensure that people are not getting confused when they're looking just at hazard ratios.

Remember, this was not a stratified analysis for PD-L1. And therefore, there may be confounding factors due to imbalances and other prognostic factors that are contributing to those small differences that otherwise show that the results are highly consistent between these 2 subgroups and favor the zanidatamab controlling arms. I also want you to be aware that for the PD-L1 analysis, it's likely to be further compounded by subsequent IO therapy on the control arm, which would not have been possible when KEYNOTE-811 was conducted, noting that the zani, tisle and chemo arm showed a median overall survival of more than 26 months regardless of the PD-L1 status.

So again, for me, the key message here is that zani went head-to-head with Herceptin. It definitively beats Herceptin across all efficacy measures and truly should be the HER2 agent of choice for all patients, as Dr. Ku mentioned. And then just coming to that very last question of -- I agree with Dr. Ku, I don't have a crystal ball either, but I do want to just be sure that people are clear around the statistics here.

This was sequential testing. Both PFS measures hit that will not be retested. Arm C beat Arm A on overall survival that will not be retested. So the small amount of alpha that was allocated to the first interim analysis -- sorry, the remaining large amount of alpha will be carried forward to the next interim OS analysis, which will focus on Arm B versus Arm A. And then, of course, there's a final analysis as well. And given the strong statistical trend, we're optimistic about that.

Thanks, Rob. I agree with all those points. And I actually think that the -- I think one of the very happy situations where we're slowly kind of finding ourselves in is just like in breast cancer studies, progression-free survival is a validated endpoint because there are so many subsequent lines of treatment. And I think while that would be an overstatement in HER2-positive gastric cancer, I mean, we now have trastuzumab deruxtecan, we have ADCs. Certainly, patients in Arm A who did not receive immunotherapy at some point could have received that post approval of KEYNOTE-811 in their countries.

So I think that the overall survival results are great, but they are likely to be confounded by post-progression therapy. So I think the purest distillation of the results is if you focus on the progression-free survival and certainly, Arm B versus Arm A shows that zanidatamab is superior to trastuzumab. And certainly, in Arm C versus Arm A suggests that all the hazard ratios and all the median numbers and all the percentages of long-term survival are all inch up a little bit versus B, although again, that's not a statistically valid comparison at this time. So I think certainly zani and chemo, I think likely with tislelizumab for many, many patients is -- again, I think will be the new standard of care, hopefully very shortly.

Our next question comes from Ami Fadia from Needham.

I wanted to just ask about the difference in the PFS and OS data that we saw between the pivotal trial and the prior Phase II studies. How do you think that the baseline HER2 status or the choice of chemo may have contributed to the difference that we saw between the 2 studies? And then maybe just a follow-up for Dr. Ku. If you sort of think about the various settings where GEA patients are treated, do you think that there might be any difference in the rate of adoption based on either PD-L1 status or HER2 status?

Yes. I think that it's a great question. I mean I think that -- so I mean, I was the last author on the ZW25-201, which was the Phase II study that was performed with zani and chemo. And as you know, it evaluated several chemotherapy regimens, specifically FOLFOX, CAPOX and 5-FU cisplatin. And certainly, I think virtually all U.S. investigators preferred FOLFOX, and that certainly will be our preferred regimen to combine -- preferred chemotherapy backbone to combine with this regimen moving forward.

Again, I mean, I think as everyone on the call is aware, I mean, there can be differences. I mean, typically, the efficacy drops from Phase II to Phase III for numerous reasons. And I think that the results from Phase II to Phase III actually are broadly consistent. Probably the one kind of outcome that I was a little bit surprised about was that there was not a more significant improvement in response rates for the zanidatamab arms versus tras and chemo. In the Phase II studies, that response rate was in the 80%, 85% range.

But I think -- I mean one of the analyses I'm certain will be interested to see is kind of sites of disease and maybe some -- delving a little bit into some of the RECIST measurements. But other than that, I actually think that the Phase II results translated pretty reliably into the Phase III. The -- I think maybe -- I can't remember whether there was a question about toxicity or not. And I think it's difficult to comment on the toxicities of FOLFOX versus CAPOX, for example, because there are also kind of ethnic and geographic differences in patients who received FOLFOX versus CAPOX.

And I guess finally, in terms of the last question, in terms of adoption, the -- again, I think my personal interpretation of the data is that in a patient who's otherwise fit, I think the triplet combination of zani, tislelizumab and chemo would be something I would strongly consider. But I think at the same time, is there specific reasons to contraindications against an immune checkpoint inhibitor, zani plus chemo itself is highly, highly active.

And certainly, not to speak for community oncologists, but I think in the community, and I think certainly with patients as well, I mean, there typically is a strong preference for an immunotherapy-based treatment. So I actually do think that there will be pretty brisk uptake of the triplet combination. HER2 testing and PD-1 testing are extremely robust. I don't think there's going to be any issue in terms of biomarker testing with rolling this out.

I mean I think a more granular response would be the study uses TAP. TAP is rarely used either through commercial panels or at academic institutions, but we also know that TAP and CPS are highly concordant. So I think that -- again, I mean, to me, it seems like there is benefit irrespective of PD-L1 status. But PD-L1 and HER2 assessment are the 2 biomarkers that are almost always performed, and we have that data available when we make treatment decisions about first-line therapy.

Our next question comes from Annabel Samimy from Stifel.

So I just wanted to look at some of the subgroup analyses. I'm curious if you think there would be any limitations based on IHC status -- for IHC 3 versus IHC 2 and for GEJ patients given what we've seen in some of the subgroup analyses?

Yes, that's a great question. So -- sorry, go ahead, Rob.

No, I didn't mean to speak over you, Dr. Ku. I was just going to maybe start the answer if that's okay. We've given this actually a fair amount of thought. It's very important to note that as you do multiple subgroup analyses, there's going to be some variability. And there's -- it's particularly prone to variability when you have very small subgroups. As was expected, this trial recruited largely IHC 3+ patients more than 80%.

So you wind up with a very, very small subgroup in the IHC 2+ patients. And it's clear that, that small group could be potentially confounded by other prognostic factors that are driving different results in the control arm. So we don't think that's a meaningful result and don't expect there will be a limitation either on approval or in practice.

I would -- I mean -- sorry, go ahead. Well, I mean, yes, let's just say I would agree with the response. Maybe in the interest of time, we can certainly move on.

Our next question comes from Joon Lee from Truist Securities.

Congrats on the strong data. How will you be addressing FDA comfort around U.S. general liability given the absence of U.S. patients in the HERIZON-GEA trial? And will you be seeking label expansion for both the doublet and the triplet or prioritize triplet? And will you be taking priority review?

Yes. So we certainly will be seeking a broad label approval of zanidatamab as well as the triplet with tislelizumab as a broad label PD-L1 agnostic. And we do think the data are compelling enough for this to be considered under priority review. But of course, that is an FDA decision. With regard to your questions about regional results, we're actually quite pleased in this trial with what we're observing in terms of results across the globe.

I just want to remind folks that the regulatory standard here is that the patient population is representative of the U.S. population. It's not necessary to recruit patients directly in the U.S. And as Dr. Ku mentioned earlier, there were very good reasons not to include U.S. specific patients in this trial. So we did include other patients from North America and Europe. We do believe the enrolled population is very representative of the U.S. population. This is in part based on the eligibility criteria, but also in terms of the supportive care standards that were implemented as part of the study itself.

And there's strong evidence that this turned out to be the case. When you look at the PFS curves in the control arm for this trial, HERIZON-01 and compare it to the most recent trial in a similar population, KEYNOTE-811, they essentially are identical in a pretty remarkable way. And so that demonstrates that there's high comparability in the patients who were recruited when judged against how they performed in the control arm. And of course, KEYNOTE-811 did recruit patients from the U.S.

And then I would just highlight that Dr. Ku, I think, made a really critical point around focusing on PFS as being the best distillation of the effect of the experimental treatments given that it's not confounded by subsequent therapies. If you look at PFS, highly consistent and clinically meaningful results across all regions and the OS results are consistent with that as well. So overall, yes, we'll be seeking a broad label, and we do feel this trial was enrolled patients who are representative of the U.S. population and that the results are consistent across regions. And we do not think that this in any way would be an approvability issue.

Our next question comes from Andrea Newkirk from Goldman Sachs.

I apologize if I missed this. But Rob, just as a follow-up there. As you think about the profile of the zani doublet and triple -- the triplet, many of those measures that you're speaking about, including PFS, do appear to be somewhat comparable across the doublet versus the triplet. I would just be curious to hear your thoughts on why you think that might be? And then second, does that pose any risk to the regulatory agencies as they assess or view the value of the incremental benefit of a triplet versus a doublet here?

Yes. Thanks for the question. So as Dr. Ku pointed out, when you look at PFS at the later time points, you do begin to see separation with the triplet relative to the doublet. Of course, the trial was not designed to compare the triplet to the doublet, and that's not the regulatory standard. So it's not necessary. But as you look at that sort of underpowered comparison, you do begin to see separation.

But also, we've known for a long time that the benefit of immunotherapy PD-1s is often better appreciated on survival, and that shows up in this trial as well, where the survival curves tend to separate even more. So for me, my interpretation is that this trial was fundamentally a comparison of zani versus Herceptin, and that's -- and zani definitively beats Herceptin across all efficacy measures and all measures of benefit risk. And then when you look at the addition of tislelizumab, it also contributes to efficacy really on all measures.

And the important thing is this is consistent with the broader very large body of literature showing that PD-1 antagonists are effective in gastric cancer, whether you look at HER2-positive or HER2-negative, whether you look at the metastatic setting or more recently in the neoadjuvant setting, PD-1s are effective in this setting.

What's unique about this trial, and we do think it could relate to the differentiated mechanism of action for zanidatamab is the benefit of the triplet seems to be across PD-L1 subgroups, which is really differentiated. So on balance, I do think that with the rare exception that Dr. Ku highlights of a patient having a contraindication of sorts that the best therapy for this still poor prognosis disease is to get the best HER2 agent, zanidatamab and a PD-1 inhibitor upfront.

Our last question today will come from Jason Gerberry from Bank of America.

This is Chi on for Jason. I have one question for Dr. Ku and one question for [indiscernible]. And so Dr. Ku, now that you've seen the Phase III data and while we are waiting for the FDA approval, would you -- or would you expect some of your peers might start to incorporate zani in frontline GEA either right away or when NCCN updates the recommendation guideline?

And if that's the case, is there a certain patient population you would think could be an early adopter for either zani doublet or triplet regimen? And my question for [indiscernible] is, what's your expectation for the duration of exposure or treatment exposure for the semi component in frontline GEA given the disconnect between the 12.4 months median PFS and the 7- to 10-month duration of therapy described on the safety sides.

Yes. To answer your question -- I mean, actually, the simple answer is yes, actually, a colleague of mine yesterday it surprised me by saying that he's actually -- since the press release, managed to get private insurance to support this regimen in the first-line setting for one of our HER2-positive gastric cancer patients. So I think that certainly -- I mean, I think really just about everyone I've talked to, I think, really feels that this is practice changing.

And I personally cannot wait to -- for it to be included in NCCN guidelines, which will then make it an option for patients on Medicare and Medicaid. But I think based on my colleagues' example, yes, the next patient I see with private insurance. I think now, especially since the dataset has been presented, I certainly would be willing to appeal to the insurance to see whether they will approve zani even at this point. But I think that once it's included in listings, once it's FDA approved, everyone I've talked to, I think we'll move quickly to adopt it.

And based on the results published now at ASCO GI, we have submitted for NCCN consideration. And of course, we'll update that if need be with a full manuscript publication when that comes, which we're working quickly to get published.

We are out of time for questions today. I would like to turn the call back over to Renee Gala for closing remarks.

Great. Thank you, operator. And just in closing, we are thrilled to deliver the results we've discussed today and to deliver a scientific advancement of this magnitude that can redefine outcomes for patients with first-line HER2-positive GEA. We do believe zani has the potential to transform treatment for multiple HER2-expressing cancers, and we are focusing on its broad development plan.

Zani exemplifies our approach to corporate development as well as we seek to identify and acquire differentiated therapies that improve patient care are strategically aligned with our development and commercial capabilities and can create substantial shareholder value. We're excited about the potential for zani to become the preferred HER2-targeted agent of choice and the opportunity that zanidatamab represents going forward. So thank you all for joining us today.

This concludes today's conference call. Thank you for your participation. You may now disconnect.

Citi Annual Global Healthcare Conference. My name is Geoff Meacham. I'm the senior biopharma analyst here. We're pleased to have Jazz Pharmaceuticals with us. We have Philip Johnson, EVP and CFO. So welcome Phil. And then, we have Jack Spinks from Jazz as well. So thank you, guys for joining us.

Phil, you want to kick it off with some kind of opening comments, and we can get right into some questions?

Happy to. Thank you very much for the invite. Pleasure to be here at the conference. In addition to having Jack with me from our IR team, I also want to give a shout out to John Bluth, who just recently joined us last week as our new Head of Investor Relations. So, we're pleased to have John onboard. A number of you may know him from different of his roles in the past, including most recently with BioCryst. So look forward to having a chance for you to get to know him further in his new role at Jazz.

Maybe just to start out, a couple of disclaimers. Please do consult our most recent earnings call for more details on our business as well as our SEC filings, for a number of the risk factors that do affect our business. If we're referring to guidance during the discussion today, that would be referring to the guidance provided on our November 6, 3Q earnings call. And then we'll probably refer to some non-GAAP financials as well. And you can find in the earnings materials more complete reconciliations to the GAAP equivalents.

Had a very strong quarter in the third quarter, record revenues for the company. Revenue is up about 7%, coming in at $1.13 billion. Really strong growth from our two largest brands, Epidiolex and the Xywav, strong growth underlying both of those from a demand perspective that gives us great momentum as we head into the back part of this year and then into 2026.

We did on the back of that strong performance, we gave some updates to our guidance. We had narrowed the range for revenue given that we've gotten very few months left in the year, and everything was tracking to our expectations, took down the top and pulled up the bottom to give a tighter range there. We did go ahead and bring up our ANI and EPS guidance given the strong momentum and disciplined execution on expenses that we've been seeing through the year.

And there had been some things also that generally had pulled up the overall level of results for the year. I want to highlight one in particular. That was a recognition in the third quarter of a $206 million deferred tax asset related to the Chimerix acquisition.

One of the reasons why I bring this up is just to explain quickly what that is. Effectively, those are tax loss carryforwards and the tax attributes that Chimerix had that we'll be able to utilize to reduce our future tax liability by $206 million, providing another source of significant value from that acquisition, which is I'm sure we'll talk later.

Modeyso, the main asset that we acquired with Chimerix is off to a phenomenal start. We're really excited with that initial performance. We also finished the quarter with about $2 billion in cash and investments for the first 9 months of the year, had about $1 billion of cash flow. That puts us in a great position to continue to do business development like we did with Chimerix.

And then, as we think about things have happened since we had finished the third quarter in October. We got approval for the first-line maintenance indication for Zepzelca and then most recently and most notably, had the data readout for the first-line GEA trial for zanidatamab with very strong results. This was for those of you that have been following us or maybe not the final PFS readout in the first of three overall survival readouts.

We're extremely pleased that for the doublet zanidatamab plus chemo. We show statistically significant, clinically meaningful progression-free survival and a very strong trend towards overall survival benefit as well, although not at this first interim reaching statistical significance.

And then for the triplet in addition, adding on top trastuzumab had both clinically meaningful and static, progression-free survival as well as overall survival.

We look forward to presenting the results in detail at an upcoming medical meeting in the first quarter of the year and feel like we did accomplish our objective in this study of showing that zanidatamab should become the HER2 treatment of choice in this first-line GEA setting supplanting Herceptin.

Maybe I'll leave that for the opening remarks and see we'd like to go with the questions. But really, really pleased to be here talking about Jazz and the excitement we've got moving forward.

Sounds good. Thanks, Phil. Yes. So I guess let's go in reverse order maybe with respect to BD capital allocation, then we'll get obviously into the commercial portfolio. Talk a little bit about the Chimerix deal, kind of the rationale going into it, what were you guys looking for from a contribution perspective and talk about how the -- we have a strategic fit here.

Yes. So it really hit a number of things that we look for and we're looking for business development opportunities that we think we can be really successful with. There is a huge unmet need. This is one of few therapies in development for this particular mutation in this really rare form of glioma. And frankly, we had a little bit of controversy with it. There have been some physicians who have written the letter criticizing some of the development that may have scared some others away. That's not the kind of thing that Jazz will get scared away from.

We dove in, in detail, got into diligence, looked at the data. We're very pleased with what we saw at a patient level in terms of durable responses of these patients we're seeing. The asset has really good patent protection, so a long-lived asset as well, another one of our criteria, a very focused call point, really built on a lot of things that we have in terms of capabilities, knowledge and experiences and felt we could be really successful with the launch of the product.

There are some other things we saw as potential sources of value that frankly, we didn't put into the original model. And one of them I mentioned, the tax attributes that came with it as well, but we think this really lines up well for us to be able to contribute meaningfully to improving on patient care in an area where there's really been no new therapies available for about 60 years and bringing something that's meaningful. We'd love to be able to build upon this new presence for us in brain cancer and glioma. We'll look for opportunities to do that over time.

Really been pleased with the colleagues at Chimerix that we've added to Jazz, a number of them who are staying in key positions for us moving forward and bringing great expertise in this area for us to continue to build on the success of Modeyso.

And then, I guess, same question on the SAN2355 licensing agreement. Talk about maybe the rationale there.

So Jazz had not been an epilepsy before the GW acquisition. We are a leader now because of that acquisition, the primary role that Epidiolex plays in the treatment of a number of these epilepsies, also a very combinable drug that's sort of a backbone other treatments can be added to. Not too long ago, we had greater clarity on exclusivity for Epidiolex out to the very late 2030s given the resolution with all the different ANDA filers. So certainly we want to make sure that we're building upon our presence there and have looked at a number of opportunities to do that and really liked the attributes in the Saniona molecule to potentially overcome some of the potential limitations for dosing, therefore, efficacy of other KB 7.2, 7.3 directed molecules and look forward to quickly advancing this through clinical development.

We will, over time, look to build sort of more generally on the corporate development theme, the existing areas that we're present in. There are most opportunities probably in oncology and in epilepsy. There are a few opportunities given the state of the science in sleep. But there are some there as well. And then we have said in the past, we do continue to look at other areas within rare and orphan diseases, even if we're not there currently, where we could apply our capabilities and knowledge to be successful.

Yes. And talk a little bit about the kind of the BD climate today. There -- I mean, you guys are mostly focused on later-stage kind of assets. But are there new indications that are peripheral to the ones you're at or newer technologies that you feel like you could really add value, maybe that are in more mid-stage development versus later stage?

There are definitely -- from, I'd say, very early stage like we do with the Saniona deal, mid-stage to even later stage, even marketed opportunities that we see as really fitting well with Jazz. We are open to a range of transaction types. It doesn't have to be acquisition like we did with Chimerix, although we're certainly open to that. I feel we had a really successful well-structured deal, that shared risk and value appropriately between Zymeworks and Jazz for zanidatamab. We're certainly open to additional licensing deals like we did with the Saniona transaction.

And it does not seem like there are as many sectors maybe where there's froth in valuations or outsized expectations. I think things are on a relatively even heel with sellers or licensors of assets at this point where it's more likely you can get to crossing on value.

Yes. Makes sense. Let's go to the commercial product performance. So Xywav, your overall sleep franchise has been growing quite nicely. Talk a little bit about the composition of new patients, maybe the mix between IH and narcolepsy and how you think that kind of evolves over time?

Yes. So, IH has been a real success story for Jazz. We're the only oxybate with Xywav that is approved for that indication. And it has been driving the majority of our new patient adds. In the most recent quarter, about 325 adds an IH and about 125 in narcolepsy and it is a place where we see the greatest opportunity for continued growth in patients for Xywav.

In narcolepsy, we've been really pleased with our performance even in the face of authorized generic competition and additional branded competition. There had been a point in time where we're signaling to the Street that we could envision having met patient losses in narcolepsy given that competition. We actually not experienced that to date.

And that speaks volumes to the benefit that Xywav offers is the only low sodium oxybate in a patient population in narcolepsy patients, IH is very similar, where those patients were at a 2x to 3x increased incidence of cardiovascular events. So certainly, having low sodium, less incidence of hypertension, we think, is a really important contributing factor to the overall health of these patients and a strong reason why Xywav has done so well, not only in idiopathic hypersomnia but also in narcolepsy.

Going forward, as I said, we do see the bulk of the opportunity to add new patients in idiopathic hypersomnia. This is just based on the numbers that are available, a market that would appear to be about half the size of narcolepsy when you look at patients that are currently being treated, but we do hear reports from many physicians that they feel in their practice, they have as many IH patients as narcolepsy patients. And maybe as we're building this market, building awareness but there could be upside to those current number of patients being treated that could benefit from Xywav.

I do want to mention, we talked about this on our quarterly call, we do hit this time point upcoming as we move into 2026, where there can be generic versions not of Xywav or low sodium oxybate, but of Xyrem, our high sodium oxybate. We do currently expect one or more generics to come into the market in 2026. And any impact on Xywav would be dependent upon the number of generics that come in, the timing in the year, what their pricing positions are. We feel we're well protected as well as we can be. Having established Xywav is really important with physicians and patients. based on being the only low sodium oxybate, but we do recognize payers may take actions depending on the opportunities that they have with the other generics that could create some headwinds for Xywav over the course of '26.

Just real quick on the IH indication. Do you feel like there is appreciation in the physician community about the subtleties of the indication and awareness? Or is there more sort of build to come from the commercial investment?

There's more, I think that we can do with some of the physicians to help them understand why you would use an oxybate for this particular patient population. I think, when they understand the kind of benefits that you're seeing in sleep and what that leads to in terms of the daytime benefits, they do understand then the rationale for it, but there are some who at face value might question, why would I use an oxybate with this particular patient population. But to date, those efforts have been going really well, and we'll continue to drive penetration in the IH market over time.

Awesome. Let's switch gears to Epidiolex. So talk a little bit about the drivers of growth here as you're about to hit blockbuster status for this. So it's a pretty impactful drug for you. What are the big drivers? And kind of what should the -- trend should be going into next year?

Yes. So, we're definitely on track to achieve blockbuster status. I believe it was maybe 11% growth year-to-date. We need 3% growth over last year effectively to hit blockbuster status. So, well on track to achieve that. We're seeing really good results from a number of initiatives that we have, some around ensuring that there is appropriate titration in the initial experiences that patients are having as they come on to Epidiolex. We have some nurse navigators that are assisting with that process, and we're seeing really good results with increased persistence in patients that are receiving that service.

We've also increased some of the resources that we have that are providing more information on the benefits not only for seizure, but non-seizure benefits, making sure that some of the publications that we've been presenting at medical meetings are fully understood.

The combinability of Epidiolex, again, as physicians are looking at things that they can use to treat their patients best, really using this as a backbone therapy and making sure that they understand not only again the seizure benefits, but the non-seizure benefits that come.

Jack, and there's a couple of other things we may have talked about over time. I was wondering if you want to add any?

Yes. I think a focus of ours has been on patient identification. So, doing things like utilizing tools that healthcare providers can have to better diagnose patients, such as the REST-LGS tool has been really quite effective for us. We've also implemented commercial initiatives like the Nurse Navigator program, which really helps patients titrate through the initial course of therapy and really working to improve persistency across patients. So, there's a number of commercial initiatives that we've been working on.

LGS patients, in particular, are ones that often diagnosis can take over a decade. So that patient identification has been really key and that REST-LGS tool has been very helpful for physicians as they're trying to identify patients that could benefit from Epidiolex than potentially other anti-seizure medications as well.

Let's talk a little bit about the persistent rates. So, maybe how has that evolved over time? And what is sort of typical for the category?

So, we've not quantified the persistence. We have talked about pretty substantial increases in persistency in those patients that are using that Nurse Navigator program to titrate up and get to a therapeutically effective dose that gives them the kind of benefits that they're hoping for and expecting. But beyond that, we've not gotten into the specifics of the number of months of average persistence. Certainly, these are patients where there can be loss early on, those patients that once they're on and are perceiving benefit, they do tend to stay on for multiple years.

Yes. and then, the evolution to the adult -- more adult population. Talk a little bit about the growth opportunities there and maybe the timing of when you could see the impact of that?

So, we are already seeing some impact to our efforts to ensure that there's appropriate understanding of the benefit that can be particularly for LGS patients, for example, achieved in adult patients. We've had for the last couple of years, focus on some of the long-term care centers and other centers where these patients are most prevalent. And those efforts do continue. I'd say it's not a bolus. It's sort of like a bit like we're seeing with the IH population with Xywav, sort of a continual build over time as we get more and more awareness of the product for those patients, more and more physician experience treating those patients and seeing the benefits that Epidiolex can bring to those adult patients.

And Phil, you mentioned kind of the payer mix here as well. Talk a little bit about how that has evolved over the course of the past year or so on gross to net and on formulary positioning. Like -- this is a unique skill for you guys to try to get better access, but it's been a bit of a challenging environment right this year with some more policy uncertainty.

Yes. So I'd say, just from the pure payer perspective, apart from the policy side of things, compared to what I was used to prior to coming to Jazz, these are categories where the gross to net is nowhere near as high. It certainly exists, but it's not the same kind of both competitive intensity and then just mass market that leaves those very large gross to net reductions that you see with some of the primary care products.

Our payer mix has not changed dramatically in the last few years. It depends on which product sort of our exposure to some of the government programs getting to some of the policy questions. To date, there is some potential exposure to some of the policy initiatives, most favored nations and things that have been discussed, but nothing has really been put concrete out there for us to really react to and to quantify.

I would say Epidiolex is one of those products that does have a decent amount of some of the government pay. But I think compared to other maybe larger pharma, the exposure we have probably is proportionately not quite as large as they would have.

On the policy side as well, obviously, unrelated to the pricing or gross to net, we've had discussions of tariffs for much of this year. As a company that has 90% of its revenue in the U.S. and much of its production outside, there are a lot of early interest and understanding steps that we could take to mitigate that exposure. We've significantly built and continue to inventories here in the U.S. to buffer any impact from tariffs to date and the most recent example being the U.K./U.S. agreement.

I think, we're getting to things that seem much more reasonable and manageable, not some of the initial fears that had been put out with some of the very large tariff rates that were being represented by the administration. So at this point, we have a very manageable potential impact as we look forward into 2026 from tariffs as well. So not 0, but not something that's particularly concerning to us at this point in time.

So, you're comfortable with where Jazz is today on an MFN and a manufacturing. Have you guys talked about the level of investment with respect to onshoring that you could make?

So, there's been a lot of work done through bio primarily, I think making sure the administration understands that there are certain participants in the industry that are really well positioned to actually sink their own capital into the ground and build facilities.

Some of the smaller and midsized players really aren't in that position and probably definitely open to and we are moving production to the U.S., but using third parties to do that. So, it is bringing employment to the U.S., in some cases, additional investment into the U.S., but not something being done directly by Jazz.

It's possible for us in the future to potentially have our own U.S. site. I think, our first protocol would be to work with known, trusted, established contract manufacturing organizations that can do that work here in the U.S. We're already set up to have a CMO that can do all of our oxybate needs and have that supply up and running and are working on some other moves of that drug product manufacturing here to the U.S. as well for a number of products.

Okay. Let's switch gears to oncology. So Zepzelca, I wanted to ask you maybe about the small cell lung market, how that's evolved? How do you think this product -- there's some new entrants. This has been historically though, a tough indication, I think.

Definitely tough indication. I know, in one of the medical meetings this year, one of the people asking questions of the discussions after a couple of the presentations that they felt there had been more presented in that 1.5 hours or so block on advances in small cell lung cancer than they've seen for probably 30 years before. So, a lot of really exciting things for patients. We're very pleased to be participating in that.

The first-line maintenance data with Zepzelca and atezolizumab, we think should become standard of care in that setting. As we've noted and presented, PFS benefit, OS benefit, very meaningful, significant advance for patients there.

Now we're not the only one making advances in this area. Certainly, IMDELLTRA has had in the second-line setting, a similar PFS and OS benefit has been building its share. We'd expect that likely to continue.

And then in the first-line setting, about 70% of patients are extensive stage. That's where we had studied Zepzelca, about 30% are limited stage. There's been some really stellar first-line data in extensive -- sorry, in limited stage with durvalumab that is giving great results for those patients, leading to fewer patients progressing into the second line.

So, as we think about Zepzelca, very strong opportunity for us to benefit patients and build first-line maintenance share. But there in the second-line life, there will be fewer patients that are coming from limited stage, because of the durvalumab data and then greater share over time to IMDELLTRA with their second-line results. So, really excited for patients for what's happening in that segment of the market in small cell lung cancer and with the data that we've got for first-line maintenance.

So you have a combination, you have maybe more runway in the maintenance. What are maybe the other opportunities that you would see for growth, maybe line extensions?

For Zepzelca, I think just given the remaining patent life, it's unlikely that we would make substantial new investments in that product at this point in time. We do see, though, great growth in oncology for Jazz. But it'll be different molecules like Modeyso, Ziihera and others hopefully to come with our continued corp-dev efforts.

Yes, Modeyso, let's focus on that. So you've had a good initial launch. Talk about the initial physician feedback kind of positioning? Is it kind of what you thought?

Yes. We're real pleased. I'm going to let Jack take this one and get involved here.

Yes. Yes. Thanks, Geoff. We are really pleased with the initial uptake we've seen. It's been very strong since our approval on August 6. We did recognize $11 million in net sales in 3Q '25, and that's after being on the market for only a couple of weeks. That's about 200 patients, which is really exciting to see. I mean, there's huge unmet need here with existing treatments around for the last 60 years, this represents the first advance for patients with H3 K27M-mutant diffuse glioma in a very long time. So, it's been fantastic to see.

The majority of those 200 patients were de novo patients, about 60%, with the other 40% coming over from EAP. And given that massive significant unmet need, we do have very strong relationships with patient advocacy and support organizations, which have helped drive that uptake. So,, I think, we're excited about the initial launch. We see this product as being around north of $500 million in peak sales. And then, there have been a number of initiatives ongoing to make sure we continue to drive that awareness and uptake.

I think it's a little too early at this point to change our peak sales expectations. But certainly, the initial uptake has exceeded our expectations. So really pleased with the results to date and the trajectory that we're on.

And there hasn't been really much in the way of limitations on diagnostics, right? I mean, it's a fairly straightforward path.

It is typically done on your academic centers. It's been part of the protocol for these patients for quite some time now. It's possible that not everyone was getting tested since there really was no product that was approved for the specific mutation. So, we're making sure that we're educating not only in the academic centers, but in community centers about testing for patients that may have this kind of mutation so that they can be identified as often as possible and then available to receive Modeyso.

And talk a little bit about the impact that you would see over time with sort of an OS benefit moving -- expanding the opportunity a little bit.

Yes. Jack, do you want to?

Yes. I think, we have an ongoing confirmatory trial, the ACTION trial in frontline, which would serve to confirm benefit in that second line post approval. We've talked about having OS results for that trial late '26, early '27. So, we're very excited about having that option for patients. Again, this is an extremely aggressive brain tumor. And while frequently tested for these patients are certainly in need of additional options. And we look forward to being able to bring additional options for patients in the front line with hopefully positive results from that ACTION trial.

And from maybe a guideline context, would that be another driver of growth? Or do you think it's mostly awareness and kind of patient testing as maybe the next, call it, 12 months or so?

So the awareness of the drug itself, I think, is extremely high, making sure that there is appropriate awareness of testing, is something we're focused on. This is one where there's strong enough awareness. Clearly, we promote to label. So, we will promote to first-line post getting the positive confirmatory study and then approval from the FDA. But we do know of physicians who have really no other choices. And there's probably some utilization that we'll have in this interim period in that first-line setting given physician choice, not motivated by Jazz actions. That could be part of what's driving some of the additional early uptake that is a bit beyond the expectations that we had originally.

I think, it does speak to the strong unmet need and the confidence that physicians have in this product. Also, relatively benign safety profile, so very easy for them to administer. And again, we're seeing a relatively 20-some percent patient overall response rate, but within those, some very long and durable meaningful responses that are delivering significant benefit to these patients.

And the ACTION trial is going to take, I think, a little bit of time to mature. But are there any other studies that maybe you could continue to look to as they mature, maybe longer follow-up that could...

We are looking at other opportunities for Modeyso. And just real quick on the timeline for the ACTION study. We did make a determination that we wanted to have overall survival be the main endpoint for that study. We thought that was the most appropriate. So we did go ahead and increase the number of patients from 410 to 510. So, if you're comparing some of the prior statements that Chimerix had made on potential trial readout and comparing that to what we're talking about now, that's the driver for a bit of that shift out in time is for that additional patient accrual and then getting to the overall survival readout.

Got you. Okay. Let's switch gears to Rylaze. So walking down the oncology portfolio, talk a little bit about the growth drivers there when you look at the adolescent young adult setting.

Yes. So definitely, the adolescent young adult setting is the area where there's more opportunity for growth. For quite some time, Rylaze has been widely adopted in almost all of the pediatric protocols. So, within that AYA setting, those treating physicians are using a mix of asparaginase-based therapies or others. So, our efforts there have really been focused on ensuring that they understand the benefits of an asparaginase-based regimen and then the role for Rylaze, if they have any issues with their patients in that first-line asparaginase setting, hypersensitivity reaction in particular.

So, it's been relatively stable in terms of the product given some of the overall dynamics we've seen to date, again, probably minimal opportunity for growth in that pediatric setting since we're highly penetrated there. We'll work to maintain that positioning and then increasingly look to drive penetration into the adolescent and young adult patient population.

And then, the switching component, maybe talk a bit about what -- kind of, what inning we're in with respect to that and how much you -- that could be a driver.

So the -- I think, the product here is really well positioned as the go-to after you've had hypersensitivity reaction in the first-line with one of the other asparaginase therapies. So that -- I don't -- at this point, I think that's sort of played out, and we're sort of into a steady state for that and the positioning is well known and respected and understood by physicians.

Yes. That makes sense. Phil, you mentioned we started off with a bit of a discussion on BD and oncology. Would you say if you had to rank them, would that be a therapeutic area that you probably would be most acutely focused on? And obviously, your -- the kind of history of Jazz is more in the rare disease space. How do you kind of look at those from an ROI perspective?

So, I'd say even before we get to ROI, just what's happening in terms of the science, there certainly is a lot going on in oncology, including in rare diseases. So it's a fertile area for us to continue to build just like we did with the acquisition of Chimerix and dordaviprone. Also quite a bit going on in epilepsies in terms of new mechanisms of action, improvement upon existing mechanisms of action. So, quite a bit of scientific substrate there.

Sleep, the other main area that we've been in, frankly, there's less. There's sort of at this point in time, orexins and there's not a lot else. Now there are some things that are percolating in preclinical that could come to the fore over the coming years. But just for a scientific substrate, that's how I would view our current areas of participation.

We have been looking -- I know we haven't done a deal yet. We have been looking in areas that are in rare and orphan diseases that aren't sleep epilepsy or oncology. And there is quite a bit of substrate there as well. So we're looking for opportunities for us, again, high unmet need, significant improvement upon standard of care, relatively limited call point, a lot of the things that characterize the product we've been successful with that we think could translate into a new therapeutic area for us as well. So there's certainly opportunities there.

When you get to actually the return piece, there, I think it's probably more gated by at what point in time you're entering with your acquisition or your licensing. Clearly, as you get beyond proof-of-concept, things get a little more fully priced. So as you're accessing those, probably more of that value goes to the seller or the licensor. If you're pre-proof-of-concept, then obviously, you're taking more of that clinical risk and retaining more of that potential future value. In general, I'd say we're comfortable taking that earlier clinical risk, including preclinical in areas where we've got significant existing expertise like we did with the Saniona molecule in epilepsy.

And what are your thoughts on -- I think in the bigger pharma category, we've seen CVRs dominate a lot of activities in BD. And we've also seen assets coming from China that are more bio-buck, sort of, back-end loaded. What are your thoughts about the creative structures that we've seen and be what could Jazz use going forward?

Yes. Definitely open to structuring. CVRs, I think, have been used for quite some time, a little more in vogue at this point in time, probably more to bridge final discrepancies on value that typically not a large percentage of the overall deal value, but certainly something that's been employed in the past by Jazz and we'd be very open to that kind of structuring.

And then definitely want to continue to build out the sources for innovation that we have access to. China, as you know is exploding, and that's one of the areas that I think we do need to continue to build our relationships into that market and innovators, particularly for those drugs that are going to be applicable to rare and orphan disease so that we're a port of call for them to come to with those opportunities as well.

And you mentioned upfront the strong cash position that you guys are in. So, do you have -- how do you balance that? Are investors more biased to investing internally in commercial? Or is it be aggressive on the external kind of BD M&A front?

So, I'd say if you ask 10 investors, you're going to get a variety of responses to that. In fact, Jack and I just recently have been on a CEO listening tour with Renée, our new CEO, both in person and then on video calls with investors.

I would say the mass balance of those individuals expressed a strong interest in Jazz continuing to invest externally to bring in molecules that would be in their minds more innovative. And often Modeyso and Ziihera were cited as good examples of that kind of asset.

Certainly, people across the board, I think, interested in understanding our plans to maximize the value of zanidatamab given this most recent first-line GEA readout. So I'd say don't drop the ball on the internal opportunities that you've already got, but definitely an expectation that we'll continue to build on the future growth prospects of the company through corporate development.

Awesome. Well, Phil, Jack, thank you very much, guys.

Yes. Thanks for having us.

Good day, and thank you for standing by. Welcome to the Jazz Pharmaceuticals 2025 Third Quarter Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Jack Spinks, Executive Director, Investor Relations. Please go ahead.

Thank you, operator, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its third quarter 2025 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors should also refer to the press release and the quarterly report on Form 10-Q that we issued earlier today. Both are available on our website and filed with the SEC.

On the call today are Renee Gala, President and Chief Executive Officer; Sam Pearce, Executive Vice President and Chief Commercial Officer; Rob Iannone, Executive Vice President, Global Head of R&D and Chief Medical Officer; and Phil Johnson, Executive Vice President and Chief Financial Officer.

On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results. Growth potential and anticipated development, regulatory and commercial milestones, which involve risks and uncertainties that could cause actual events, performance and results to differ materially from those contained in these forward-looking statements. We encourage you to review these risks and uncertainties described in today's press release and under the caption Risk Factors in our annual report on Form 10-K for the fiscal year ended December 31, 2024, and our subsequent filings with the SEC, including our quarterly report on Form 10-Q for the fiscal quarter ended September 30, 2025, which identify certain factors that may cause the company's actual events, performance and results to differ materially from those contained in the forward-looking statements made on today's webcast. We undertake no duty or obligation to update our forward-looking statements.

As noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website. I'll now turn the call over to Renee.

Thanks, Jack. Good afternoon, everyone, and thank you for joining us to discuss Jazz's third quarter 2025 results. I'm delighted to be speaking with you today as Jazz's CEO. The past 3 months have been energizing and productive. We delivered 2 FDA approvals that underscore Jazz's ability to bring highly differentiated therapies to patients with serious unmet needs. These milestones reflect the strength of our execution, dedication of our teams and our continued momentum to drive sustainable growth and meaningful value for our patients and our shareholders.

Beginning on Slide 5, the results of the quarter reflect that momentum. Starting with commercial, we achieved our highest ever revenue quarter over $1.1 billion, driven by robust growth from Xywav, Epidiolex and the early successful launch of Modeyso, the first and only drug treatment for recurrent H3 K27M-mutant diffuse midline glioma, an ultra-rare and aggressive brain tumor.

Approval of Modeyso followed the acquisition of Chimerix earlier this year, reinforcing our ability to strengthen our portfolio through corporate development. We also secured FDA approval for Zepzelca in combination with atezolizumab as a first-line maintenance therapy for extensive stage small cell lung cancer. Both therapies are now included in NCCN Guidelines, reflecting the meaningful advancements these therapies bring to patients.

Moving on to our pipeline. We look forward to sharing the highly anticipated top line results from the Phase III zanidatamab HERIZON trial in gastroesophageal adenocarcinoma, or GEA, later this quarter. In addition, we strengthened our early-stage epilepsy pipeline through a global licensing agreement with Saniona. This agreement provides Jazz with worldwide rights to develop and commercialize SAN2355, a promising preclinical candidate designed to overcome the limitations of nonselective Kv7 targeting compounds.

On the financial front, we remain strongly positioned to invest in the key growth drivers of our business. We narrowed our 2025 revenue guidance to a range of $4.175 billion to $4.275 billion, reflecting increased confidence in our outlook at this point in the year. In additions, we were pleased to have reached settlement agreements across the entirety of the Xyrem antitrust litigation and the litigation with Avadel. With these matters behind us, we can focus squarely on executing our strategy, maximizing our impact for patients and creating meaningful value for our shareholders.

Finally, we're thrilled to welcome Dr. Ted Love to our Board of Directors. Ted's extensive leadership in the biopharmaceutical industry and track record of driving scientific innovation, commercial success and shareholder value will complement the capabilities of our existing Board and deepen our commitment to innovating for patients.

In summary, we delivered a highly productive third quarter with record revenues, FDA approval and rapid launch of Modeyso, completion of the Saniona licensing agreement and in October, litigation settlements and first-line maintenance combination approval for Zepzelca, all of which position us for a strong close of the year. I'll now turn the call over to Sam to discuss our commercial performance, after which Rob will cover our R&D pipeline. Phil will provide a financial update. And after that, we'll open the call to Q&A. Sam?

Thank you, Renee. I'm looking forward to sharing the progress of our growing and increasingly diversified commercial portfolio today. Starting on Slide 7. During the third quarter, we continued to build on the positive momentum we've seen across our sleep portfolio this year. Total revenue from our sleep therapeutic area, which includes Xywav, Xyrem and high-sodium oxybate authorized generic royalties was $520 million. Xywav net product sales grew 11% year-over-year to $431 million. We're pleased with the strong execution of our field teams, which drove an increase of 450 net patient adds exiting the third quarter with 125 net patient adds from narcolepsy and 325 from IH.

Our field team's efforts have been bolstered by our disease awareness digital campaigns that have now been expanded to include narcolepsy in addition to IH. Our field nurse educator program continues to drive positive impact for patients starting therapy. This program enables new Xywav patients to interact in person with a registered nurse to receive education on titrating and optimizing their oxybate therapy and have been effective in helping patients remain on treatment.

The health benefits of reducing sodium intake continue to resonate with HCPs and patients, solidifying Xywav's position in the market as the only oxybate that provides a significant and clinically meaningful reduction of sodium. In August, the American Heart Association and American College of Cardiology published the 2025 high blood pressure guidelines, which recommend daily sodium intake should not exceed 2,300 milligrams per day. For patients predisposed to high blood pressure, the daily intake of sodium should be less than 1,500 milligrams per day, a level which is exceeded by the recommended daily dose of all high-sodium oxybate treatment options.

These recommendations are supported by the recently published XYLO study that showed switching to low-sodium Xywav from high sodium oxybate was associated with a clinically meaningful reduction in blood pressure. These guidelines, alongside the XYLO data reinforce our belief that every patient taking an oxybate to treat narcolepsy or IH should have the opportunity to benefit from Xywav.

We carry very strong momentum with low-sodium Xywav into 2026, which is a year that brings the potential entry of one or more generic versions of our high-sodium Xyrem. As a reminder, generics of Xyrem are able to enter the market early next year. The revenue impact to Jazz will depend on which companies enter the market, how many may enter and how these products will be priced. We, therefore, recognize that the availability of generics could result in payer actions that cause some level of disruption to Xywav revenue. However, even in the market with generic competitors, Xywav's offers a differentiated profile, and we will partner with payers to ensure that patients continue to have strong access to Xywav, the only low-sodium oxybate on the market and the only FDA-approved treatment for IH.

Moving to Slide 8 and Epidiolex. Net product sales were $303 million, resulting in a 20% increase compared to the third quarter of 2024. We continue to see healthy underlying demand for Epidiolex with 10% volume growth in the quarter. Revenue this quarter also benefited from a release of reserves following refinement of certain accrual rates here in the U.S. We are seeing sustained benefit from the robust body of real-world evidence supporting both seizure and nonseizure benefits of Epidiolex with new data from the EpiCom study expected at the AES Annual Meeting next month.

In addition, the Nurse Navigator program has driven a meaningful improvement in persistency amongst Epidiolex patients enrolled in the program. Given our solid year-to-date performance, we remain confident that Epidiolex will reach blockbuster status this year.

Moving to oncology on Slide 9. For the third quarter of 2025, Rylaze net product sales were $100 million, representing a 1% increase compared to the third quarter of 2024. Whilst overall asparaginase use has declined following implementation of updated pediatric protocols, the use of Rylaze within the asparaginase class for pediatric treatment has remained stable. Our efforts continue to be focused on ensuring optimal use of Rylaze in the pediatric setting, ensuring patients are switched to Rylaze at the first sign of a hypersensitivity reaction and increasing Rylaze use in the adolescent and young adult population.

On Slide 10, net product sales for Zepzelca for the third quarter of 2025 were approximately $79 million, a decrease of 8% year-over-year due to continued competitive dynamics in the second-line setting. We were pleased to have received FDA approval for the combination of Zepzelca plus Tecentriq, expanding Zepzelca's indication into first-line maintenance therapy for extensive stage small cell lung cancer.

Data from the Phase III IMforte trial demonstrated a statistically significant improvement in overall survival for Zepzelca in combination with Tecentriq, reducing the risk of death by 27% compared to the Tecentriq-only arm of the trial. We believe these data are practice changing, and we are excited about the opportunity to help improve patient outcomes. We currently have the right team and capabilities in place to deliver a successful launch of Zepzelca in this new indication.

Turning to Slide 11. Modeyso became commercially available less than 2 weeks after receiving accelerated approval, generating $11 million in net product sales during the third quarter of 2025. We were pleased to receive early inclusion into the NCCN Guidelines as a preferred treatment for both adult and pediatric use. Given the very high unmet need, exceptionally high awareness of Modeyso and strong patient advocacy support, we've seen rapid uptake in this early phase of the launch with more than 200 patients having received Modeyso at the end of the third quarter.

The majority of these patients were new patients with a smaller proportion transitioning from the early access program. We're hearing positive early feedback amongst physicians. Our comprehensive launch plan includes direct engagement with about 3,000 health care providers with an additional 7,000 targeted through nonpersonal promotion, focusing primarily on academic centers of excellence where these complex cases are treated.

We've implemented robust patient access and support services through our exclusive distribution partnership with Onco360. These investments were made to ensure patients can access treatment quickly and easily, and we're pleased with the strong payer access thus far. The launch of Modeyso highlights Jazz's proven ability to advance rare disease and oncology programs through regulatory approval and commercial launch. I'll now turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

Thank you, Sam. Slide 13 provides an overview of the key clinical programs in our diversified pipeline, including the comprehensive clinical development program that is underway for zanidatamab. There are multiple ongoing registrational trials for zanidatamab, including the confirmatory first-line BTC trial, the HERIZON-GEA-01 trial in first-line GEA and the advanced breast cancer trial evaluating zanidatamab's efficacy following treatment with T-DXd. In addition, we have earlier trials like the DiscovHER PAN-206 pan-tumor trial and the neoadjuvant, adjuvant breast cancer trial. These trials are progressing well with significant interest from sites, and we look forward to sharing an update on potential time lines for these trials as appropriate.

Regarding our confirmatory Phase III ACTION trial of dordaviprone in newly diagnosed H3 K27M-mutant diffuse glioma, we are in active dialogue with the FDA regarding potential updates to the trial. Pending regulatory alignment, our intent is to increase the sample size to power the trial for a primary endpoint of overall survival, which we view as the most appropriate endpoint for this confirmatory trial. Based on these proposed updates, we currently estimate an interim analysis of the overall survival could occur in late 2026 or early 2027. The trial is active at more than 95 international sites and remains on track with more than 50% of patients enrolled.

Moving to Slide 14. Our next major catalyst is the top line readout of the Phase III zanidatamab HERIZON-GEA-01 trial. As we announced today and after alignment with FDA, we have updated the intent-to-treat patient population for PFS to now include the fully enrolled patient population, increasing the PFS cohort from the targeted 714 to 920 patients, which is the actual number of enrolled patients as detailed on clinicaltrials.gov.

As a reminder, we previously took the opportunity to expand the patient population for the overall survival analysis by expanding the sample size for that endpoint. With progression events accruing more slowly than anticipated, combined with the study being fully enrolled with sufficient follow-up on enrolled patients, we aligned with the FDA to conduct the PFS analysis on the entire randomized patient population. Following this change, we continue to have robust powering to show a benefit for PFS, and we remain highly confident that we will announce top line results later this year, consistent with our prior guidance. With that, I will turn the call over to Phil for a financial update. Phil?

Thanks, Rob. I'll start on Slide 16 with our top line financial results. As a reminder, our full financial results are available in our press release and in our 10-Q. During the third quarter of 2025, we generated $1.126 billion in total revenues. This represents an increase of 7% compared to the third quarter of 2024. Epidiolex grew 20% and Xywav grew 11% compared to the third quarter of last year. And continued strong performance of these products positions us well for the rest of 2025 and beyond. In total, revenue from our oncology products increased 1% compared to the third quarter of 2024. This modest increase was driven primarily by the inclusion of Modeyso and Ziihera, partially offset by lower sales of Defitelio and Zepzelca.

Adjusted net income, or ANI, for the third quarter of this year was $501 million. ANI was affected by several items that you'll see outlined in our press release and 10-Q, including the recognition of deferred tax assets related to the Chimerix acquisition, charges related to litigation settlements and the Saniona licensing agreement. Cumulatively, these items increased our third quarter non-GAAP adjusted EPS by $0.66 per share. We continue to generate robust cash flow with nearly $1 billion recorded for the first 9 months of 2025. And our balance sheet remains strong with $2 billion in cash and investments at quarter end.

Turning to Slide 17 and guidance. Revenue is tracking to our expectations. So with just 1 quarter left in the year, we're narrowing our full year revenue guidance to $4.175 billion to $4.275 billion. We've also made several adjustments to our non-revenue guidance. In terms of ongoing run rate, we've reflected lower litigation costs in our revised SG&A guidance as well as continued portfolio optimization and prioritization in our reduced R&D guidance range.

In addition, we've also incorporated the additional antitrust as well as Avadel litigation settlements into our revised SG&A guidance. have included the additional IPR&D charge from the Saniona deal and have reflected the Chimerix income tax benefit I mentioned earlier. To help as you refine your models, I'd like to reiterate a point I made on last quarter's call. In the fourth quarter, we'll have 13 shipping weeks for our U.S. oncology products. While this is a normal number of shipping weeks, it is 1 less week than we had in the third quarter of this year as well as in the fourth quarter of last year.

Finally, I'll close by providing a shout out to our internal teams who played a key role both in our acquisition of Chimerix and in the licensing of Saniona's potentially best-in-class Kv7 molecule. These transactions have strengthened our oncology and epilepsy portfolios, and we remain focused on improving Jazz's growth outlook by investing in external innovation. I'm confident that in the months and quarters ahead, we'll leverage our strong financial position to execute value-creating deals that benefit patients and shareholders. With that, I'll turn the call back to Renee for closing remarks.

Thank you, Phil. I'll conclude our prepared remarks on Slide 19. Jazz's third quarter results underscore the strength of our diversified portfolio and the exceptional execution of our teams. We've delivered meaningful progress across our commercial portfolio, including the launches of Modeyso and Zepzelca, and we'll continue to focus on ensuring our therapies reach more patients quickly. Looking ahead, we remain on track to share top line results from the Phase III GEA trial of zanidatamab later this quarter, an important milestone for Jazz and for patients facing this aggressive cancer. Our focus on strong execution and disciplined capital allocation, combined with the momentum we've built, position us to deliver meaningful value to shareholders. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Our first question comes from the line of Marc Goodman with Leerink.

Rob, you mentioned the Kv7 is potential best-in-class. Can you talk about how is that best-in-class? And on the Epidiolex, can you guys just quantify what that benefit was to gross to net?

We believe -- sorry.

Go ahead, Rob.

Thanks, Renee. We believe the Kv7 that is in development after the Saniona deal is best-in-class because of the specificity for Kv7.2 and Kv7.3, differentiated from other molecules which have broader activity and the broader activity tends to give off-target toxicity without adding to the efficacy. So we think we're in a precedented validated mechanism that's potentially very impactful, but with higher specificity that will potentially allow us to hit the relevant targets harder and stay off of the targets that are causing unwanted side effects.

And I'll just jump in on the Epidiolex question, Marc. It's Sam here. Yes, so for Epidiolex this quarter, it was a good quarter, as you saw, $303 million, 20% revenue growth. Important, I think, for us to highlight that we saw 10% volume growth this quarter. So a good healthy double-digit volume growth. The revenue in the quarter was boosted not only by the volume growth, but also by the refinement of certain accrual rates here in the U.S. that gave us an impact in that third quarter, and we don't expect that to have a very material impact on future quarters.

You don't want to quantify it?

Marc, this is Phil. I'd say it's the majority of that remaining difference between the 10% volume growth and the 20% revenue growth, but it's not all of it.

Our next question comes from the line of Jessica Fye with JPMorgan.

You mentioned that 2026 brings the generic entry of one or more generic Xyrem. Can you just elaborate on how you're thinking about the potential for other filers to enter in '26? And is your base case that there is at least one ANDA entrant? And then if you'll indulge me, I am so curious, the change to the population being used for the PFS analysis for the HERIZON-GEA trial, can you just walk through the potential benefits of using the ITT population for the PFS analysis in addition to OS, given it just seems like you're already well powered for PFS. So curious kind of what brought that about?

Rob, why don't we start with the second question, and then we can turn to Sam.

Sure. And thanks for the question, Jess. So as a reminder, when we first took the study over from Zymeworks, we knew we wanted to increase the sample size to ensure adequate power for overall survival, even though the study was clearly well powered with the 714 for PFS. At the time, given our assumptions around how the PFS events would roll in, we thought there would be a big gap between the time that we were ready to read out PFS on 714 versus having enough maturity on the fully enrolled sample size.

So over the course of time, the PFS events came in more slowly than we had predicted, as you know, and the trial enrolled very briskly. So we found ourselves in a situation where we actually have enough maturity on the full sample size. And so it only makes sense to look at all the patients enrolled rather than a subset. We checked that with health authorities, including the FDA, and they were aligned with that approach.

And just coming, Jess, to your question around Xywav's. Yes, I mean, as you know, and as a reminder, generics are able to enter into the market from the beginning of next year. At this stage, we don't know the number of generics that would enter when they might enter or the price at which they will enter the market. So there are some unknowns there. But the availability of generics could result in payer actions that cause some disruption to Xywav revenue. We are going to continue to partner with payers to ensure that patients have access to low-sodium Xywav. We believe that's important. And we believe that, of course, Xywav continues to offer a really differentiated proposition to patients being the only low-sodium oxybate in the market and the only FDA-approved treatment for IH. So yes, that's what -- that's how we're currently viewing 2026. Of course, still some things that need to -- we need to see how they'll play out in practice.

Our next question comes from the line of Andrea Newkirk with Goldman Sachs.

Sam, maybe I can follow up on Jess's question there. Just as you think about potential generic entrants outside of maybe these negotiations with payers, are there any other strategies you might be willing to contemplate to defend against the competitive threat that might arise to the sleep franchise?

Yes. Thank you for the question, Andrea. We've been focused now, as you can see that we've had very, very strong momentum with Xywav through the course of this year with 11% growth, and we continue to add net patient adds each quarter. We've got the highest number of active patients on treatment now. So we're carrying really strong momentum into the market. And the things that we've been doing are going to be as relevant in 2026 as they are in 2025. The execution of our field teams has been very strong. The differentiating -- the differentiation that we've been communicating to HCPs has really resonated well.

Even in a changing environment in 2026, Xywav is going to be the only low-sodium oxybate on the market. We believe that, that's still a really important differentiating proposition for customers and for patients. And we're going to continue to invest in ensuring that is that differentiation is understood. I think the AHA guidelines, which just reinforce the importance of having a low sodium option as well as our XYLO data, which shows the impact of switching from a high-sodium oxybate to a low-sodium oxybate. These are all really very important differentiating features, and we'll continue to communicate those to HCPs as we enter 2026.

And just to add on to that, while this is not a direct strategy relative to defend against impacts, I will say just noting that we did report in our 10-Q that we entered into an amendment with Hikma and that amendment to our agreement extends the agreement by 2 years -- we do recognize that a portion of the narcolepsy market does continue to choose high-sodium oxybate by providing more therapeutic options. We think that's a good thing for patients. And so of course, our royalties on the sale of authorized generics by Hikma provide us the opportunity to continue to participate in that market. We've extended the agreement by 2 years. Our royalty rates are the same through the end of 2025 and then subject to specific reductions. Of course, Hikma does maintain a right to launch a generic. If they do so, they no longer have access to our authorized generic or our REMS. But as part of this, we also gained termination rights that we did not have previously, which allows us to better manage our business. So that's another element of our business that we think makes sense for Jazz and is important to understand.

Our next question comes from the line of Akash Tewari with Jefferies.

So we've seen some increasingly unpredictable interactions with biotechs and the FDA recently. How confident is your team that the FDA is okay with HERIZON-GEA having no U.S. patients in the trial? And was that discussed when you updated the PFS analysis with the agency recently?

Rob, do you want to jump in on that one?

Yes, happy to, and thanks for the question, Akash. So we've had multiple interactions with FDA and other health authorities, and we're aligned on the overall design. There was a clear rationale for not accruing patients from the U.S. with the approval of KEYTRUDA would have been a confounding factor. What the FDA is really focused on is not so much whether patients are being enrolled from the U.S., but whether the enrolled patient population is representative of patients in the U.S. in terms of disease characteristics, that the trial design is well controlled using a control that's relevant to U.S. patients and that the trial conduct, including supportive care is in line with typical supportive care. So that overall, the results would be applicable to the U.S. population. And we -- so we've had this discussion with FDA over multiple interactions, and I'm comfortable that it's not an issue for us.

Our next question comes from the line of Jason Gerberry with BofA or Bank of America.

Just another follow-up on the oxybate generics next year. I would assume by now like November, I remember like around this time 3Q ahead of Avadel coming the subsequent year, you guys had a line of sight on being a parity access as an oxybate. So yes, I'm just wondering why that is, maybe you don't have a line of sight. And would it be your base case that to get Xywav, you're going to have to step through a generic with most insurers?

And then I'd love to get your thoughts just on emerging orexin data in narcolepsy type 2. I think NT1, the data and profile is pretty reasonably well understood. But I think we are seeing less of a treatment effect size in NT2. And I'm just kind of curious how you think about the value proposition of that as a potential competitive threat to Xywav as well?

Yes. Thanks for the question, Jason. Why don't you hop in on the first one, Sam, and then Rob, you can cover the second.

Yes. Thank you. Thanks for the question, Jason. Yes, we -- so far, there has been no material change to our engagement with payers. We continue to engage with them as we normally would do on 2026. We don't have a line of sight into exactly how 2026 will play out. We know that generics are able to enter the market, but we don't know yet how many there will be, when they might enter and what the precise pricing conditions will be. And all of that obviously will have a bearing on the year ahead of us. Of course, we do expect that to have an impact on Xyrem revenue, but the materiality of impact to Xywav will depend on all of those factors yet to be determined.

Yes, happy to answer the question related to NT2. So first of all, not a surprise that NT1 is more sensitive than NT2 or IH would be given what we know about the underlying biology. And I'm also not surprised to see that as data emerge that we're learning still. It's fairly early days and still learning what we'll have, which compound will have the best-in-class profile, how to dose, what half-life is maybe most optimal and ultimately, the benefit of orexin agonist relative to other options such as oxybates and Xywav. And I think all of the data that are emerging continue to reinforce our position that Xywav, oxybate. Xywav being the safest of all, oxybate given the low-sodium is really the only way to address the disruption and the abnormalities in nighttime sleep, which are the root cause of NT1, NT2 and idiopathic hypersomnia.

Some of the data that we published on Xywav and World Sleep recently, I think, highlighted that, the benefit of Xywav in terms of improving those sleep parameters, which appear not to be improved when you look at total sleep or deep sleep, which is important, not to be improved based on the available data that we have on orexin agonist. In fact, orexin agonist, especially depending on the half-life can cause insomnia and disrupt sleep. So we continue to think that while orexin agonists are very potent wake-promoting agent for daytime symptoms, that the combination could be very powerful. It's always been the case for oxybate that patients sometimes take wake-promoting agents during the day. And we think that, that will continue to be the case and that orexin will be another option there. But as data roll out, it continues to reinforce the value of Xywav for patients who are benefiting from it.

[Operator Instructions] Our next question comes from the line of Ami Fadia with Needham & Company.

Maybe just a broader one. How have your business development priorities between CNS and oncology evolved with some recent successes that you've had on the oncology side, the GEA data around the corner, but also looking a little bit ahead, the changing landscape in the sleep space. So how are you thinking about sort of where your priorities might be?

So first and foremost, we are highly focused on where we believe we can have a meaningful impact for patients. And whether that is within oncology, neuroscience or neuro-oncology, that's where our primary focus is. Rob, do you want to comment further?

Sure. As we highlighted in our prepared comments, we're certainly very excited about some of the near-term readouts. The fact that we now have approval in frontline small cell lung cancer, completely changed paradigm and a new standard of care for those patients who are in desperate need of new therapies. Approval of dordaviprone, first drug therapy approved in high-grade gliomas already having a huge impact and a very high unmet need.

And zanidatamab approved in BTC and a lot of anticipation and excitement around the potential in GEA and beyond. So certainly excited about our oncology franchise, but also a lot of promise on the CNS side as well with Epidiolex evolving into the critically important drug that it is and our capabilities around epilepsy enabling us to do deals like Saniona and to develop other pipeline agents that we have that haven't necessarily disclosed the specifics of, but continue to make us excited about areas such as epilepsy as well.

Our next question comes from the line of Mohit Bansal with Wells Fargo.

I would love if you could comment on how should we think about the authorized generic royalties for next year? When would you know that Hikma has opted in or opted out at this point given that we are in November at this point? What should be our base case?

Sure, Mohit. I'm happy to go ahead and take the question, it's Phil. So at this point, our assumption is that we will have the AG provided by Hikma during 2026. The royalties, as Renee mentioned, sort of stay at their current rate here this year and then will be subject to step downs. We're not providing the specific percentages that will be applied other than to say it continues to be a meaningful royalty back to Jazz and a potential meaningful revenue stream for us moving forward.

Our next question comes from the line of David Amsellem with Piper Sandler.

I wanted to come back to Xywav and dynamics in 2026 with Xyrem generics in the market. So you made some comments about access, shoring up access. So should we take that to mean that you're going to be making some concessions on Xywav pricing? In other words, you will see some degradation potentially in net realized price for Xywav and sort of a cost of continuing to have access and preventing switching away from Xywav. Is that a reasonable way to think about it? Or is it just too early to go there?

Yes. This is Renee. I'll jump in on that one. I would say going into the year, we are feeling good about our current position. But I would emphasize some of the comments that Sam made previously that with the availability of generics, there could be additional actions that take place that could cause some disruption. And it really does depend on how the market evolves. We have a very high focus on ensuring that we have access, and that is strong access. Sam talked about where we are today with little to no step through in order to get access to Xywav. We have focused on the clear differentiation of the product. So I would say more to come as we get into 2026. We have not provided guidance for '26 yet nor do we typically provide guidance by product. But I would say based on where we sit today and we're poised to enter 2026, we're feeling good about the position that we're in.

Our next question comes from the line of Annabel Samimy with Stifel.

I'm going to shift gears to oncology. I'm wondering for Modeyso, that seems like it was a great start. Is this a bolus? Does it include stocking? And what can we expect for the cadence of uptake in the coming quarters? How familiar are docs with this treatment? And I guess, in the same way for the new approval or expanded label for Zepzelca, I realize that it's probably too early, but the data has been out for some time now. Has there been any contribution yet in the first-line setting? And what can we expect on the cadence for approval post approval there with the compendia inclusion and the fact that it was already an available drug?

Thanks Annabel. I'll start and then hand it over to Sam to cover Modeyso. So why don't I just start with Zepzelca, which is it's pretty early given that we just received the actual approval. So we're excited about the reaction we're hearing from physicians. They're obviously already very comfortable in using Zepzelca in the second line, but too early to tell how much use is happening in the first line. With respect to Modeyso, little to no stocking. That's not really how our distribution works, but super excited about this on the back of a successful corporate development transaction. Sam?

Yes. I'll just add to that, Renee, in relation to Modeyso. We're obviously really pleased with the launch so far, I think $11 million in the first quarter following FDA approval in August. And obviously, we received the NCCN Guidance in pediatrics and adults as well. There has been, I think, there are really 3 factors that I'd like to kind of highlight. First of all, obviously, the very, very significant unmet need. We've had very strong HCP and patient engagement.

You had a question around awareness. Awareness of the product is exceptionally high, and we're seeing that in the rapid uptake. We have a really experienced team behind this product dedicated to Modeyso. And I think they're doing a terrific job. And access has been really, really very strong. We've got a very good partnership with our specialist distributor who are supporting patients to get on to treatment rapidly. In terms of -- we did see -- we had about 200 -- just over 200 patients by the end of the third quarter. Some of those did come from the expanded access program. But more than 60% of them were new patients, so new to Modeyso. And that's how we would continue now, and that's the outlook for the forthcoming quarters as these patients will all be new to Modeyso. And we're seeing a steady uptick there. So confident launch and really just reinforces our belief in this product as a potentially $500 million plus peak in the U.S.

Our next question comes from the line of Brian Skorney with Baird.

Maybe for Rob on the GEA readout. Now the sample size of 920, can you just review -- are there 4 separate comparative analyses here that are B versus A, C versus A for OS and PFS? And how to think about powering across them and the alpha split? And is there any hierarchy to the analysis?

Yes. I mean while there were some early publications that detailed the specifics since Jazz took on the trial, as is our usual, we don't get into the nitty-gritty of the statistics. But I would say that we do have the opportunity at this point to look at both PFS and an interim on overall survival. And I would say a silver lining of the PFS events coming in a little more slowly as we probably have more maturity on overall survival than we might have had under protocol assumptions. And yes, there is the opportunity to make the comparisons between both of the experimental arms and the control arm. Having said that, we think we're very, very well powered for PFS. Obviously, the trials at 918 is powered for overall survival, and that sometimes even makes it somewhat "overpowered" for PFS. So we think we're well powered for PFS, and we have a well-timed first of 3 interim analysis for OS.

Our next question comes from the line of David Hoang with Deutsche Bank.

I just wanted to ask, I guess, another one on HERIZON-GEA. Can you just help us, I guess, maybe set expectations for the level of disclosure you would have in the top line data? Would we see things like subgroups broken out by PD-L1 expression status? And once the data in hand is your expectation to approach the FDA and be able to receive a full approval on this data?

Yes. Thanks for the question. So on the latter part of it, yes, we do expect this would -- as a randomized controlled trial with a primary PFS endpoint and supportive overall survival, if we see a large enough benefit in PFS, and we see a meaningful support from OS, it should bring full approval. To remind you, the primary experimental question here is really is zanidatamab superior to Herceptin, which we think we have lots of data to support that it would be. That's the primary comparison.

And then between arms B and A. And then in arm C, we have the opportunity to see if the addition of a PD-1 inhibitor, specifically tislelizumab adds to the benefit. We certainly will be measuring PD-L1 as a subgroup. Those subgroups aren't powered in any way, but we have an opportunity to look across subgroups.

But the primary question is zanidatamab versus Herceptin. And then to your question of what would we be disclosing, we'll try to be as transparent as possible as I think we were with the recent IMforte data release where we indicated stats clinically meaningful and tried to provide some color around that. We want to be careful about disclosing specific data in a press release ahead of a peer-reviewed publication because sometimes that can compromise our ability to publish at a high-impact congress and in a high-impact peer-reviewed journal, which then supports, of course, submission to NCCN Guidelines, et cetera.

Our next question comes from the line of Ash Verma with UBS.

Rob, just on the GEA study, if you can comment on this. So I think you said when you adopted from Zyme, the study, you wanted to change just the powering assumption for OS. Is the PFS powering assumption still the same that Zyme had? What I mean is the 95% for the HR of 0.65 for Arm C and the 80% for 0.73 for Arm B...

Yes. I mean what I wanted to point out is that when we did the deal, we knew that the study, and of course, Zymeworks did as well, that the study was underpowered for OS. It was for a 3-arm study, it had a similar sample size to KEYNOTE-811, which had only 2 arms. So we knew we wanted to increase the sample size to better support power for overall survival and give us an opportunity to have 2 interim analyses before the final and third overall survival.

At that time, we felt that PFS was well powered even with 714 patients under the specific protocol assumption. So with the full sample size, we continue to think that it's very well powered for PFS I do acknowledge that there was a publication from Zymeworks that detailed some specifics of the statistics, but we haven't commented since then on specific details of the stats. But just to reinforce that very, very comfortable with the powering around PFS. And now we have, I think, a more robust opportunity for overall survival, including even the first 2 interim analyses before we have a final look.

Our next question comes from the line of Joseph Thome with TD Cowen.

Maybe one on the Kv7 acquisition. Can you talk a little bit about where you are going to be looking at developing these therapies? Obviously, 2 competitors are reasonably ahead in the focal onset seizure space, but we've also seen companies look at ALS in pain. So is there any more room left in focal onset seizures? Or are you going to be looking to look elsewhere where maybe you have a little bit more of a time line advantage?

Yes. We haven't detailed or disclosed our full development ambitions for that program yet, and we are certainly thinking through that as we bring it forward to the IND stage. I think what's critical, though, is what motivated us to do this particular partnership is that we feel it has the potential to be meaningfully best-in-class in a category where I feel there is substantial scientific and clinical proof of concept around the target. But what we do know is that when you hit Kv7 broadly, you not only get efficacy, but you see unwanted tolerability issues, which have been observed in the clinic.

And we think that we've been able to parse them out around the subtypes so that this particular molecule being specific for Kv7.2 and 0.3, we think has the potential to be much more on target for producing maximal efficacy and avoiding Kv7.4 and 7.5, which don't contribute meaningfully to efficacy and contribute to some of the tolerability issues that have been observed. So in short, we think we have best-in-class opportunity across certainly focal onset seizures, but in other areas where it would be relevant as well.

Our next question comes from the line of Asim Rana with Truist Securities.

Congrats on the quarter. This is Asim on for Joon. Just a couple from us. Where are you exactly with your orexin agonist, JZP441? I know it's an open label. Just curious when we can expect an update. And as a follow-up, ulixacaltamide recently reported positive top line data in essential tremor. Is there any interest in reviving suvecaltamide?

Rob, do you want to jump in?

Sure. Happy to. So no new news yet on JZP441. We are enrolling a small NT1 trial, and we're seeing data emerge. Nothing to disclose yet at the moment. But I would say we also have a backup program that we continue to pursue. Again, we think that the mechanism is of importance, has the potential to be a meaningful daytime alerting agent and very complementary to Xywav. So we continue to be interested in that area. In terms of the recent announcement by Praxis around Cav3 and essential tremor, we read what you did. I still have some questions around what the data actually show given that the IDMC initially called the trial futile. So it would be very -- it will be ultimately interesting to see what data they have and what we can learn from that. From our own study, we felt that the data just didn't support progressing that program relative to the other really meaningful opportunities that we have in our pipeline.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

This is Michael Riad on for Sean Laaman. I wanted to drill down on some of your prior commentary. The Xywav results from DUET at World Sleep seem really compelling. Can you help to contextualize the restoration of sleep architecture versus wake promotion with orexins? Are they like more of an accelerant instead of a competitor? And if so, would you ever think about getting like the results from DUET formally into the label? And are the results from DUET sufficient in that regard?

Yes. Thanks for the question because I do agree that they are meaningful results. We had prior data on the effect of oxybate at night, and we do think that Xywav is really the only -- oxybates are the only drug that really address the root cause of narcolepsy and idiopathic hypersomnia. And Xywav, of course, is the safest, best option to do that given that it's a low-sodium oxybate. But again, it reinforces that for patients like NT1 patients or even NT2 and idiopathic hypersomnia, where nighttime sleep is severely disrupted. If you take narcolepsy patients, for example, they might have over 80 -- on average, 80 awakenings a night and very, let's say, disrupted or less N3 or deep sleep than a typical patient.

And when you give Xywav as the study showed, you meaningfully improve that. And that results in improved daytime symptoms, both wakefulness as well as cataplexy. So we think it's critical to address the underlying root cause of the disease with any therapy in these hypersomnias. And some patients certainly will benefit from additional wake-promoting agents during the day. We just haven't seen that with any of the other wake-promoting agents and orexins included.

The only data I've seen so far suggests that there may actually be insomnia and that may be worse with drugs that have a longer half-life that just don't wash out in time for the evening. Even the PSG data, which hasn't really been fully shared suggests that there's not improvement in key parameters such as total sleep time or deep sleep. And it's concerning that the insomnia may be actually resulting in worsening sleep in that first part of the night at least.

And so again, we continue to think that it's an important new mechanism in hypersomnias, but ideally, will be used in combination with Xywav, certainly for those patients who are finding meaningful benefit already from Xywav. As to whether this could ultimately end up in the label, we certainly think that it's important information for prescribers to have, and that's why we published it. I won't comment on necessarily where we are in terms of discussions with FDA on label changes related to it.

Our next question comes from the line of Gary Nachman with Raymond James.

This is Denis Reznik on for Gary Nachman. Just on zani, assuming a positive GEA readout, how would you be thinking about pricing in that scenario relative to what it currently is for BTC?

Yes. When we -- this is Renee. When we priced zani for BTC, we were already looking at the GEA market and keeping that broader opportunity in mind. So I would not expect to have a different price as we are launching GEA.

And I think with that, that was our last question. So I'd like to close today's call by thanking all our Jazz colleagues for their efforts, all of our partners and stakeholders for their continued confidence and their support. Thank you all for joining us.

Thank you all for your participation in today's conference. This does conclude the program. You may now disconnect.

Thank you very much for joining us today. My name is Mohit Bansal. I'm one of the biopharma analysts here at Wells Fargo. And this is my first session, not the conference's first session. And I'm happy to have the team from Jazz Pharmaceuticals with us. We have Phil Johnson, the CFO of the company; and Amal Bertrandt with us. She's heading the -- you are the VP, Oncology Therapy Area Head, and most importantly, Clinical Development Head. So we'll have a lot of questions for you. Thank you very much for joining us today.

Thank you for having us.

So Phil, why don't we start with the overview when you were here last year and how do you see the year heading for you and the investment thesis at this point, which investors should hear about?

Thanks, Mohit. Thanks for the invite to be here. It's always a pleasure. And there's quite a buzz in the hallways this year as well. So great to have a chance to meet with a number of investors. So it's been a really fun last year. I've been really pleased with the decision that I had made to come join Bruce, Renee, Amal and others and the Jazz team and the progress that we've been making driving the business, both on the commercial side as well as on the R&D side with progression of zanidatamab clinical trials and on corporate development as well, we've had a couple of recent announcements.

I think we can get started with remarks. Let me just reiterate some of the disclaimers. For full understanding of the risks that may impact our business, please do consult our SEC filings, some of those recent updates we provided, look at our second quarter earnings materials. If we do refer to guidance during the Q&A session today, know that, that's the guidance that was issued as of our second quarter call. Maybe to start with a couple of comments, Mohit, on just recent developments even since we would have had our earnings call. So really pleased that we've received approval for earlier than the PDUFA date. Many were concerned about would there be regular and consistent interactions with FDA that would lead to a timely action on our Modeyso or dordaviprone application. So really pleased there.

We actually got approval prior to the PDUFA date, are already out now serving patients. This is a really dreadful disease, especially this K27M-mutant diffuse midline glioma, often affecting pediatric and adult patients who really had no therapeutic option and really nothing new since the advent of radiotherapy 50, 60 years ago. So really pleased with that development. It shows our ability to spot and then acquire opportunities to advance patient care in really hard-to-treat diseases where there's significant unmet need. Initial read in these first few weeks have been really strong and look forward to providing an update when we get to our third quarter call as well.

Also concluded a licensing transaction to build out our epilepsy franchise, preclinical deal we did with Saniona for what we think could be a best-in-class asset. So really pleased to have announced that. And then notably, announced the conclusion of the CEO search looking for Bruce Cozadd's replacement and very pleased that Renee Gala has been selected and looking forward to her continued leadership. I think her and the management team Board are very focused on driving the legacy that Bruce has created, but then also taking it further. And I think Renee has got insights to be able to do that, knows, I think, the strength she can build on here at Jazz and also the things that we can do much better as well. So looking forward to that new leadership that Renee will provide.

I'm also pleased with the way the year has been going, really strong results with Xywav, really strong net patient adds in the second quarter, 400 or so within idiopathic hypersomnia. We're the only approved treatment and have no near-term competition. And then we continue to see really strong performance in narcolepsy as well, where there is another branded competitor and we have authorized generic competition as well. We think this points to the value that patients and physicians see in low sodium. In these patient populations, those with narcolepsy and pathic hypersomnia, they are at an increased risk of cardiovascular events. So certainly, driving up sodium in these patients is not probably something that physicians would want to be doing.

At a recent sleep meeting, have presented data from our XYLO study, in fact, showing that when patients go from a high sodium oxybate to a low sodium oxybate that produces clinically meaningful reductions in blood pressure. And this is a benefit that only Xywav can offer. So we feel we're really well positioned with that franchise here and the strong net patient adds in the first half of the year as we think about the second half of the year.

Maybe I'll turn it over to Amal to talk about some of the developments on the clinical side of things.

Great. Hello, everyone. A lot of exciting catalysts in oncology. The most imminent one for us is the Zepzelca approval. We have an sNDA that's been filed with the FDA for Zepzelca in combination with atezolizumab in patients with extensive stage lung cancer who have previously received induction and then go on to maintenance Zepzelca. The PDUFA date is right around the corner, October 7. So really excited about this upcoming milestone. We have several other important data readouts that we are expecting this year.

And obviously, the major one is the HERizon-301, which is our frontline GEA study with zanidatamab in combination with chemotherapy in patients with HER2-positive advanced or metastatic GEA cancer versus the standard control, which is a combination of Herceptin and chemotherapy. And we're anticipating those results and readout in fourth quarter 2025. So a lot of exciting upcoming catalysts. We've also recently initiated a Phase II trial in the neoadjuvant setting for breast cancer and zanidatamab HER2-positive breast cancer. So we're expanding on the promise of what zanidatamab can deliver in breast cancer. That's the 208 study.

And we also have 3 ongoing Phase III studies for zanidatamab. So the 301 trial, the HERizon-303 trial, which is zanidatamab in combination with chemotherapy versus Herceptin and chemotherapy in patients with HER2-positive metastatic breast cancer who have previously received T-DXd and have progressed on it or are intolerant to it. And then we have obviously our 302 trial, HERizon-302 trial, which is the frontline study of zanidatamab with chemotherapy plus or minus an anti-PD-1 in frontline metastatic BTC that will be supporting our accelerated approval for zanidatamab in BTC. So a lot going on. And we also obviously have the ACTION trial that will support the accelerated approval of dordaviprone. So 3 large Phase III trials are ongoing. So quite exciting.

A lot of action going on.

Yes.

Great. So I don't know where to start at this point. So maybe let's just talk to -- talk a little bit about oxybates. I mean, Xywav, I mean, again, we were -- like last couple of years, people were worried with generics and Avadel like Lumryz and all competition. Seems like Xywav has been growing through all that, not just in IH, but also in narcolepsy as well. So can you talk a little bit about where is this growth coming from? And how much confidence does it give you for second half and 2026 as well going forward?

Yes, absolutely. No, you're right. We've been really pleased with how well Xywav has done. Obviously, the big driver of growth, if you look at the net patient adds also translates into revenue is coming in idiopathic hypersomnia. We do expect for that to continue to be the case going forward. That is still, I'd say, a market that we're building, building awareness in physicians and patients as well on the benefits of oxybate therapy for idiopathic hypersomnia. It's difficult to know exactly what the epidemiology is there.

Anecdotally, we do hear from a number of treating physicians that in their practice, they feel like they have as many idiopathic hypersomnia patients as narcolepsy patients, although you look at some of the published epidemiology, it might indicate that, that population might be half of the narcolepsy population. But again, we still see good opportunity for continued growth in IH. Narcolepsy, we'd indicated a while back that we could see quarters where there were not net patient adds, but net patient decreases. We've not seen that. So we're very pleased with the performance of Xywav with both branded competition and with authorized generic competition. Definitely think this speaks to the benefit that patients and physicians see to low sodium, as I mentioned earlier, which is the unique attribute that Xywav can offer.

We do have upcoming the potential for generic Xyrem to come to the market beginning effectively at the beginning of 2026. Technically, the unlimited volume authorized generic player, Hikma has the ability and they have had for quite some time to come in with their own generic. To date, they have elected not to do that. And [indiscernible] the situation going forward. But certainly, the introduction of generic Xyrem would affect potentially not only that authorized generic revenue that we have, the Xyrem revenue that we have. And then I think a question mark on would there be an impact or not, and if so, to what extent on Xywav? I think that will depend also on how payers are looking at the space and how payers are thinking about this dynamic of the unique benefit that Xywav offers in terms of low sodium for these patient populations.

Got it. So I mean, 2026 could also be an interesting year given that there is a possibility of generics. So what is your internal expectations regarding these generics? And I mean, again, you cannot guide for next year, but again -- like again, directionally, should we be expecting growth? Or should we be concerned about these challenges a little bit [indiscernible] smaller number?

So I'll probably stop short of saying, should you look for growth or not at this point in time? Obviously, that would come with our guidance in 2026. I do think we're planning for a variety of scenarios. I think it's prudent to plan that generics would come in beginning in January of 2026. Again, as I mentioned, let's take the example where Hikma is one of those coming in, they can only do the authorized generic with us or their own true generic. They can't do both. So if they were coming with a generic, the impact for us would be that authorized generic income would go away.

Clearly, we'd expect a significant impact on remaining, which is pretty small now, remaining Xyrem revenue. And again, very uncertain what would be the impact to Xywav from the introduction of a generic Xyrem. Again, the only product that has low sodium. We've talked before about the benefits that we've seen and been publishing data on of low sodium in a patient population that has an increased risk for cardiovascular event. So we think we're as well positioned as we can be. We're prepared for a number of different outcomes, and we'll be flexible and react as we go forward to the market condition.

Got it. And at least from Hikma, you would know beforehand that...

We have -- so we haven't said the exact notice period that they have, but they do have a notice period to tell us that they want to stop with the authorized generic. We also have commented we'd expect that would be of high interest to analysts and investors. And should we receive such a notice, we pretty promptly make a public statement to that effect.

Got it. Very helpful. And then the other question is about the orexins in this market. So how do you see orexin as a challenger? And what investors should look at the World Sleep data to understand the profile better? I mean, I'm sure you are looking at that as well.