Jazz Pharmaceuticals Plc Aktie

The potential synergy that you can get when using zanidatamab, a highly immune active antibody in conjunction with immune checkpoint inhibitor like tislelizumab. So really pleased with that. And on the heels of it, remember, we had static overall survival benefit for the triplet arm at the time of the first interim analysis with 2 additional scheduled OS analyses. And at that time, the Arm B or the doublet arm was trending very favorably, but not quite static.

On the second interim analysis, we now have a static result for the zani chemo versus the control arm. And encouragingly, as we said in our press release, the hazard ratios for both of the experimental arms continue to improve even from the first interim analysis when you look at the overall survival, which is consistent with highly immune active drugs where you tend to see that benefit beyond the medians later on that curve, you see more durable benefit and you start to see the curve separate.

We're excited to publish those data as soon as we can in an upcoming medical conference. Just quickly mention some other areas that we're leaning into on Ziihera. We have our frontline BTC trial, which is well underway. We have our late line pivotal trial. We have our late-line breast cancer pivotal trial that's well underway. We also have a pan-tumor trial that could get us a tumor-agnostic indication, meaning any patient whose tumor overexpresses HER2 and is refractory to standard therapies could potentially get it.

Within that trial, we've had some interesting colorectal cancer results. So that combined with other data we had us breakthrough designation with the FDA, and we're working with them to plan on an approval path in colorectal cancer while we pursue broader indications, potentially even including non-small cell lung cancer. So clearly, Ziihera has made a lot of progress.

We think it's unique mechanism of action that's highly differentiated and is really best-in-class, going to be a new standard of care in biliary tract and gastric cancer. And we're investing heavily behind that, as I mentioned, in our pivotal trials. Super excited about our epilepsy portfolio as well.

We announced recently that Epidiolex, which has a very long period of exclusivity into the late 2030s. We're initiating 4 new clinical trials as well as having submitted an application for a solid oral dose or capsid formulation. And those new trials include a Phase II in focal onset seizure as a kind of evidence generation trial. It includes a Phase II/III potentially pivotal trial in juvenile myoclonic epilepsy. It includes a Phase III in a broad array of DE. So of course, we have an indication for seizures associated with 3 orphan DEs, and this potentially will broaden that label even further.

And we have an evidence generation study in LGS and adults to further support the use in that setting. So super excited about Epidiolex and its impact it's having and the longevity there. We certainly think of ourselves as an epilepsy company. We've mentioned in the past, we have 2 pipeline products, one for absence epilepsy in Phase I. And we've now recently brought our plan to bring our Kv7 into Phase I, which we think is potentially a best-in-class Kv7 opener.

In addition to that, very pleased to say that yesterday, we closed on the Actio deal. You haven't seen the data on that yet, and we certainly have as part of the due diligence, and we hope those data will be published soon. But we are very excited to be in another rare epilepsy where, in this case, we think this inhibitor addresses specifically a single gene mutation, which is responsible not only for the epilepsy in these patients, but the developmental challenges that they experience and a targeted personalized medicine here could make a tremendous difference based on the preclinical and clinical data that we've seen.

Also excited that the ACTION trial for Modeyso continues to progress as planned, and we've reiterated the timing next year on the interim analysis for overall survival that would give us an early opportunity for approval in frontline high-grade glioma. Currently, our approval is in refractory high-grade glioma. That's an interim analysis, so if it doesn't hit the trial continues until completion.

And lastly, just recently announced that our next-generation orexin-2 agonist has cleared the IND and is expected to go into healthy volunteer studies this year. So that's kind of the key highlights from my perspective.

So maybe I'll pause there and David open to any questions you might have.

Great. Thanks, Rob, for that intro. So maybe if we could unpack a little bit of the history on Ziihera on [indiscernible]. Could you remind us what got you interested initially in doing the deal with Zymeworks to bring in the asset? And maybe you could also speak a little bit to the HER2 mechanism and its differentiation within the class and how that might, for instance, impact what we're seeing in both the PD-L1 positive as well as negative patients.

Yes. Thanks. Great question. So we were interested in Zanidatamab, I would say, in kind of the earlier stages because of the novel mechanism of action. So this is the first HER2 antibody that had a biparatopic engineering structure. So what that means is that each antibody actually has specificity for 2 different binding epitopes on the receptor.

Now those binding epitopes were selected because they were clinically validated. It's active domain 4 and 2, those correspond to where Herceptin and Perjeta would bind. What differentiates it is when you put it on the same antibody, each FAB fragment of the antibody has to bind different receptors unlike giving Herceptin and Perjeta together. And when that happens, the antibody binds to one receptor, the other FAB fragment can't reach that binding epitope on the same receptor, so it grabs a different receptor and pulls it in. And then sequentially happens with the additional antibodies.

What that does is cause -- and this was demonstrated in the Nature Communication paper, it causes receptor capping and clustering internalization, but also importantly, fixation of complement. So what really differentiates this molecule is it triggers the complement cascade, and that does not happen with any other antibody. It was also engineered to have a highly active Fc fragment. If you think of the antibody is Y, the Fc fragment is what typically induces immune responses, recruiting macrophages and NK cells.

And so you have complement cascade activation, you have recruitment of NK cells and macrophages. And so you have an antibody that not only blocks HER2 and HER3 signaling internalization of the receptor, but triggers the immune system in a way that other antibodies don't. And it's for that reason that we have the hypothesis that this could synergize with PD-1 inhibitors. So when people were surprised that we had activity in the frontline gastric trial in the PD-L1 negatives, and I could see why that would be a surprising result because 4 prior studies with 3 different PD-1 antibodies all showed no activity in PD-L1 low patients, including the KEYTRUDA trial in HER2-positive disease and including tislelizumab in the all-comers population.

Yet our Phase II show we had activity in PD-L1 negative patients. And we think it's because of the immune activation that happens with zanidatamab. So that mechanism of action is what really first got us interested. It was early days, though, and we hadn't seen much clinical data. So we did some -- our business development group made a $50 million bet to say, we get an option once the biliary tract data come out. And if we don't like it, we walk away and we give up to $50 million.

Well, we were very pleased with the biliary tract cancer data. As you know, over 40% response rate, very durable. If you look at the IHC 3 population, which is what's in the label, response rate. And that really is very differentiated from any historical data with Herceptin and Perjeta, which never achieved approval in that setting. We also thought they had very logical development path. So fast to market in biliary tract, going after some clear white space where it could win in frontline gastric cancer where only Herceptin was approved. And then we felt the deal paid for itself on the basis of those 2 indications. But we also saw in the Phase I data and based on the mechanism, the opportunity to go much further beyond that, as I described earlier.

Great. Great. And I know you've articulated a little bit about your thoughts on the label that you received for Ziihera. But as we think about how docs will employ the product in practice, you have a triplet as well as a doublet regimen. How do you think the physicians will start to utilize those regimens? And the doublet I noted is restricted to IHC3+ patients. Is that in any way a limitation?

Well, I'll address that first, and then I'll talk about what I think is the best use for this drug. So I think it's not really a meaningful limitation. First of all, it's a very small proportion of patients from an epidemiologic perspective and the trial was less than 20%. But I also think it's clear from the data that in that small subgroup, if the trial wasn't designed to address, there's clearly confounding factors that explain it. So for example, if you look in the label, you can see that the trastuzumab control arm was wonky.

What do I mean by that? Well, the IHC 2+ did better on tras/chemo than the 3+, which is not only biologically and plausible, but it has never been seen before. It's always been the case that Herceptin does better in 3+ and 2+. So it tells you that small proportion of patients is not behaving the way you think. And when we look patient by patient because it's a small group, you can see that their baseline characteristics weren't balanced. And so we think that's not a meaningful result. We don't think it will impact practice anyhow. We certainly had that discussion with FDA. But they tend to follow the data, and we'll see maybe with additional updates, we could revisit that. But in any case, I don't think it's meaningful, and I don't think it will impact practice.

To your first question, which I think is the more important one, what's happened here is it's a little bit maybe the victim of our own success. Zanichemo looks so good that now we get the question, well, should you just use zani/chemo and not add tislelizumab. And for me, absolutely, the answer is to use the triplet for a number of different reasons. One is that the triplet data are stronger in our trial. Clearly, it's adding. And you can't look at just the medians for OS. You have to look at the whole hazard and you look at -- and you'll see when we put the update out, it persists, you get this flattening of the curve.

Interestingly, with both the triple and the double it becomes pretty flat. That's why you're seeing an improvement in the hazard ratios over time. And so over -- at those later time points is when you really start to see some differentiation. And you see that added benefit of a PD-1 inhibitor, which is highly consistent with all the results previously. There have been now 5 trials of PD-1 inhibitors in frontline gastric cancer and another in early-stage gastric cancer where PD-1s have a survival benefit.

And we know that immune therapies are the potential curative therapy. So the idea -- I talked about the synergy potentially between zani and a PD-1, if you're a patient with, by the way, still a very poor prognosis disease, where the risk of death is high at 5 years, you want to give all your therapies upfront, and you want to potentially take advantage of that synergy between zani and a PD-1.

So I think unless there's a contraindication to a PD-1 inhibitor, which is relatively rare, patients should get that. There are some additional toxicity, but it's easy to distinguish what's coming from where based on timing and the nature of the toxicities, and it's manageable in the right hand. So I do think that the right approach is to use the triplet irrespective of PD-L1 status and then IHC 2+ or 3+. And that will certainly be the focus of our marketing and our education.

I want to get into the commercial dynamics a little bit of the Ziihera GEA launch. So I think you have talked about 8,000 HER2-positive patients as a population that came out there. You've also talked about, I think, a 3,000 to 4,000 number as the Ziihera treatable population. And so can you help us understand how you -- what cuts you employ to get to the 3,000 to 4,000 addressable patients? And is there any consideration, for example, for potential competition, let's say, from ADCs? I'm thinking, for example, the DESTINY-Gastric trial...

Yes. Maybe I can jump in there, David. Thanks for the question. When we think about that 8,000 patient population, that's really an incidence of HER2-positive GEA. When we think commercially that 3,000 to 4,000 treatable patients, that's really taking into account unresectable disease, treatment in the first line and [ taking rates. ] So it's a true treatable population. And we do think -- to Rob's point, we do have a differentiated asset here.

So we did just launch 3 weeks ago. I know Chumi and Sam and team are -- they were out there on the first day, and I think we're all quite excited to get that on the market. When we think -- when we look forward and we think about competition, I do want to be very clear. We are the only -- we do expect to be the standard of care. We're the only regimen that's being actively promoted in the first line.

We do think zanidatamab should replace trastuzumab in every patient in first-line GEA. And to Rob's point, we think most patients should be treated with triplet in combination with tislelizumab. When we look to the future, there are some first-line trials. David, you mentioned T-DXd or in HER2. Those don't read out until 2029. And frankly, we've set a very high efficacy bar to which they will need to beat. The data we've seen to date has been Phase II data. And I think our data certainly speak for themselves when we look at the marketplace in the future.

And I would just add both on the addressable population and the future competition. So we do see opportunities to grow this market. One thing that's personally frustrating to me as a practicing oncologist is that the utilization rate in frontline GEA of HER2 drugs in general is lower than you'd expect. I mean for me, it should be 100% even before the zani data, but especially with the zani data. And it hasn't been for one reason or another, even though testing rates are high, not everyone is benefiting from HER2 therapies.

Now could that be because maybe the benefit wasn't as significant as we now know it is with zanidatamab. And so we're certainly going to get out there and educate around your patient who has HER2-positive disease as defined in the trial, should get Ziihera and is going to benefit from it, not only directly, but through the synergy with the PD-1 and hopefully increase those treatment rates. So I think there's an opportunity to grow that market a bit.

And then with regard to the competition, ultimately, we'll have to see the data, and I think the data will win the day. To Jack's point, there is Ziihera has a head start and has very strong data. The other thing I would point out is that frontline chemotherapy, whether it's FOLFOX or CAPOX or metastatic GEA is quite good. And the practice here has been to use a targeted therapy and a PD-1 inhibitor on top of that backbone chemo and to give the chemo for a period of time. And there's probably some interaction there. And we've learned over the years that giving some chemo there, especially the right kind of chemo can help synergize with PD-1 inhibitors.

And so that's generally the practice is to give some chemotherapy for a period of time. And then as patients begin not to tolerate it, you can modify the dose, you can drop it entirely, you can stop it. And then the paradigm really is continue the HER2, in this case, zanidatamab, continue the PD-1. These are the drugs that drive long-term survival.

When you use an ADC, you don't have that opportunity. We're talking about gastric cancer. It's true for frontline breast cancer as well. You give an ADC, you're stuck with the chemotherapy. You can't drop the chemotherapy component. So we think the treatment paradigm is pretty well entrenched and the flexibility that you get from zanidatamab, which is highly immune active yet not an ADC doesn't carry that toxic payload is a real advantage there.

And we're also thinking about that in the breast cancer context where really the paradigm even in frontline breast cancer has been to drop chemotherapy over time and continue the HER2 agent, which I hear more and more talk about that for in HER2 conduction with Enhertu and then move to a maintenance non-ADC HER2 agent.

Well, investors are certainly looking forward to seeing the GEA launch play out. So we'll definitely keep count on that. But I want to spend some time on the next chapter for zani and that's in breast cancer, as you pointed out. So I believe coming late '27 or early '28, we should see results from the Phase III EMPOWER-303 trial in HER2 -- post HER2 metastatic breast cancer.

As we now approach this next key readout, how should we think about the probability of success here for this study? And keeping in mind that this is a later line population that has previously been exposed to prior HER2 therapies, how should we think about the performance of the zani arm versus the comparator arm, which is Herceptin and chemo?

Yes. Thanks for that question. I mean I love your first question because it took me back 3-plus years where it's sort of like what did you see there that others didn't see. And as we've started to get data, I've asked myself, what are we learning from these data? And as a principle, what we've learned is that wherever HER2 is the backbone or wherever there's cancers that overexpress HER2, but don't get Herceptin as a backbone, Zanidatamab is going to compete very well.

The other principle is when you can combine with a PD-1 inhibitor, that's going to do well. And I'll come back to other settings where we think we have an opportunity to do that. But what's relevant to your current question is why do we think this trial is likely to succeed? Well, this is another opportunity to go head-to-head with Herceptin in the design of the trial.

Now we acknowledge that this is a later line trial. It was, to me, the obvious first place to go, and it's certainly, I would say, very consistent advice we got from all of our breast cancer experts to say, in a world where patients get in HER2 upfront, at least upfront or in second line, it's unclear what to give then as a HER2 agent. And every one of these breast cancer patients will continue to get HER2 therapy even as their subsequent line chemotherapy changes. And so it was the obvious first place to go. And we think that our chances are good because, again, we're head-to-head against Herceptin. It gets our foot in the door in breast cancer.

But by no means, and we revised our projections on what we think the potential is for Ziihera. By no means is that the only area of breast cancer that we're interested in. So we are planning to get into earlier lines of breast cancer. And we think our path to do that will be in combination with a novel HER2 TKI. So why is that? Well, we know when you're combining with the TKI, there is some synergy there because TKIs tend to at least stabilize HER2 on the cell surface.

They sometimes cause upregulation of TKIs. And that really plays right into zani's mechanism of action where when you have a lot of HER2 on the surface, it clusters, triggers the complement cascade. So we think that combination makes a lot of sense. We're now seeing next-generation TKIs that are much safer because they're -- and more effective because you can go to higher exposures because they're more targeted. They don't hit EGFR, for example. And so we have a collaboration with Boehringer Ingelheim on zongertinib that's ongoing in breast cancer.

We also partner with Iambic on their IAM-1363. And both of those have the potential to be best-in-class TKI. So we think that through a combination with a novel TKI, we can move not only up in line in breast cancer, but we could also potentially get into more difficult-to-treat populations such as brain mets.

We're also interested in early-stage breast cancer because zanidatamab as a monotherapy is so well tolerated. We talked about the advantage of not being linked to a chemotherapy payload that, in some cases, causes fatal pneumonitis as in the case of Enhertu. You can then use that as a de-escalation strategy in highly curative setting. So that's the whole goal of the I-SPY collaboration is can you use zani upfront as a more effective therapy and minimize ultimately the amount of chemotherapy that a patient gets, which would be a super advantage.

But it also has the flexibility then to be used in other settings. So we've got the I-SPY collaboration. We've got an MD Anderson collaboration, and we've got a Phase II of our own in that presurgical or so-called neoadjuvant and adjuvant breast cancer setting. And we'll look at those data and decide what our best path forward is in terms of a registration trial there. So very excited about breast cancer. We're really pleased that we took that step of starting the breast cancer trial when we did even before we saw the gastric data, but I think opportunities to lean in there as well.

Great. Well, so to recap here, you've given previous guidance of $2 billion plus, I believe, for Ziihera, now thinking about building towards $3 billion to $5 billion number with some of these additional indications you've talked about. Maybe to wrap up here with Ziihera, could you just tell us a little bit about your efforts with the pan-HER2 label, a tumor-agnostic label? And how important is that label -- potential label to building towards your potential peak sales number?

Yes. It's a great opportunity, we think, because everywhere we've tested Ziihera in patients who have overexpression regardless of their tumor type, it works, and it seems to work better than prior agents. So we think we can generate the data in our so-called basket trial or pan-tumor trial that would give us a tumor-agnostic indication. And we're enrolling that trial and we're well on the way.

In that trial, interestingly, we are enrolling some populations that are less rare. We got the really rare salivary gland tumors, for example, and other rare tumors. But we also have some colorectal cancer patients coming on, some non-small cell lung cancer patients coming on. And what we saw -- we haven't published the data yet, but we're seeing activity there in colorectal cancer. That, in addition to what we saw in colorectal cancer in the Phase I and in addition to the dedicated trial we did in frontline colorectal cancer with backbone chemotherapy, altogether, it looks like we've got some significant activity in colorectal cancer.

We brought that to the FDA. We received breakthrough designation for second-line colorectal cancer, and we're in discussions with the FDA on what the path is to a rapid approval in colorectal cancer. And we don't have as much data in lung cancer, non-small cell lung cancer, but that's an interesting space as well because the HER2 approvals in non-small cell lung cancer have been around activating mutations. They haven't been around overexpression, but we think the epidemiology is such that overexpression is as common there. And there, there's no approved HER2 therapy. So this pan-tumor trial is not only potentially going to get us a tumor-agnostic indication, it will give us some data we need to perhaps set a path toward approval in colorectal cancer and maybe down the road further non-small cell lung cancer.

And then maybe since I know you want to wrap up on Ziihera, I'll just mention a couple of other things. I talked about the principles of where we can go head-to-head either with Herceptin or nothing in a HER2-driven tumor or combined with a PD-1 inhibitor, where would you go? That's the situation with frontline BTC, which is an ongoing pivotal trial that's already enrolling. No approved HER2 therapy. So it's against nothing. We know we're highly active in BTC.

Most patients, I think probably 80% of the patients globally will be getting a PD-L1 inhibitor or a PD-1 inhibitor in combination. So we're very optimistic about that trial and looking to enroll and bring that in. And I'm super excited about it because other biomarker-driven trials in that setting have failed. If you look at the EFGR experience, I think they screened 5,000 patients and never enrolled.

We now know that this trial is going to be successfully enrolled on the time lines that we're planning for. And I think that's first, which speaks to Jazz's ability to execute in rare disease spaces.

And then lastly, we haven't made a commitment yet in gastric cancer. But again, to illustrate those principles, we have highly active in gastric cancer, HER2-driven disease where there's no HER2 approved therapies in the resectable space, early-stage resectable gastric cancer and Imfinzi is approved there. So we're deep into planning on can we do early-stage neoadjuvant, adjuvant gastric cancer study as well. And I think overall, that illustrates kind of like what we're thinking about when we revise the potential into that $3 billion to $5 billion range.

Great. Well, I would be remiss if I didn't spend some time on the rest of the programs and pipeline since you have so much going on, but maybe this is a good time -- a good segue to pivot to sleep wake. So here, I think 2 straightforward questions. We know that this is an evolving space with multisource generics, oxybates, things like that. And so how are you thinking about the durability of the Xywav franchise looking forward? And then given so much of the activity around orexin, how important is having an orexin molecule of your own to be remaining competitive in the space?

Yes. Of course, I'm the R&D guy. So what I say on the first question, take it in that context. But for me, Xywav is not Xyrem for Lumryz. It's highly differentiated because of the low sodium, the lack of sodium there that for the other formulations really causes a meaningful cardiovascular risk. And so prior to generics on Xyrem or prior to the Lumryz, we really entrenched ourselves and I think educated well physicians on the importance of low sodium and published data showing that if you use a high sodium oxybate patients develop hypertension in pretty short order.

So I think people understand that benefit. They also understand that Xywav because of its optionality of giving it twice a night and giving it in different put doses, the flexibility that comes with that and the added efficacy that you get by using a second dose is differentiated from Lumryz and that a once-nightly formulation really isn't the advantage that people might have thought.

So I know less about the payer dynamics as the R&D guide, but I think what we're seeing is durability of Xywav through some of that competition and through the Xyrem generics.

And then in terms of what we're learning about the orexin space, we've been pretty consistent from the beginning. And I think it's kind of interesting to see that now the data are coming out that the field is kind of coming around to our position on this. We've said that hypersomnia, narcolepsy type 1, type 2, idiopathic hypersomnia are at its root cause a disease of disrupted nighttime sleep and all the symptoms of sleepiness during the day and cataplexy come from that.

And while the mechanism around orexin is interesting and is somewhat directly related to the underlying pathology, at least in the NT1 population, giving an orexin-2 agonist is not the same as repairing the damage to the orexin neurons that happen through autoimmunity. You don't recapitulate the orexin system. You simply hit that target and it causes wakefulness. And so what's the evidence of that? Well, when you give an orexin agonist during the day, which we hypothesize and we now feel has been proven even though all the data are out there, you don't fix nighttime sleep.

And if you look at the PSG data out there, right, everyone has done the PSG the only discussion about the potential benefits at nighttime PSG is around REM, which is not surprising at all because if you give a stimulant, then you avoid some of the symptoms that narcolepsy patients get when they go too quickly into REM. But it doesn't address the root cause of sleep disturbance, which is not getting enough sleep, total sleep time and not getting enough deep sleep, which is called N3 sleep. In fact, especially when they're longer half-lives, orexins are probably disrupting that further.

And if they were improving nighttime sleep, we would have seen all the PSG data that companies already have, and we don't see it. And we'll evaluate that with our own for sure, because we think ultimately, orexins are a very good daytime weight-promoting agent and could be complementary to Xywav, but we don't think it's going to replace it.

The second part of that question, David, is just a little bit more on the field. The approvals in NT1 requires a much lower dose. What happens is when you get loss of orexin neurons, the receptor levels for orexin go up and then much less drug to hit those receptors. There's not an approval yet in other hypersomnias. And that approval is with a drug that has a very long half-life and the other ones in development also have a long half-life.

So I think there's an opportunity to optimize, have a drug that's very good brain penetrant so you don't get systemic toxicity, has a much shorter half-life that can either be used as is or formulated in a way that you get enough coverage during the day because we're hearing loss of effect at night, onset of cataplexy in the morning. You get enough of an effect, but you don't have the carryover of insomnia.

So we'll see. It's early days. We just cleared our IND as we announced. Our programs goal to have a shorter half-life drug, something that's differentiated also in terms of other features like brain penetrants. And so this is a mechanism that you could test pretty well in healthy volunteers, and so we expect to have some data in the near future.

We could spend just a minute or so on the epilepsy franchise. So Epidiolex is obviously a very successful product since you did the GW acquisition. We're continuing to see nice growth and a long IP now on that molecule. Could you talk us through a little bit about the clinical development plan for Epidiolex here? I know you have some potential additional follow-on indications and how you see those growing the product beyond the current label?

Yes. Thank you. So Epidiolex now is the largest grossing epilepsy drug and has a very long exclusivity period into late 2030. So it makes us bullish on wanting to do more evidence generation and development there.

The other characteristic that makes us pretty bullish is that it's very well tolerated and very combinable. And for many of the indications, patients are on multiple different drugs, and it's important to be able to combine drugs. We're also beginning to elucidate the nonseizure benefits as we published on caregiver survey showing perceived benefits on behavior, cognition, et cetera.

We recently published an EpiCom study, which is one we did to look at behavior and cognition in TSC patients. So we think there are beyond seizure benefits. Now the current indication for Epidiolex is seizures associated with 3 different DEEs, Dravet, TSC and LGS. We -- while we don't promote on it, we certainly know that there's probably use beyond that because Epidiolex certainly has activity across different types of seizure types.

So our goal in the additional development programs that we recently announced is first to support the label indications with additional data, and that includes the adult study in LGS. We're bringing forward a solid oral dose capsule, which may facilitate dosing in adults.

And then to, again, continue to get -- generate data and get that message out that there are certain seizure types where Epidiolex works particularly well. So we're looking at a Phase II in focal onset seizure.

Then the next piece of this is actually expand the label into other orphan epilepsy such as juvenile, mild chronic epilepsy, where we have a -- we're starting a Phase II, Phase III. Lastly, what seems to be happening in the field, you asked earlier about the pan tumor trial and the tumor-agnostic indication. Something similar is happening in epilepsy where we know Epidiolex is effective across a number of different seizure types, yet the indication is specific DEEs.

So we've approached the FDA to say, if we were to generate more data in DEEs outside those 3, could we have a broad label that just says any patient with epilepsy and DEE could get Epidiolex. And there was an openness to that in the same way that there was to a pan-tumor trial, provided that you show the evidence that it works broadly. And so we're initiating a trial that will enroll beyond those 3 DEEs that we already have an indication for. And hopefully, that will help us broaden our label there.

Great. Great. So I know we're approaching time here. I'll see if there are any questions from the audience. Otherwise, I can ask one to close this out.

What do you think your mix is going to look like between oncology, epilepsy and the rest?

Yes, great question. And 2030 is kind of right around the corner. So I think about -- I started 8 years ago really coming to Jazz to help create a more innovative biopharma and build that. At that time, we had a real strength in narcolepsy and some rare oncology areas. So we didn't -- it was hard to develop a strategy right then. It took us a little bit of time to figure out, well, where else can we go and be successful.

We're in a very different place now. I mean, for one thing, we have proven capabilities across an array of different rare diseases. And I think that core capability underlies our strategy to say, we are -- we have been a rare disease company, and we think we can continue to be successful in rare diseases, even if it means that we go out and branch into a different rare disease the way we did for epilepsy.

But in addition to that, we also have some real core strength. So epilepsy, to me, and this underpins the deal we did with Actio. There's scientifically a renaissance happening in epilepsy. The way I experienced as an oncologist 30 years ago when the human genome was mapped, we then figured out all the oncogenic drivers in cancer and we developed targeted therapies. This took a little longer in epilepsy. But now we know, in many cases, the genetic drivers for some of these rare epilepsies. The Actio deal in KCNT1 is a perfect example. It's a single gene that's mutated causes epilepsy. We do that in mouse models. It's a gain of function. So it activates the potassium receptor.

And so it lends itself to a small molecule inhibitor, which Actio developed, a very targeted small molecule inhibitor with very little off-target activity. We also knew experimentally, you could knock down that channel and have a benign phenotype, very little toxicity. You can take the gene out in mice entirely and see no problems. So we knew that the premise there was solid, and we were convinced that their molecule was effective based on preclinical data.

By the time we finally did the deal, we saw clinical data that aren't out there yet, but will be soon. And for us, I think when you see it, you'll agree that it represents a perfect example of the renaissance that's happening in epilepsy that we want to be part of. So building on Epidiolex is a major platform.

Our existing pipeline where we have absence epilepsy and then we have another DEE play with the Kv7 molecule, adding into that Actio answer your question, I think we'll continue to look for opportunities in epilepsy for sure.

In sleep, there's less going on there, but still opportunities. And as I said before, I think we have an opportunity to have a best-in-class orexin. And then on oncology, I mean, what a difference in the 8 years that I've been here, I think we show we can do oncology well. We had a Lancet publication on the IMforte trial, which no one had really done before, gone into a maintenance setting in small cell lung cancer.

And there were a lot of people who said, you're not going to be able to do it because patients don't want more chemotherapy after their induction. So we did that well. We showed the benefit there. It's published in Lancet. And then we took an asset that, I guess, frankly, others weren't seeing the value in Ziihera. We executed on the plan that was in place, DTC, GEA, and we've expanded into other areas where I think there's a lot of potential. That now gives us a foothold in GI malignancy for sure.

And I think there's a lot of areas where we can then build on that and take lessons learned from that experience as well. So that's kind of a little bit of a framing around our rare disease strategy, building on the expertise and capabilities we have to really go into areas where Jazz, we're confident that we can compete. And we think that will continue to transform and shape the pipeline through the 2030 period.

Okay. Great. Well, with that, we are out of time. But Rob and Jack, thanks so much for joining us.

Thank you.

Good afternoon, everyone. I'm Sean Laaman, the Head of U.S. Mid-cap Biotech Equity Research here at Morgan Stanley. Welcome to the Morgan Stanley Global Healthcare Conference. Before we commence, I need to make you aware of certain disclosures. For those disclosures, visit the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

For this session, we have the pleasure of hosting from Jazz Pharmaceuticals, Chumi Khurana. Welcome, Chumi, and Jack Spinks. Thank you to the both of you. Next, might throw over to you. I think you wanted to make some statements.

Yes. Yes. Just as we make any forward-looking statements, I'd encourage you to look at our SEC filings filed on 6/30, along with our earnings statements and look -- take a look at our risk factors. If I do refer to guidance today, that would be the guidance I've spoken to on 6/30 of this year. And maybe I'll pass it over to Chumi just for a brief intro of the portfolio for those who might be new.

Yes. Thank you. Thank you, Jack. Thank you, Sean. Chumi Khurana, I lead the U.S. oncology commercial team at Jazz Pharmaceuticals. And it truly is a very exciting time at Jazz right now, specifically for the oncology team. We have shown great revenue growth in oncology, 32% year-over-year. In 2025, we crossed the $1 billion mark. More importantly, we're bringing some truly innovative therapies to the marketplace. We've had 3 launches in the last year, Zepzelca, IMforte regimen, Modeyso and most recently, just 3 weeks ago, our frontline launch in GEA.

And we're very pleased with how we're performing. It's a transformative time. Oncology is going to be a growth driver for Jazz Oncology, and we really look forward to continuing the trajectory and with that, we can go to questions.

Okay. Thank you. Maybe just to zip through 3 quick macro questions we're asking all our companies. So first one is on China. How is the rise of China-originated innovation changing your competitive positioning, if at all, or your BD and R&D playbook?

Yes. I think it's a good question. And I certainly think it's something we keep a close eye on both from an R&D and a BD standpoint. I will say we have made it a focus of ours to continue doing smart business development across our 3 verticals in sleep, epilepsy, and rare oncology. And we did recently hire this year, Tom Riga, our new Chief Business Officer, to help us continue with that effort. So it's something we're watching closely. I don't think it's impacting us today, but certainly something we keep an eye on.

Sure. And what about the adoption of AI across your business? And well, first of all, are you? And second of all, can you point to somewhere where it's changed the decision, a cost outcome or even a POS assumption?

Yes. Maybe I can start, and then I'll pass it over to Chumi for some specifics. I do think, Jazz, as an innovative biopharma company, we are looking to leverage things like AI to improve the speed of drug development, improve our decision-making, and really be more strategic overall. I know I use it quite extensively. And Chumi, I know her team is leveraging it quite well. I'd love to toss it over to her for a couple of examples.

Yes, for sure. I mean I think it's the way of business now, right? So from the way that we communicate with each other, even internally to how we're communing externally, getting the insights being faster, more agile. I think the goal for AI for my team specifically is to use it to get faster customer insights and action on it so that we can bring innovation and information to our customers as soon as possible.

Wonderful. And last question, just on the policy variable, which seems to be fairly stable at the moment, but which of the following do you consider the most important to your economics at the moment? Is it FDA, Medicare negotiation, MFN, tariffs, or global pricing?

I think it's a good question, Sean. I don't know if we're seeing a ton of impact from any of those at the moment. As you know, and I think most in this room would agree, it's a quickly changing environment. So it's something we watch pretty closely. I think we've commented on tariffs historically. There hasn't been much impact to Jazz. We've certainly taken steps to mitigate that. And MFN is something we certainly keep our eyes on to date, recognizing that nothing has been finalized. But again, all things we watch really closely, but no huge impacts we'd speak to today for the Jazz business.

Sure. Thank you. And given we have it, we're going to focus this more on the oncology side. But Ziihera, obviously, zani, one of the most debated topics occupies most of my inbound on Jazz. But following the HER2 plus 1L GEA approval. What percentage of eligible patients are currently being HER2 tested appropriately? And how much upside exists simply from improving testing rates?

Yes. The HER2 GEA market is actually relatively well established because trastuzumab has been out in HER2 for a while. So testing rates are currently somewhere around 80%. So pretty high. So there's still opportunity, obviously, to influence the testing, though that's not like a huge area of focus for us. What is a huge area of focus for us is that right now, trastuzumab is only used in about 60% of the patients that are eligible. And that's simply because really no one is proactively promoting trastuzumab and/or KEYTRUDA in GEA. So driving that treatment rate to be 100% and for every patient to that is HER2 positive to receive HER2-directed agent -- is our goal, and to obviously replace trastuzumab given the data that we see.

Okay. I guess your sBLA was approved for both the doublet and triplet regimen. You recently updated the peak sales opportunity for Ziihera to $3 billion to $5 billion, I think, all the way up from $2 billion plus. I mean it is plus $2 billion. But noting there is potential for targeted HER2 therapy to expand into breast, non-small cell lung, and colorectal. How much of the increase in that upgrade reflects greater confidence and higher penetration assumptions in GEA, BTC versus incremental revenue from CRC and lung?

Yes. I think that's a really good question. So like you said, originally, our numbers that we shared were around GEA, BTC, early breast cancer. We don't give indication-level guidance, as you know. But I think it's everything. Honestly, it's the great data that we saw in GEA. So that's giving us more confidence, and we have a lot of ambition there. But then obviously, adding indications like CRC, lung cancer, early breast cancer, and even metastatic breast cancer with TKIs, those are all the drivers for us to take the number up.

I guess what has to happen to reach the $4 billion to $5 billion case?

Yes. Do you want to...

Yes, I can maybe jump in there. I do think we recognize that we did provide a range of $3 billion to $5 billion and do recognize that there are risks inherent to drug development, not everything will be successful. But to Chumi's point, I think zanidatamab has really shown with this GEA data that it is a differentiated product. We know we have a differentiated mechanism of action. We're seeing that in the data. So when I think about what gets us to the high end of that range, I think about the broadness, where can we take this drug? I think if we can develop the drug as we think we can and have a number of shots on goal here and replace trastuzumab, which we think fundamentally zani is the best HER2 antibody, I think we can certainly get there.

But again, we do provide a range recognizing not everything is 100% probability of success. But all the data we've seen to date from zanidatamab, that's from BTC, that's GEA, that's late-line studies, that's breast cancer, early breast cancer, colorectal cancer has been very positive and I think does help define the thesis that we have that this can be the HER2-targeted therapy of choice.

Awesome. And I guess you have more than 90% physician overlap between BTC and GEA. So how much commercial infrastructure is already in place for the launch? And what incremental SG&A is required to grow GEA uptake?

Yes. So from a commercial footprint and investment perspective, we're -- obviously, we're investing in the launch. But as you said, the sales force that is selling frontline GEA has already been in place. It's actually also the sales force that promotes Zepzelca. So we have a really good presence in both the academic and the community settings. And so we did invest a little bit in -- we did expand our MSL team just to make sure that we had the right scientific exchange. And then other than that, a lot of our investment is really in the community and making sure that we're educating around the change of standard of care that needs to happen with using zanidatamab.

So at this point, there's really nothing in the way. We have an established J-code. We have a team that's ready to go. We have supply. Our JazzCares program is up and running. We have really no payer kind of barriers. So there's -- we're very pleased with the label. So there's really nothing in the way for the ramp-up.

All right. And I think Jazz has estimated approximately like 8,000 U.S. HER2-positive GEA cases, but only 3,000 to 4,000 treatable patients after accounting for things such as unresectable disease, first-line treatment eligibility and HER2 testing. Which part of that funnel represents the largest near-term opportunity to expand the addressable population?

Yes. So just to clarify, right? And so we've been very consistent. The incidence of GEA in the U.S. is 8,000 patients. And then when you look at our label, if you put in the filter of unresectable frontline, right, and then also the testing rate, that's how you land at the 3,000 to 4,000. And as I said earlier, the biggest opportunity is to make sure that all those patients are treated because currently, some of them are treated with Herceptin, but not all. And that's where really our opportunity is to leave no patient behind.

Sure. And on the second interim OS analysis for zani -- the doublet change. Could a positive doublet ultimately be more commercially relevant than the triplet?

Yes. So we just -- and it was good news that we had statistical significance for the doublet as well. We had the OS data for the doublet in our label. We have it now. I think what we'll see, and we'll be presenting the data at an upcoming meeting, and we're excited to do so is a very consistent way that we're looking at both arms. We truly believe that for those patients that are eligible, the triplet is the treatment of choice. It's where you can see the best results with the overall survival. And I think we all know that PD-L1s also have a great tail of the curve in terms of overall survival. And really, the doublet comes into play for those patients that might not be eligible for the triplet. So that is how we see that splitting out.

And I do just want to point out that, that triplet what's important here is that, that triplet is eligible for all patients regardless of PD-L1 status. So that is new in this patient population where it was previously bifurcated into PD-L1 positive and PD-L1 negative. Now patients have the opportunity to receive one regimen, the triplet regimen with Ziihera, chemotherapy, and trastuzumab if they're HER2 positive. And that's regardless of PD-L1 status, which is important.

Sure. Thank you, Jack. I guess how consistent was the benefit across HER2 expression levels?

Yes. So in the triplet arm, we were approved in both IHC3+ as well as IHC2+. So very consistent across -- in the doublet, we're approved in IHC3+, it was interesting. There were some confounding factors like the Herceptin arm really overperforming there. But in the triplet arm, we are -- we can be used across the IHC2+ to make a patient population.

And what are the key determinants of regimen selection between Ziihera plus chemo and Ziihera plus chemo plus tisle?

Yes. I mean, to me, I mean, there really isn't anything that should bar a physician from using a triplet unless there's a contraindication. It should really be the triplet.

Okay. And how do you expect in HER2, the emerging HER2 ADCs and bispecific competitors to influence long-term share dynamics?

Yes. So the current potential competitors are a few years out. They would get approved or we'd see data towards the end of the decade. To be honest with you, at this point, we're not too concerned. Some of the early data is actually not that positive. And I think the burden of proof is on them, right, to beat our overall survival -- by then we'll have more long-term follow-up. So at this point, not too concerned and believe we can compete. But of course, it's always good to have other options for patients out there.

And how should we expect the I guess, the launch curve to look. I mean what have you learned from early academic center adoption? And how effectively may that be translating into the community setting?

Yes. I mean it's very early. We're 2 weeks into the launch. So we don't really have any data yet. We'll obviously be sharing that at the right time. But we -- as I said earlier, there's no barriers to ramp up. We have great ambition there. So we don't see anything getting in the way to achieve our ambition. So we're hoping to achieve peak sales. Usually, we don't share those details, but it usually takes about a year or 2 to get there. But again, no barriers in place to achieve that as soon as possible.

Sure, sure. And how quickly do you expect NCCN inclusion after approval? And is the guideline inclusion a meaningful gating factor for adoption?

Yes. To be honest, we're surprised that we're not on the NCCN Guidelines yet, but they have all the information that they need, and we're expecting that, that will happen any day now. We're obviously looking forward to the inclusion of the -- in the NCCN Guidelines. However, in terms of adoption, it's really not a barrier for us, again, because there is access to the drug. The drug is already on market. We have an established J-code. So it really isn't a barrier to uptake at this point.

Sure. Thank you. Before I move on, is there anything that I didn't ask on zani and the launch that perhaps I should have?

No, just that we are thrilled with the label that we got. Honestly, Jack spoke to it, the fact that we're indicated in both PD-L1 and PD-L1 positive and negative is great. We are very, very pleased. And really, there's nothing in the way for zani to become standard of care and replace trastuzumab and treat every HER2 patient in GEA.

Wonderful. Maybe to move on to Zepzelca -- so really strong growth. How much runway remains as physicians convert eligible patients?

Yes. So we've had over 40% growth, as we've shared. 30% to 40% of that growth is actually coming from our new indication, the frontline indication in IMforte regimen. Very pleased with our performance there. We've seen great adoption of that indication and have the ambition and believe that we can continue to grow that. And so our strategy has always been to shift into frontline for Zepzelca -- so that is a growth opportunity for us as we look forward. And I think what's important to know is that it's also where we see a longer duration compared to second line. So it's a great opportunity for the small cell lung cancer patient. As you all know, unmet need is very high there. And again, we're seeing very good uptake there, specifically in the community setting.

And looking at Amgen's DeLLphi-305 study, if the Phase III confirms the early survival signal, what is the strategy for maintaining durable Zepzelca growth?

Yes. I mean, first of all, I think it's great news for small cell lung cancer patients that they're going to have more choices. The tarlatamab regimen, and we'll wait to see the data. And hopefully, it will be positive for patients. However, IMDELLTRA is not going to be right for every single patient. There's some biomarker data out there that says that tarlatamab is better in DLL3 patients. Zepzelca doesn't really have that limitation.

And then even though there has been some recent news around updating our monitoring, there's still a lot of monitoring required and follow-up for tarlatamab, which we don't see with Zepzelca. And this is one of the reasons why we lead in the community space, the operational issues with IMDELLTRA are real. So again, we believe we can compete in that setting, and there's patients that will benefit from Zepzelca. Frankly, probably what would be good from a sequence perspective is to use Zepzelca in frontline and then save IMDELLTRA for the second line because patients need options.

Sure. And still on Zepzelca, what are the key milestones over the next 6, 12, 24 months that could meaningfully change the peak sales expectations?

So I think it's continuing to compete with IMforte and really doubling down in the frontline setting and driving that frontline use. That is really our main focus to drive Zepzelca business.

Moving on to Modeyso. Since launch, what has surprised you the most versus your prelaunch expectations?

I don't know that we've had any major surprises. We're incredibly pleased with the launch uptake of Modeyso. We've had great uptake in the academic setting, which is where most of our business is, great adoption there. I think one of the things that we're continuing to try to understand is what will be the duration of therapy in the real world. It's too early for us to say, but it's something that we're watching and there's a potential for that to be an inflection point. This is ultra-rare disease. It's what Jazz does really well. So the team is really focused on patient finding.

And so now really also looking to leave no patient behind in the community setting. So that is another way that we're finding patients there. There's also been a lot of focus and investment on driving diagnostic testing so that we find our DMG patients. So these are some of the inflection points for Modeyso. And then, again, we're very excited about the ACTION trial that will read out next year that will put us in an earlier setting. So still very much in launch trajectory mode with growth forecasted.

How large could the opportunity become if ACTION reads out well?

I think what we've communicated at this point is a peak sales of $500 million. Anything else that we need to share there?

No, I think it's $500 million plus in the U.S. That's first line and second line. I will note that the ACTION trial would serve as a basis for submission ex U.S. as well. So certainly an opportunity there should the ACTION trial be positive, which to Chumi's point, we're quite excited about. So hopefully, we get to flip that data card early next year in the first half of '27.

Yes, it's incredible progress in that space.

Okay. Maybe moving along to Rylaze. -- being the established product, what's the biggest remaining opportunity to grow the Rylaze franchise?

Yes. I mean Rylaze for us has been a real success and obviously, is what we consider at this point a stable business. And so that's what we continue to do. I think the team is focused on making sure that treaters are treating as soon as hypersensitivity appears. So again, a good success for us. And I would say what we would consider a stable business in the oncology portfolio.

Okay. I guess more broadly, maybe a question for you, Jack, although just oncology. Ziihera, Modeyso, Zepzelca, and Rylaze, what do you believe is the most underappreciated asset investors. We know what the biggest opportunity is, but what do you get the least questions about and you wish there were more.

Yes. That's a really interesting question, Sean. Maybe I'll start and then Chumi can add in here. There's a couple of areas that I think are underappreciated. I won't tell the room full of investors what's undervalued, that's certainly for you to decide. But when I hear feedback we get, I mean, I still spend a lot of time helping people understand the zanidatamab opportunity. I recognize that we did just put out a peak potential. But when we think about this product, this is something we licensed in 2023 that I think many had expectations for just in BTC and GEA.

And now we're looking at a very broad development program in late-line breast cancer, early breast cancer, colorectal, non-small cell lung. I think anywhere HER2 agents are used, we see potential with Ziihera. So I do think there's a lot of potential there. And maybe just taking a step back, I do think the overall portfolio of Jazz is something that we're still helping people to learn about because as Renee outlined this year, we have ambitions in rare disease to be looked at as an innovative biopharma company, something I think with a product like zanidatamab, and Modeyso, we're well on our way.

But when you think about our portfolio and where we come from 3, 4 years ago, the vast majority of our revenues from a single product. Now we have a diversified portfolio with $3 billion-plus verticals that are all performing well. And I do think that's something that I spend a lot of time helping educate on. Maybe lastly, Chumi, I'd be happy to toss it over to you. When I think about Epidiolex, I mean, we've obviously acquired this asset from GW a number of years ago. And last year, we did hit blockbuster status with that.

But as I think about the runway we have here with the settlement of our 10 ANDA filers, we have runway into the very late 2030s. We have a $1 billion drug today that's growing. And we just announced a number of new initiatives here from the clinical development stand -- or excuse me, clinical trial standpoint to continue to grow this asset. This is something that I think people have looked at as it's currently indicated -- these 3 currently indicated indications and said, okay, that's it. But we obviously see a lot more there, both with Epidiolex and our broader epilepsy portfolio. So Chumi, I don't know if you have anything to add to that.

No, that was great. I think the only other thing is that I would mention is it's the how we do things at Jazz across oncology, neuroscience, which is I think we're really showing that we can compete. So we might be rare disease, but we're not -- we are in competitive spaces. And so I'm incredibly proud of how our teams are competing and executing in the marketplace. So...

I've got some neuro questions here. Yes. So just maybe remind the audience where we are on the outlook for your oxybate franchise. And where are you seeing growth amongst NT1, NT2, and IH. And maybe what's your latest perception on the potential impact of the orexin-2 agonists?

Yes. I think it's a great question. Obviously, Xywav has been an asset that's performed extremely well. And again, this is in light of 2 multisource generics that have come to market this year. I think we've been very clear at the outset of this year that there did exist some uncertainty in the sleep portfolio. And I think what we've seen is that Xywav's differentiation, it is the only low-sodium oxybate has been really meaningful.

And Sam and her team have done an excellent job of going out there and really executing commercially. You've seen that through our patient adds this year. You asked about opportunity for growth. I mean, certainly, on the IH front, I think there's still room to go there. I mean it's still fairly early on in the launch.

And I think we have close to 6,000 patients today, but we do see that market potentially as big as narcolepsy. So, I think on the Xywav front, we've been performing extremely well commercially. And when we do think about the orexins coming to market, certainly, we've seen data that has shown in NT1 patients, they are a potent wake-promoting agent. But when I think about Xywav specifically, I think it's important to note here that Xywav is offering something that a wake-promoting agent is not, and that's the ability to get a better nighttime sleep. So when we think about that in light of wake-promoting agents that are used today with these narcolepsy patients, again, and these orexins would be used in NT1, I think we do see a pretty resilient Xywav.

And we've said for a number of years that we view these as complementary. There's still a number of things we'll need to see in the orexin front, pricing, scheduling. But I think where we sit today with Xywav and the broader market, we've obviously performed very well. And I think we're looking forward to next year. I will note that in -- on our second quarter earnings call, we did note that we expect Xywav to grow double digits this year, which I think is incredible when you think of where folks thought we'd be last year with the launch of multisource generics but the branded competition. So certainly, kudos goes to Sam and team as they look to continue that performance.

Sure. Thanks, Jack. Moving over to financials and capital allocation. So you've got full-year revenue guidance was raised to $4.60 billion to $4.75 billion. What are the largest second-half swing factors we should be focused on? Is it the GEA launch timing? Is it generic and generic oxybate pressure or Modeyso demand or something else?

I think it's a good question, Sean. I mean when I think about that guidance and the reason behind us raising that guidance really was a number of things. It was performance of the portfolio, both on the sleep side, where we did raise our guidance from -- to $2.025 billion to $2.125 billion with Xywav growing double digits. Our epilepsy and oncology portfolio combined growing double digits. Chumi's team doing an excellent job on oncology performing. I mean, you've really seen the business perform extremely well. So certainly, as we think about the latter half of this year, you're right, there are a number of things that are still ongoing, the Zepzelca transition in first-line maintenance where we see 30% to 40% of revenue today in first line. We expect that to grow. We expect Modeyso still early in its launch. And to Chumi's earlier point, we just launched many zanidatamab 3 weeks ago. It's something we're extremely excited about.

We'll only see a month of contribution or so in the third quarter. We'll get a full fourth quarter, but certainly, all of that's included in our expectations. And we certainly hope to continue on the trajectory commercially that we have been for the first half of this year, where, again, it's been excellent across the portfolio from sleep to epilepsy to oncology.

Sure. Still on capital allocation. So like $2.2 billion of cash, I believe, and $4.4 billion of debt and announcing a $1 billion convert and then a concurrent $225 million share repurchase program, which suggests confidence in both your balance sheet and your equity value. How are you thinking about target leverage and balance sheet capacity?

That's a great question. I don't know if I'm ready to give guidance to this audience on a target leverage, but I can give some of our thoughts on that leverage because I do think -- as we think about the cash we generate in the business, I think we generated $824 million in the first half of this year. To your point, we had $2.2 billion, and we just raised another $1 billion. I think what that allows us to do is, a, invest in our commercial business, and I'm thinking about like our capital allocation priorities, invest behind Chumi and team and Sam's broader team to ensure that they're able to execute on their strategy, allow Rob to continue to develop on the R&D side.

And then what we haven't talked to yet, Sean, which I do think is an important part of our strategy at Jazz is doing and continuing to do smart business development. As you may have seen this morning, we just closed the Actio acquisition, which, again, is exciting for us because it's another asset that we think really builds on our strength in epilepsy. And as I think about leverage over time, while I won't give you a target, what I can say is that we've been consistent in how we view business development, how we view capital allocation priorities.

And I think we'd look to certainly continue to do smart business development, continue to generate cash from our business that allows us to invest further in it. So certainly, we'd love to see the leverage. I think we were less -- maybe less than 1x if you're looking at net leverage this last quarter. I think as we look to execute on that strategy, certainly, it's something we think about. But I don't think we need to necessarily box ourselves in with a leverage right now.

Sure, sure. And I guess are you able to characterize your preference for rare oncology or rare neuro? And then there's certain metrics that you look at around deals. I mean, we'll judge each one in its case. And how do you think about how fertile the ground is there out there for BD?

Yes, it's a great question, Sean. I think there's a lot of substrate right now. And I do think Jazz benefits when we think about BD. I mean you all heard Renee speak to our rare disease strategy for Jazz. We think Jazz really has found differentiation in being able to take these rare disease products and commercialize them, develop them. And Jazz has these 3 distinct verticals in sleep, epilepsy, and oncology. And what that allows us to do is we don't have to focus on any one area. We can say, okay, oncology valuations are getting a little hot. Well, maybe we can look at epilepsy.

And so I think that gives us a lot of flexibility on the business development side. And I think, again, another strength of Jazz is we can look at late-stage products like Modeyso from the Chimerix acquisition, which we closed last year and is in its launch now. We can also look to earlier stage like the Actio acquisition in areas that we do have that expertise. So I look to -- I would look at us to continue on the business development front with these Jazz-like deals where I think we can compete and win. And Chumi, I know you have a lot of thoughts on how Jazz competes on the commercial side in that kind of phenotype.

Yes. Yes. I think just having worked in big pharma now being at Jazz, like what we do really well is I think we're rightsizing the teams. It's not really about these huge sales teams anymore, but having a cross-functional collaboration, really leaning into omnichannel, investing in the right channels and doing patient finding exquisitely well. We have teams that are highly trained with very strong relationships. And I really think that, that's been our winning combination.

Wonderful. Well, we're just about out of time. Is there anything I didn't ask that I should have?

I don't think so. We didn't spend a ton of time on Epidiolex. But again, that's one of those products that I think we're quite excited about. I think with the addition of the Actio, ABS-1230, it really allows us to go deeper on the epilepsy side, and we're looking to expand that program broadly. So -- with that, Sean, thank you so much for the time today. Thank you.

Thank you.

We might close there. Thank you. Thank you, everyone.

[Audio Gap] School Summit. We're thrilled today to have Jazz Pharma. Guys, maybe just give us the 2-minute kind of high level, and then we can kind of get into some specific questions. We got a lot.

Yes. Thanks, Geoff, for having us here. And before we start, I'll just mention, we'll -- Sam and I will be making some forward-looking comments. So please do refer to the risk factors in our SEC filings. And if we do refer to any guidance, we're referring to our most recent guidance provided in our earnings update. And any non-GAAP financial measures we reference are reconciled there as well. Samantha Pearce is our Chief Commercial Officer and would be happy to give you an overview of the company.

Great. Well, thank you for inviting us, and thanks for joining us today, everybody. So I think I would just start by really reiterating and highlighting the strong commercial performance over the last few quarters. Our second quarter performance was obviously very strong, our best quarter ever, $1.2 billion, double-digit growth. And I think what's really encouraging about what we're seeing right now from Jazz is that performance is across all of our key brands. So double-digit growth across all of our key brands puts us in a really strong position.

Really strong foundations when you look at Xywav, which has been our brand that has been generating really good revenues for a long time now, continues to grow strongly with 13% growth in the last quarter, still adding significant numbers of net patient adds each quarter, and even in the face of new competition, continues to perform extremely well.

What we're excited about is the way that we've executed on some of those new launches as well. So the performance with Modeyso, with Zepzelca, and I think that, combined with the outlook for Ziihera now as we launch into GEA has given us the confidence to raise our guidance for the full year in 2026.

Looking ahead, we're obviously all really excited about the Ziihera potential. We were delighted with the label that we got in first-line metastatic GEA, and I'm sure we'll talk a little bit more about that. And I think that label, combined with the development program, has given us the confidence to raise our expectations for Ziihera for -- to $3 billion to $5 billion for that asset.

So a really exciting period for Jazz. A much more diversified portfolio with lots of inflection points to come, and we're excited about the future and where we can take Jazz with our new kind of rare disease focused strategy as well and some of the corp dev that we're doing there.

Great background. Thanks for that, Sam. Yes, maybe to your last point about the evolution of the portfolio. So you guys have gone from sleep primarily to now oncology, epilepsy. You've targeted sort of a natural evolution of the portfolio. Is there sort of a longer-term kind of objective in terms of therapeutic focus? I know obviously, rare is the underpinning of all of them, but I wondered if there's a longer-term objective in terms of where you want to be in some of the different therapeutic areas?

Yes. I think as we've set out our strategy at the beginning of this year with our focus on rare disease, you're really seeing us now kind of execute and pull that strategy through. We've built real strengths in rare disease and particularly real strengths in particular therapeutic areas. So the leadership position that we have in epilepsy with Epidiolex, we're looking to build on that now with some of the corp dev deals that we've done that will enable us to leverage those strengths in epilepsy with other assets.

Similarly, we've got strengths in rare -- some of the rare oncology areas like neuro, oncology, the deal that we did with Chimerix really enables us to leverage our rare disease capabilities there, and we'll be looking to kind of augment that with other opportunities as we can.

And of course, the big focus at the moment is in Ziihera, which is being launched in a rare disease indication. But of course, as we look ahead to the full potential of Ziihera, we're excited to take that into other tumor types, which would include more broad tumors like breast cancer, for example.

So where we are at the moment, are focus very much on rare disease. We can talk about some of the corporate development deals that we've done that are really kind of strengthening our position there, but that's really the focus.

Let's talk about Ziihera. So give us a kind of the where you are and what maybe approximate time lines for expanding the kind of the indication base? What are the growth drivers that we should be focused on in the next, call it, 12 to 24 months?

Yes. So commercially, obviously, right now, we are focused on launching well with Ziihera in the first-line GEA segment. We were delighted with the label that we got there. And this is an opportunity for us to really leverage the strengths that we've built in launching in rare oncology. We've obviously got a team there that was built for BTC. So we have that established team. The -- we're not expecting reimbursement headwinds. We have the permanent J-code. And we've also got a lot of experience of launching in this space where academic adoption is obviously going to be very important. But what's also going to be important is that we can get a rapid adoption in the community setting as well. And this is a launch that is somewhat similar to what we succeeded to do with Ziihera in the first-line maintenance segment, which was also driven by community adoption.

So we're excited there to start with, and obviously, key commercial focus is really doing that well and getting to peak sales as quickly as we possibly can. Beyond that, of course, we're excited. The data shows Ziihera to be a really new standard of care for HER2-directed treatment. And we're excited about taking that drug into other tumor -- other HER2-expressing tumors.

Looking ahead, obviously, breast cancer is significantly larger, and we have the study, the Phase III study ongoing in metastatic breast cancer. We also have a full development program that is looking -- our pan-tumor program, early breast cancer, colorectal, non-small cell lung cancer. And when you look at the totality of that development plan, gave us the confidence to increase the peak sales projections for Ziihera in the $3 billion to $5 billion range. So obviously, a very, very important asset for Jazz and one that we're committed to kind of maximizing the potential of.

Next milestone in the breast cancer study, we expect the top line data from that Phase III study to read out second half of '27, early '28.

Yes. On the GEA launch for Ziihera, maybe can you talk about -- I mean you mentioned that you expect a rapid kind of uptake because you have a kind of 90% prescriber overlap with BTC and permanent J-code and you expect limited payer fiction. Maybe talk about like high level, over next 3 to 6 months, what should investors be looking for in terms of launch metrics that would indicate that launch is kind of getting ahead of expectations or like just a general thought on what we should be looking for?

Yes. So we'll be reporting Ziihera revenues to you on a quarterly basis. And I think that's going to be the best measure of how this launch is going. We had already achieved the point of launch into GEA. With BTC, we had already achieved the standard of care there with more than 50% share. So everything that you see from here is really going to be driven by the GEA uptake. And some of the important things for us to be able to achieve there is, obviously, we are focused on ensuring that the product is adopted in those academic centers of excellence. There's already very high awareness and appreciation of these results, which are obviously very strong.

As I mentioned, what's really going to be very important as well is that we ensure that community doctors also appreciate the benefits of Ziihera. And that when patients are diagnosed with HER2 GEA, that we can support them in those moments to ensure that they're aware of Ziihera and that they are considering the most appropriate treatment of which, obviously, Ziihera would be an option.

Right. And there's a mixed Medicare and commercial population, right? Are there differences like in terms of like pathway placement or speed or regimen across this different kind of population? And could that create an even early adoption? Like how could you see like differences in adoption between these 2 kind of populations?

Yes. So we've learned a lot from our experience with Ziihera, particularly in the adoption in the community setting and working with GPOs on contracting to make sure the adoption is rapid and appropriate for these patients. So we're not anticipating significant difference in Ziihera. I mean I think it's going to be important that all patients, irrespective of the channel, have the opportunity to get Ziihera.

And then you mentioned you got really good label for Ziihera as well, right, in terms of triplet versus doublet. Maybe talk about like the utilization you expect initially with tripled versus doublet. And especially with respect to like older or less fit patients, where do you see like the use across different kind of patient population?

Yes. Well, when you look at the totality of the data, we believe that the most appropriate choice for patients will be the triplet regimen. More than 2 years' overall survival benefit in that regimen. We know that patients will -- the PFS there is long. And the fact that this treatment within the label is available to both PDL positive and PDL negative patients is a real differentiator. It's probably the first time that that's been available to both those types of patients. So -- and that means that, obviously, patients can get on treatment earlier. They don't need to have a test for PDL and patients can get the benefit of Ziihera sooner. So our communication will be very much focused on the triplet regimen.

Clearly, there may be some patients for whom an immunotherapy is not appropriate and the doublet will be available also for those patients, which also have strong efficacy associated with that, but that's going to be our focus at launch.

Question for you. Maybe the last one on Ziihera. When you think about the peak opportunity, I'm assuming that breast is the majority of that. How do you think about kind of the different segments over the medium to longer term?

Yes. Well, GEA is a sizable part. When we talk about the $3 billion to $5 billion peak, GEA does represent a sizable proportion of that. So that's a really important focus for us now. But clearly, breast cancer longer term is one of the largest tumor types. So as we kind of get towards that launch, that's going to be obviously critical for us to execute well around metastatic breast. We've also got the studies in early breast cancer as well ongoing there.

But the HER2 -- I mean, obviously, you don't have to reinvent the wheel. I mean there's many other tumor types, right, that are kind of longer term good opportunities as well. I guess maybe you'd anticipate raising the peak as you get more clarity on beyond breast?

Yes. So we have the pan-tumor trial ongoing. We've got our focus on colorectal cancer and non-small cell lung cancer as well. I mean, we do see with Ziihera's mechanism of action and the data that we already have in hand that Ziihera can represent a new standard of care for all HER2 expressing cancers.

Yes. Sean, do you want to go to Epidiolex in epilepsy?

Yes. Sure.

Yes, so...

We can like ask about like Zepzelca, maybe talk about like, it has a good quarter this year, second quarter. Maybe how quickly can we see like the first-line build offset like the erosion of the historical like the second-line business? How do you see the first-line, second-line dynamics play out in Zepzelca?

Yes. Zepzelca did have a very good quarter. We're exceeding $100 million in the second quarter, a 42% revenue growth. Obviously, the launch into the first-line maintenance segment happened in October last year. What we have been seeing is a gradual kind of tapering down of that second-line business over time with increased competition there even before the LAGOON study readout. Our focus commercially has been 100% on the first-line maintenance segment since we launched there, and we've seen really good growth.

In the second quarter revenue, if you split that down, between 30% to 40% of that revenue was being generated by that first-line maintenance segment, and that's obviously growing. So we can expect to see that second-line business continue to taper down, and we'll be focused on continuing to drive growth in that first-line maintenance segment.

[indiscernible] Epidiolex.

Yes. Sure. Yes. Let's talk about the -- kind of broadly the neuro franchise. So what are the largest maybe remaining opportunities as you look at Epidiolex across pediatric, adult and kind of some of the long-term care settings? Just want to get your perspective on that before we move on to [indiscernible].

Yes. Yes. I mean we're really pleased with the growth that we've driven with Epidiolex in the last few quarters. We delivered 16% revenue growth in the second quarter and 14% volume growth globally. What we're seeing there is continued opportunity for us to grow Epidiolex in the current label indications particularly in the adult long-term care segment, where many patients there, LGS patients don't yet have a definitive diagnosis. So we've been investing in certain tools that help physicians diagnose patients with LGS so that they can be considered for Epidiolex.

We also know that persistency is a hallmark of Epidiolex. Patients do tolerate the drug very well and they stay on the drug for a long time. But we know if they get enrolled in our JazzCares Program program, which is our patient support program, they stay on drug even longer. So we put a lot of effort into making sure that as many patients as possible can benefit from that program. So continued growth in the adult segment, continued growth as a result of persistency.

One of the other strategies that we're pursuing that will support our continued penetration in the adult segment is the recent NDA capsule filling that we made. So that is a formulation that is going to be particularly beneficial for adult patients who have to take quite large volumes of the oral solution, which is a sesame oil-based solution. So the capsule formulation is going to be better tolerated, more convenient for adult patients.

You mentioned about capsule formulation and you could expect that it could expand the patient pool, I guess, for Epidiolex. Maybe talk about how should we distinguish between generally incremental kind of adult starts and improve persistence from capsule versus just conversion from the existing kind of solution patients?

Yes. I mean there will be a combination of both those 2 things. We do think there will be some conversion of oral solution patients onto the capsule, but we also do believe that the capsule formulation will provide an incremental growth opportunity, particularly in the adult segment. So yes, I mean we -- there will be an element of both of those.

Qualitatively, can we talk about like the growth you could expect from capsule formulation like just like at a broad level?

Yes. We haven't been specific around what that would look like, but we will absolutely -- we will expect to see growth in that adult segment. So more patients who otherwise might not have tolerated Epidiolex or perhaps come off treatment because of the issues of the oral solution for -- it's a weight-based drug. So they're obviously taking quite large volumes of oral solution. We do believe that it will expand that opportunity for Epidiolex.

How would you say -- is there another kind of barrier in terms of adoption with respect to kind of guidelines or reimbursement or access? Are there like new verticals that you could still invest in to see an uptick in growth in the next couple of years?

Access has always been very strong for Epidiolex. That's not really been a barrier. But we do believe that Epidiolex has -- can offer benefits to patients beyond the current label indication. So we've invested in 4 really important clinical studies that are going to have longer-term strategic upside potential for Epidiolex. We have a Phase III DEE study that we've initiated. We have a study in juvenile myoclonic epilepsy, which is actually utilizing the capsule formulation. We have a study ongoing, a Phase III/IV study in adult LGS providing us more data to help us penetrate that adult segment. And then we have an earlier stage focal onset seizure study.

And these studies really come about the fact that having settled the ANDA filers, we know that we have exclusivity out to the late 2030s. So it's opened up the aperture for us to make these additional more strategic investments in the continued growth of Epidiolex.

Maybe just help frame those opportunities, the ones that are -- the new ones that you're investing in, in Phase III.

Yes. So I mean they are new patient populations for us. So if you look at the Phase III DEE study, for example, there are about 120,000 to 150,000 U.S. patients in that particular segment. JME would be between -- round about 60,000 U.S. patients. So they're quite sizable opportunities.

And staying on epilepsy, you recently made an acquisition with Actio. Maybe talk about what made like ABS-1230 kind of compelling target? And how could you use your kind of epilepsy infrastructure to kind of commercialize this product once it launches?

Yes. From the commercial perspective, we're really -- I mean, as a company, we're really excited about this acquisition. I think when Renee set out our rare disease strategy at the beginning of this year at JPMorgan, we talked about where our focus wants to be, the kind of assets that we'd like to bring in that we believe are kind of Jazz assets. And I think the Actio acquisition, it falls right in that sweet spot. I mean this is an area of really high unmet medical need. These little babies actually diagnosed with KCNT1 epilepsy, really very limited treatment options, devastating diagnosis, potentially 100-or-so seizures a day. So the opportunity for us to bring an asset forward to have an impact on these little kids is obviously hugely motivating. And it gives us the opportunity to really leverage the expertise that we've built in epilepsy.

With Epidiolex, we have the #1 branded antiseizure medication. We have a fabulous team. The opportunity for us to leverage those capabilities with a new asset like this, and also, obviously, with significant commercial synergies is exactly the type of deal, I think that Jazz should be doing.

How would you characterize -- I mean, just given the presentation of these the kids, and I think you have to really raise awareness, but talk about this as maybe a global opportunity. What is the markets OUS? What's the visibility of KCNT1?

Yes. I mean it's a little early for us to go into a lot of detail on this. Obviously, the deal still needs to close. But in the U.S., there are around 2,500 patients that are diagnosed with KCNT1 epilepsy. And the prevalence, I think is similar outside of the U.S. as well. So clearly, this is an exciting global opportunity for Jazz. Testing in this space is reflexive already. It's done for the kids with epilepsy, they will get this test. I'm sure as we dig into this, there'll be opportunities for us to understand clearly how we can really leverage the rare disease capabilities that we have at Jazz with the patient support focus that we have, the support that we have and the connectivity with patient advocacy groups and the patient communities in general. But that's another reason why I think this is a really perfect fit for Jazz.

And then you mentioned genetic testing, like I know launch maybe is a year or 2 ahead. But maybe talk about the kind of infrastructure you have to build ahead of the potential launch in terms of like patient finding infrastructure or diagnosis and things like that? And is there a possibility to kind of improve the kind of diagnosis or awareness in that regard?

Yes. I think many of the areas that Jazz operates in now, obviously, with a rare disease focus, patient identification is a core capability and one that we've been investing in significantly. It's going to be relevant for Actio ABS-1230 as it is relevant for Modeyso and is relevant for Ziihera actually in GEA. So those kind of patient identification capabilities we're building, and we're leveraging right now, and we will certainly leverage that for this launch as well. Testing is a key part of that. And often, there is an opportunity to kind of improve the timeliness of the testing to enable that patients can access treatment early on. But these are all things that we will dig into as we get our hands on the asset fully and get closer to launch.

And maybe we can move to Xywav. Maybe talk about like the competition there. And you mentioned you haven't seen that much impact, like you are getting new patient starts. So maybe just talk high level of what you're seeing in the market?

For which brand, sorry.

Xywav.

Yes. For Xywav, we're very happy with the durability and the resilience of Xywav continues. Second quarter was another great quarter for Xywav, continued really strong growth, 13% growth, 525 net patient adds. As we started this year, there were many question marks around that, would we continue to be able to grow Xywav, and I think we've answered those questions. And I think that's all based around the differentiation that we've established in the minds of physicians and with patients on the importance of having that low-sodium option, which has withstood the pressure from the high-sodium generics, I think, really, really well. So I think we understand that aspect of the market much better now, and we're very confident in our position vis-a-vis the generics.

Obviously, as we look ahead, we have new competitors coming into the market with orexins as well that potentially provide a potent daytime alerting agent for patients, still some questions to be answered there around the dosing, the half-life, the impact on nighttime sleep. And we know that Xywav is an important agent for disrupted nighttime sleep. There's certainly scientifically and clinically a reason and we've heard from doctors how -- that they may be excited to use these, that they may see them as a complementary agents used together. Obviously, we don't yet know how these agents will be priced and whether payers will support combination therapy, but certainly from a scientific point of view, that seems possible.

We don't anticipate -- we have a really strong stable base of Xywav patients. We're not anticipating that those patients would be switched away from Xywav onto an orexin. But obviously, with a new option in the market, there could be some delay in the time that it takes for patients to maybe get to Xywav. So we may, in time, see some impact there on the pace with which we add patients on to the Xywav.

You just mean in the form of maybe broader step edits through generics?

Yes. Not necessarily through generics, but with the orexins on the market, could there be a delay in the time that it takes for a -- I mean, they already work through other daytime alerting agents today often. So with orexin, maybe they're working through an orexin, it maybe take longer to get Xywav, that could be one impact that we see.

Maybe frame how IH is a little subtly -- what the nuances of the opportunity there and the same idea with regard to competition?

Yes. So Xywav remains the only licensed product for idiopathic hypersomnia. And this is an area of business that we've seen particularly strong growth. If you look at the new patient adds over the last few quarters, roughly 2/3 of them have been coming from IH. So really still strong momentum there. And this is a market that is very large. There's, I believe, 37,000 patients diagnosed with IH, only 9,000 of them on treatment. So there's a lot of room for us to continue to drive growth within the IH segment.

The actual overall prevalent undiagnosed population could be significantly larger as well. So when you look at the kind of patient funnel, there's lots of opportunities for us to impact the numbers of patients that are diagnosed and the numbers of patients that get treated. And given the fact that we are the only -- still the only labeled option here, that gives us a lot to work with.

Maybe going back to your point on Xywav, kind of orexins and others might kind of delay the use of Xywav. Maybe talk about kind of the time it can take to get on Xywav? And what the -- what kind of payer sequencing that could create with like a commercial risk for Xywav? I mean, could there be like a possibility that other commercial products would delay, but it would be like a longer delay kind of for the patients to get on Xywav?

Yes. Well, I mean, even with the orexins coming on the market with the multisource generics, we believe that Xywav is going to continue to have a really important place in treatment for these patients. We know the importance of improving the sleep architecture, managing the disrupted nighttime sleep and really Xywav is a product that kind of does that exceptionally well. So with orexins coming into the market, it does give more options for that kind of daytime piece. And the time that it takes can vary significantly for patients as they move through on their patient journey towards Xywav.

So there could be an impact there on that patient journey as you insert orexin into that journey, which is what I was mentioning before. But we do believe that many patients ultimately will still need Xywav. And we know that when patients are established on Xywav, they do, do very well on the treatment. And we invest a lot in ensuring that patients are onboarded onto treatment well with our patient support programs and that they can maintain on treatment successfully for a long period of time.

Are you good on neuro?

Yes.

Okay. Yes. Maybe let's talk maybe bigger picture on BD. And I know, obviously, the Actio deal still have to close, but talk a little bit about the capacity, what the -- like therapeutic areas? Obviously, you're going to continue with the core verticals, but what opportunities are kind of you guys seeing? How should we think about the size and scale and maybe the appetite?

John, do you want to take that one?

Sure, happy to. Yes. So the focus is on rare in those verticals that we have expertise in, epilepsy, sleep, oncology. And if you look over the past 12 to 18 months, we've done several deals sort of in that category, which I think are good proxies for the kind of deals you could look for us to do going forward. So we did a deal with Saniona, early-stage epilepsy deal. We acquired Chimerix, which is how we brought the Modeyso asset into the company. We did a deal with AbCellera earlier this year for T cell engagers, and then we've just completed the Actio deal. So those are all the kinds of deals we've done, and we've got a very strong balance sheet. And so we've got the capacity to look for more deals in that category.

We'd also be open to looking in rare disease outside of our core areas of competency. If we do, do that, we're less likely to go early in development. We're going to want to make sure we're past proof-of-concept at least probably if we go outside those 3 earlier -- 3 core areas. And if we're doing more deals in those core areas, you can look for sort of a wider lens of early-stage, late-stage licensing acquisition, et cetera. But we're still very active. We're seeing a lot of substrate, especially in epilepsy and oncology, in particular. So you should expect to see more from Jazz.

Maybe a follow-up on that. You mentioned that your focus is on rare disease at this point. But with Ziihera now, at some point, you'll be in like breast cancer or colorectal cancer, which is not rare. But would that change your strategy in terms of like what kind of assets you would acquire in the future?

Yes, it's a great question. It's a very happy circumstance that we find ourselves in with Ziihera. And when we do -- if we do, in the future, find ourselves with an asset that has that broader potential, we're going to look to fully maximize it the way we are with Ziihera. So our focus is on rare disease assets, but if we do find ourselves with an asset that looks like it has some broader potential, we'll absolutely lean into that, whether it's ourselves developing it through partnerships, whatever makes the most sense for the asset.

And just as you think about deals from a sourcing perspective, is there -- obviously, there's been a big focus on Chinese assets, just given minimal upfront, but sort of a placeholder in the pipeline. Do you guys -- is there a mechanism or is there a geography that you guys would kind of tilt into? Or is it just related to the core indications?

I think the primary driver is, is it a good strategic fit for the company with our rare disease strategy. And then we look at like where is our commercial footprint. And Sam talked about some of the leverage we're going to get with the Actio product in terms of the existing infrastructure we have. So if there are overlays like that, that can be particularly attractive, but we don't have any limits in terms of geography or where we're looking. We're casting a wide net and looking for anything that would be a good strategic fit for us.

Okay. And last question, we've done this to a few companies, just sort of boilerplate kind of AI type of questions. So maybe talk about how that -- what sort of utilization has Jazz really done to deploy that? Are there efficiency gains, like looking through to maximize commercial? Like what are the kind of things that you guys have done?

Yes, maybe I'll start sort of at a company-wide level, and Sam can talk a little bit more about the commercial organization, but we're leaning very heavily into the opportunities that AI has to increase efficiency for our teams. So it's a tool that we are very active around. We have utilization goals at the company where we really want to make sure that we're getting the most out of what AI can offer us. And then within each functional area, whether it's finance, commercial, clinical, they are all specific use cases that we're leaning into. And Sam, maybe you can talk about the commercial organization in particular.

Yes. Well, we've made a very specific investment in this space, having set up a new part of our commercial organization, which is focused on the customer experience. And this is really important, particularly in rare disease, where we want to leverage data, leverage AI and the digital capabilities to make sure that we can identify patients really well, that we can use predictive algorithms to understand where they might show up and also where they might be at risk of dropping off treatment. Good example is with Xywav, where we know we're using AI and predictive algorithms to understand after a patient has been on treatment for a certain amount of time, we kind of know using these capabilities when they might be at risk of falling off treatment, and therefore, we can support them with our patient support programs to stay on treatment.

Similarly with Ziihera. It's a rare disease and the treatment in community is pretty fragmented. So we're using AI and data, and again, these -- to understand when and where patients are being diagnosed and then using our kind of systems and next best actions with the sales teams to ensure that we can support physicians to be there in those moments that matter. So there's a whole suite of capabilities that we're building that again enable us to give the best possible experience to customers that, in the end, is going to help drive good patient outcomes, too.

Thank you, guys.

Thank you.

Thanks.

Awesome. Thank you for joining us. My name is Mohit Bansal. I'm one of the biotech and pharma analysts here at Wells Fargo. And I'm joined by team Jazz today. Music, please. So I'm joined by Sam Pearce. She's the EVP and Chief Commercial Officer; and John Bluth, the Head IR of the company. Thank you very much for joining us today.

Thank you.

Thank you for having us very much, Mohit. And just a quick word to note that Sam and I will be making some forward-looking statements today. So please do refer to the risk factors in our securities filings. And if we do reference guidance, we're referencing guidance that we updated most recently on our last earnings update in early August and any reference to non-GAAP measures are also reconciled in those recent earnings.

Okay. Awesome. Thank you, John. So Sam, let's just talk about -- like just start with like the great things in the sales and marketing team have achieved in this year. I mean you have raised the guidance last quarter. Talk a little bit about the company, the setup and what do you think is going right with the company right now?

Yes. Thank you. Well, I mean, I think I'm, first and foremost, delighted with the way the teams are executing on the opportunities that we have across our entire portfolio at the moment. I think we've put together a run of really good commercial results recently, most recently, obviously, our second quarter earnings where we delivered our best ever quarter with $1.2 billion of revenue, and that represented 16% growth.

And I think what's really great about the results that we're seeing now is that, that growth is coming right across our portfolio. It's not isolated to one particular brand, but we're seeing really good growth right across all of our key brands. Double-digit growth from all of our key brands. I think the business has got really good strong foundations. I mean, Xywav has proven itself to be a really durable, resilient product, continuing to deliver excellent growth this quarter.

And now, of course, what we're also seeing is us really executing on some of the other launch opportunities that we've had recently, most recently, obviously, Modeyso. Modeyso was launched just about a year ago, really delivering exceptionally well. And we also had the launch of Zepzelca in the first-line maintenance market, which also delivered really fabulous growth last quarter. So I think as a team, we're proving our ability to really execute on these opportunities. And I think as a result of that and when you look at some of the new opportunities that we have coming, which I'm sure we'll talk about, we did, as you mentioned, raise -- have the confidence to raise our guidance for the full year.

And as we look ahead, we're very excited about Ziihera and the potential of Ziihera. Obviously, now we have the first-line metastatic GEA indication. And obviously, the data that we've seen there, the unprecedented overall survival benefit, we feel increasingly confident that Ziihera represents a new standard of care, and we're excited about executing that in the GEA indication, but then expanding our investment into other areas of opportunity for Ziihera. And we've got those exciting development plans that we can touch on as well in R&D across breast cancer, colorectal cancer, non-small cell lung cancer.

And on the webcast, when we talked about the GAE indication, we talked about the peak potential of Ziihera now increasing to between $3 billion to $5 billion. So I think an awful lot for us to be excited about with Ziihera, a lot also for us excited to be about for epilepsy as well and continuing the growth trajectory there. With our label indications, we do continue to see good growth opportunity, but we're also making some targeted investments in expanding the reach of Epidiolex to other patients with epilepsy. So I think the business is in good shape, and I think we're executing on the strategy that Renee set out at JPMorgan at the beginning of this year really well.

Got it. And like this is amazing. So Xywav has surprised us all in terms of 3 years ago, we were modeling a decline for Xywav, and we have not seen that yet. So can you paint the picture for us in the marketplace, like how between Xyrem authorized generic and generics now on the market, how it is impacting the volume price and then you have IH as well.

So there are many complications there. But can you help us paint a picture which is helping you here?

Yes. As we entered this year, I think there were question marks how resilient and durable would Xywav be in the face of high sodium generics coming into the market. I think we've answered that question to a large part as we sit in the middle of the year. We haven't really seen any material impacts from those generics coming into the market. The demand remains really strong.

I mean you saw in the second quarter of the year, the net patient adds, 525 net patient adds. So we're continuing to add new patients to Xywav. I think our teams have done a really great job really communicating the differential benefits of Xywav, low sodium oxybate continues to resonate strongly. We know that the majority of patients, 80% or more patients with narcolepsy and IH have comorbidities, cardiovascular and cardiometabolic comorbidities. So offering them a low-sodium option continues to be really, really important. So as we sit in the middle of the year, I think we feel increasingly confident about the durability of Xywav.

Obviously, there are new entrants coming into the market as well, orexin. But from everything that we understand about this market and the feedback that we're having from health care providers, we do believe that oxybate and Xywav in particular, will continue to play a really important part of treatment for narcolepsy and IH patients.

Got it. So durability of the franchise is still a little bit of question even before orexins come along. So between like how much growth in the IH market is still there? Because like most of the competition is on the narcolepsy side, not so much on IH side. Even with orexin, it is a subset of narcolepsy for now, not the entire narcolepsy either. So what are the puts and takes for this growth to be durable or this franchise to be durable for the next few years here?

Yes. So we have some new entrants with orexin. And as you mentioned, they'll be entering the market with -- in the NT1 indication, which is less than half of the overall narcolepsy space. Irrespective of that, I think obviously, the orexins do represent a new potent daytime alerting agent, and oxybates act on the kind of disruptive nighttime sleep. So looking at the science behind this, you can certainly see how these 2 drugs could be complementary.

We'll have to see how that plays out in practice, of course, with payers. But we are very confident that Xywav will continue to have a place in treatment. And from what we understand and the way health care providers are thinking about this is that they will not be considering from what we understand that the stable base of Xywav patients will be switched away from Xywav. What we may see is that it takes longer for patients to get to Xywav if they're trying the orexin first. But we don't see this business being dramatically disrupted in a significant way.

Got it. Very helpful. And then like how much growth is left in IH here?

Yes. So I mean there are estimates that say the overall prevalent patient population is very, very large, very similar to narcolepsy, maybe 100,000 patients. We know there's a...

Some doctors even said it is not even a rare disease basically.

Well, yes, exactly. Diagnosed patients around about 37,000. And we see treated patients maybe 9,000. So there's still significant opportunity for Xywav to grow into the full potential opportunity within the IH segment. And even with potential new agents coming into the market, we would probably see the market continue to grow quite significantly.

Got it. Very helpful. Moving to Epidiolex. I mean, even that franchise delivered a strong volume growth in the quarter. Now again, same way. Can you help us understand where you are finding this new growth?

And then also, I mean, this market has -- like the growth in the last few years was a little bit slower. So like what are you seeing now? And then how much of this growth is sustainable going forward?

Yes. Yes, really healthy growth in the second quarter, $292 million, 16% revenue growth, [ 14% ] volume growth. So we're really very pleased to see that. Epidiolex, when it was launched, it was launched as a pediatric drug, and we've seen really good strong penetration in that segment.

More recently, we've been focused on bringing Epidiolex to adult patients, and there's a very sizable opportunity there in the adult patient segment. That segment is more fragmented than the pediatric segment, but that's where we are seeing quite a significant amount of our growth, and there continues to remain significant headroom for us to grow there. In addition, we've been investing quite a bit in ensuring that patients can stay on treatment for longer. So we have a JazzCares support, patient support around that to onboard patients on to JazzCares and really support them to make sure that they can get the optimal duration.

In addition, we mentioned on our call that we have submitted an NDA for the novel capsule formulation. Again, that formulation is going to be particularly beneficial for adults because this is a weight-based drug. So adults can end up taking quite a large volume of the oral solution, which is sesame oil-based. That can limit the uptake in the adult segment. With the capsule formulation, we believe that addresses that issue. And so we do expect the capsule formulation to expand the overall patient pool that will be taking Epidiolex.

Looking ahead, more strategically, we've made some really important investments in some clinical development programs to expand the use of Epidiolex into -- we've got a Phase III DEE study ongoing, a Phase II/III study in juvenile myoclonic epilepsy an additional study in adult LGS as well as an earlier study in focal onset seizures. So when we recognize that we had a longer runway with Epidiolex and we did the ANDA settlement, out to the late 2030s, it really did open up the opportunity for us to make these additional investments. And we feel very optimistic about the ability for us to really continue to demonstrate good strong growth momentum for Epidiolex over the longer term.

Got it. Really makes sense. So now moving to the most anticipated launch of the year, Ziihera in GEA. So early days so far, but I mean, with this first-line launch, I mean, the label that you wanted and all that, how should we think about the launch curve here?

The product is already on the market, so doctors know about this and all that. You have all the infrastructure in place. But talk a little bit about like how should we think about the launch here? And are there any bottlenecks in terms of like some check boxes that need to be ticked before it takes off? Like is there anything like that?

Yes. Yes, we are very excited, obviously, about the GEA opportunity for Ziihera. We're excited about the label that we have. The fact that we see that unprecedented overall survival benefit more than 2 years for both the triplet and the doublet regimen and the fact that with the triplet, that triplet regimen can be used irrespective of PD-L1 status.

So this really is a fabulous opportunity for us to make a meaningful difference for these patients. I think the fact that we've been out there in the market with Ziihera with the BTC indication is very, very helpful for our launch uptake. We sized our sales teams with the GEA launch in mind. So they've already been out there developing the relationships. Physicians, there's a high degree of overlap, 90% overlap of prescribers.

So many of them will have had experience with Ziihera already. This drug is going to be -- it's important -- it's going to be important for us to make a quick start, not only in the academic centers, but also in those community centers as well. And I think the fact that we do have the permanent J-code in place already, then we should see -- we're not anticipating a lot of payer friction. We anticipate that patient access will be very much there from the beginning.

And therefore, our ambition will be to really drive uptake rapidly and get to peak sales as quickly as we possibly can, really just reflecting the fantastic data that we have and the fact that this product is going to make a very, very significant impact for patients with this devastating diagnosis.

Is it a largely Medicare patient population? Or is it a mix?

Yes. It's more of a mix. I don't know whether we've got those kind of numbers to hand exactly.

Not exactly.

But yes, it's a significant commercial opportunity in this space.

Got it. And then I had a question about OS interim and then we have already seen -- like not seen the full data, but congrats on the success of both doublet and triplet now. When can we expect to see the detailed data from the -- for the OS for the doublet as well? So we already press released it, but again, the detailed data when we can see.

You're asking about the top line readout and OS. Yes. So we reported that we hit that. And you will expect to see it at a future medical meeting, but we haven't shared with you.

Got it. Got it. Understood. So have you gone into details about the $3 billion to $5 billion? How much of this is like in each individual indications versus like -- because is it just GEA? Or is it like even breast cancer, you see a higher opportunity there?

Yes. So a few years ago, when we initially looked at the potential with Ziihera, we did talk about it being a $2 billion-plus opportunity. I think now with the data in hand and with the clinical development plan that we've initiated, we feel confident to raise that peak revenue expectation to $3 billion to $5 billion.

Previously, when we talked about the $2 billion, that was including the BTC opportunity, the first-line GA opportunity as well as the metastatic breast cancer and the pan tumor. Today, we're also now including our expectations within colorectal cancer and non-small cell lung cancer as well as early breast cancer. So together, with the data that we have and we see the unprecedented survival benefit in GEA and just thinking what that can mean for other HER2-expressing tumors, we feel confident to increase the peak revenue to the $3 billion to $5 billion range that we spoke about.

And correct me if I'm wrong, John, I mean, you have a basket trial also going on in multiple...

Pan-tumor trial, yes.

Pan-tumor trial. Is there any thoughts on time lines there? Like when could we see data there?

No, it's enrolling and enrolling nicely, but we haven't provided readout timing specifically.

Got it. That will be an interesting trial to see the data come out. Awesome. I also want to pick up on Modeyso a little bit. I feel like you are already exceeding your expectations that you set out, like $500 million, but in second line alone, you are at a $200 million plus run rate at this point. So are you saturated with second line or like $500 million, if I understand correctly, it was second line plus first line, right? So like where is the next leg of growth there? And what are people underestimating that?

Yes. We're very, very pleased with the execution behind the Modeyso launch. It's about a year now since we launched last August. Q2, $48 million. So as you say, we're already annualizing at $200 million with more than 600 patients having been treated with Modeyso. So that does -- it kind of reinforces our belief around the $500 million peak sales opportunity in the U.S. That does include first line as well. So that's -- what we do continue to believe that we can grow Modeyso with the label that we have today.

There's still the opportunity for us to improve testing rates in this space. and also improve the timeliness with which patients are referred to academic centers of excellence. So there's still work for us to do there. But we're excited about the ACTION study that will read out in the first half of 2027. And that gives the opportunity for patients to receive Modeyso immediately after radiotherapy as opposed to waiting until those patients have progressed.

That will mean, I think, more patients being eligible because in that time period, unfortunately, some patients may no longer be eligible as well as improving the duration of treatment for patients on Modeyso. So that inflection point, we're excited about, and we believe that's going to be an important to get to the $500 million peak.

And have you exhausted the market in second line yet? Or is there still some?

No, I think there are still -- we're still seeing growth there. we're still enrolling patients on to treatment and getting them converted on to active treatment. And as I mentioned, there is still the opportunity for us to improve testing rates. NCCN recently approved liquid biopsy in this space, so that will help because there are some patients that it's difficult to do a definitive biopsy -- physical biopsy. So there are areas for us to work on that will ensure more and more patients can benefit from this treatment.

Got it. Very helpful. So talk about Zepzelca as well a little bit. I mean, so now you have the first-line maintenance label as well. So how should we think about the net effect? Because as you go more into first line and as you say in second line will decline, but again, the duration will help in the first line. So help us understand like the net growth, how should we see Zepzelca from going forward at this point?

Yes. And we have been seeing over time, that second-line business taper down as we experience increased competition in that second-line segment for a while now. I mean it's almost a year since we launched in the first-line maintenance segment. And since that time, our focus has been 100% commercially on first line. That's where we believe patients will get the most benefit from Zepzelca with longer duration of treatment and in combination with atezolizumab.

So our focus has been there. The launch has been very successful. Around 30% to 40% of our overall revenue in the second quarter was coming from the first-line maintenance segment. So we will continue to focus on growing that part of our business. And at the same time, we do anticipate seeing the second-line business taper away.

Obviously, as we look ahead, the first-line segment will also become a little bit more competitive with the entrance of new competitors in that space. But we do believe Zepzelca offers something uniquely different for patients. And it's particularly appreciated in the community setting where they want something that is kind of easier to use without the monitoring, et cetera. So we will continue to kind of focus our promotional efforts there.

Got it. Very helpful. So then let's just talk about the Actio acquisition as well a little bit here. So can you give us some color on like what gives you confidence that -- confidence in the 1230 assets? And where do you see the opportunity for this product in the rare epilepsy population basically, right? So like it's complementary for sure with your epilepsy franchise, but what attracted you towards this asset here?

Yes. Well, we're very excited about this acquisition. I mean, I think when Renee described our strategy at JPMorgan at the beginning of the year, when we talked about our rare disease focus and really focusing on finding opportunities in our areas of expertise, of which epilepsy is absolutely one of them, but also looking for opportunities that kind of address a really significant unmet medical need where we can make a meaningful difference in that rare disease space, then Actio falls very much in that area.

And of course, we're excited about it, not only obviously, we've done the due diligence around what we think this drug can do for patients. But obviously, we're able to leverage there our epilepsy expertise as well as leverage our rare disease expertise. And of course, there is significant commercial synergies as we think about bringing this product to market in the future. So yes, extremely excited. I think it's exactly what we were talking about when we talked about a rare disease strategy. But John.

No, I'd just add maybe, Mohit, that the clinical data that we did see as we reviewed the due diligence for the transaction was very exciting to us. We saw meaningful improvements in the patients who were receiving this drug. So we're very excited about the potential for it to have a transformative impact for patients who are suffering from a devastating disease. So as we get through the closing of the transaction with Actio, the Jazz team will step in and drive the program forward and then look for opportunities down the road to present additional data at medical conferences.

Helpful. I mean you have also talked about investing in the commercial infrastructure for Actio as well. So like what kind of synergies do you have with Epidiolex here versus like versus building up something new with this as well?

We believe there will be very significant commercial synergies in the space. We've built real expertise in this area. We have the #1 kind of branded antiseizure medication in Epidiolex. And this new opportunity, obviously, is for a different segment of patients, the KCNT1 epilepsy. But we will be -- it will be something that has the same call point with pediatric epileptologists. So the overlaps are very significant. We haven't really got into whether -- what additional commercial investments we might want to make. But for sure, there are very significant commercial synergies.

Got it. Very, very helpful. Then, I mean, obviously, we used to have a lot more questions for Jazz on BD side, not as much I mean now that you have -- the pipeline is really vibrant. But as a customary question. So how is the company thinking about further BD transactions this year, next year? And what is the core principle behind our core thought process behind if you do any BD, like what would you be looking at?

Yes. It's really a focus on rare disease. Sam described some of those guiding principles that Renee outlined at the beginning of the year. So looking at those areas of rare disease where we have that existing competency in epilepsy and sleep and oncology. And if you look over the past 12 to 18 months, that's exactly where you've seen us do business development.

You saw us bring in the Modeyso asset with the acquisition of Chimerix. You saw us bring in Saniona to acquire Saniona in some early epilepsy opportunities. You've seen us acquire AbCellera, do a deal with AbCellera in the oncology space and now most recently with Actio in the epilepsy space. So I think you should look for Jazz to continue to be active in business development focused in those rare areas and looking outside of our current core competencies in rare disease, we're also looking there. I think if we are to look in rare outside the existing areas of core competency, we're probably less likely to go very early. We're more likely to be looking sort of at proof of concept or later.

And if we're looking in the areas where we have the existing expertise, we're a little more wide open. We're open to doing earlier transactions and also looking closer to commercial. But we've got a very strong balance sheet and a very strong team in place running business development, and we're very focused on finding more and more, and we're very disciplined. So look for more from us going forward.

You are a massive company in oncology as well at this point, right? So you have 2 core competencies at this point. One question, Sam, I get a lot is between generic oxybate versus orexins, which one do you think is the bigger -- like which one -- which competition is the bigger competitor for you right now?

Between the generics.

Oxybates versus orexin.

Orexins, yes, very different prospects. I mean I think as we looked at the beginning of this year to the entry of the generics, I think we felt quite confident in our differentiation. I mean I think low sodium oxybate is a very significant and important differentiating feature versus the generics. So -- and that played out in reality. I mean that's what we're seeing now is that physicians are reluctant to want to put their patients onto a high-sodium generic when they have a low sodium available.

I think with orexins, it's a different question. It's more of a clinical question around how can we optimize treatment for these patients for whom the condition is very debilitating. I think there is the opportunity for us to think about these 2 treatments as complementary as we talked about before. I think there's still a lot for us to understand about how that will play out. We see in the data that these are potent daytime alerting agents, but also that there are question marks around the dose, the half-life insomnia. And we also know that when patients get good quality nighttime sleep, then that has a positive impact on their daytime performance. So it's a difficult question to answer. I think the 2 competitors are quite different propositions. But I think overall, what I would say is that we feel confident that Xywav will continue to be an important treatment for patients with narcolepsy and idiopathic hypersomnia.

Got it. Understood. One last question for both of you. So fast forward 1 year, I hope you are here at Wells Fargo 2027 conference. What -- at that conference, what would make you look back at the year and say it was a great year for us?

Yes. Well, I mean, I'm responsible for commercial. So obviously, I'm going to be very focused on continuing to drive the momentum that we've seen over the last few quarters over a kind of sustained period. But I think beyond that, obviously, we're going to be looking to the way that we've executed the GEA launch. I think this is such an important launch for Jazz. It's such an important launch for patients.

There's a strong promise with Ziihera. And I think our ability to demonstrate that not only does the data show that Ziihera is a new HER2 agent of choice, but we can actually execute on that and bring that to life for patients in the real world. So a year from now, yes, I definitely want to be looking back and seeing that we've delivered a standout launch, and we've realized the potential that this asset offers us in GEA, and that will just give us even more confidence to do the same in other HER2-expressing cancers.

Yes. And I'd add 2 things probably. The continued breadth of the execution. And I think if we're sitting here next year and continue to see the strength we're seeing across our franchises, I think that's been a real area of strength for Jazz in 2026 thus far. And then continued innovation. I think we're seeing more and more innovation from the company, both from our own programs that we're starting to put into the clinic and some of these assets that we're bringing on board through business development. So I think you're going to just continue to see more innovation layer up throughout the pipeline.

Okay. Awesome. On that high note, thank you very much for joining us today, and all the best.

Thanks for having us.

Thank you for having us.

Good day, and thank you for standing by. Welcome to the Ziihera GEA Investor Webcast Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the call over to your speaker for today, Rob -- John Bluth, Head of Investor Relations. Please go ahead.

Thank you, operator, and thank you all for joining us. We're excited to discuss the FDA approval in U.S. commercial launch of Ziihera in first-line HER2-positive metastatic gastroesophageal adenocarcinoma, or GEA.

The slide presentation accompanying this webcastis available on the Investors section of our website, and you can also reference the press release we issued regarding the FDA approval of Ziihera. Also on our website, you can find a link to the approved label.

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 the statements contained in our slide deck and the risks and uncertainties described in our SEC filings. We undertake no duty or obligation to update our forward-looking statements.

Joining the call today are Dr. Rob Iannone, Global Head of R&D and Chief Medical Officer, who will discuss the approved label, Chumi Khurana, Head of our Oncology franchise; and Sam Pearce, our Chief Commercial Officer, will discuss our commercial launch strategy. Then we'll open up the call for Q&A.

The approval of Ziihera is a pivotal moment for Jazz and represents a paradigm shift for the treatment of first-line HER2 metastatic GEA. This approval is a powerful demonstration of our corporate strategy in action as we continue to transform Jazz into a highly innovative rare disease focused biopharmaceutical company. Ziihera demonstrated an unprecedented survival benefit with median overall survival surpassing 2 years and is the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor in chemotherapy approved for all HER2-positive advanced GEA patients regardless of PD-L1 status. These results give us high conviction that the Ziihera combination is positioned to significantly improve outcomes and be established as the new standard of care for this patient population. Importantly, the approval marks a major step forward in establishing Ziihera as a multibillion-dollar foundational asset in our oncology portfolio, backed by robust clinical data and our plans to expand the zanidatamab development program, we are updating our view of Ziihera peak sales potential to a range of $3 billion to $5 billion. This updated range reflects our confidence in Ziihera's clinical profile, its potential as a foundational therapy across multiple HER2-expressing tumors and supports our plans to expand zanidatamab's development into new tumor areas.

With that, I'll turn the call over to Rob to discuss the approved the Ziihera label and the meaningful impact we believe that Ziihera can have for patients with GEA.

I'll begin on Slide 7. The FDA approval of Ziihera represents a transformative shift in treatment options for patients with GEA and their families who now have access to a therapy delivers a median overall survival of more than 26 months when combined with tislelizumab and chemotherapy. These data from the HERIZON-GEA-01 trial demonstrates the remarkable advance in patient care and survival benefit that Ziihera provides. It's based on these clinical outcomes, along with the FDA approval that we believe every eligible HER2-positive first-line metastatic GEA patient should receive Ziihera in combination with chemotherapy plus a PD-1 inhibitor regardless of PD-L1 tumor status.

These are the outcomes that drive our motivation and dedication at Jazz.

I will now quickly speak to the label and supporting data. Ziihera is indicated irrespective of tumor PD-L1 status in combination with tislelizumab and fluoropyrimidine and platinum-containing chemotherapy as first-line treatment of adult patients with unresectable locally advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma for patients with either IHC 3+ or IHC 2+ and ISH+ and ISH-positive disease as detected by an FDA-authorized test.

In addition, Ziihera is indicated with fluoropyrimidine and platinum-containing chemotherapy. For patients with HER2-positive IHC3+ disease as first-line treatment of adult patients with unresectable, locally advanced or metastatic GEA as detected by an FDA-authorized test. Ziihera is administered as an IV infusion in combination with chemotherapy, with or without tislelizumab. Dosing is weight-based, with patients weighing less than 70 milligrams receiving 1,800 milligrams of Ziihera every 3 weeks or 1,200 milligrams every 2 weeks. Patients weighing 70 kilograms or greater will receive 2,400 milligrams on Ziihera every 3 weeks or 1,600 milligrams every 2 weeks. The optionality of Q2-week dosing aligns to FOLFOX administration as the flexibility allows for physicians to choose the best chemotherapy for their patients.

The efficacy results from the Phase III HERIZON-GEA trial that appear in the label are outlined on Slides 8 and 9. Both investigational treatment arms containing Ziihera 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 with the trastuzumab control arm. Likewise, both combinations containing Ziihera exceeded 2 years of median overall survival, setting a new benchmark for survival in this disease.

The Ziihera plus tislelizumab and chemotherapy arm demonstrated a clinically meaningful and statistically significant improvement in OS with more than 7 months improvement in the median OS, reaching 26.4 months and a 28% reduction in the risk of death versus the trastuzumab control arm. Nearly 40% of patients treated with the triplet regimen were estimated to be alive after 3 years. Again, the benefit was observed irrespective of tumor PD-L1 status. In the intention-to-treat population and as published in the New England Journal of Medicine, Ziihera plus chemotherapy showed a clinically meaningful survival benefit with a median OS of over 2 years, a strong trend towards statistical significance at the time of the first OS interim analysis. The top line results from the second interim overall survival analysis from the HERIZON-GEA-01 trial doublet regimen are expected this quarter.

As outlined in the label, the subgroup of patients treated with Ziihera plus chemotherapy whose tumors were IHC 3+ for HER2 showed a median overall survival of 25.5 months, and a hazard ratio of 0.74, with an upper bound of the 95% confidence interval that did not cross 1. We are very pleased with the approved label and we believe the unprecedented benefit supports the use of Ziihera as the new HER2-targeted agent of choice in HER2-positive first-line metastatic GEA. And we expect that Ziihera in combination of tislelizumab and chemotherapy will become the new standard of care for these patients, irrespective of PD-L1 tumor status.

Turning to Slide 10. I'll review the important safety information. Ziihera has a boxed warning for diarrhea and embryo-fetal toxicity. Ziihera in combination with fluoropyrimidine and platinum-containing chemotherapy with or without tislelizumab can cause severe diarrhea, including life-threatening cases. Physicians should prescribe antidiarrheal prophylaxis during the first cycle when Ziihera is given in combination with these drugs and supportive measures should be implemented during treatment as clinically indicated. For modifying the dose of Ziihera, it is recommended to evaluate, modify or discontinue drugs contributing to diarrhea in accordance with their respective prescribing information. Treatment-related diarrhea that led to Ziihera discontinuation in the HERIZON-GEA-01 clinical trial was uncommon, occurring in less than 5% of patients across both experimental arms. Based on clinical trial experience and input from treating physicians and patients, we view these AEs as manageable with prophylaxis and active management considering the significant antitumor and survival benefits of Ziihera.

In addition, physicians have the option to use FOLFOX in combination with Ziihera, a chemotherapy regimen more widely used in the United States relative to CAPOX, which was primarily chosen as the chemotherapy backbone in the HERIZON clinical trial.

Other warnings and precautions related to Ziihera administration include left ventricular dysfunction and infusion-related reactions. The most common AEs with Ziihera in combination with tislelizumab in chemotherapy were diarrhea, nausea, decreased appetite, hypokalemia, vomiting, fatigue, peripheral neuropathy, rash, and infusion-related reactions. The most common adverse reactions with Ziihera in combination with chemotherapy or diarrhea, nausea, vomiting, peripheral neuropathy, decreased appetite, fatigue, hypokalemia, infusion-related reactions and rash.

I'll cover zanidatamab's unique mechanism of action on Slide 11, which gives us conviction to expand our development program into areas where we think zanidatamab can outperform historical benchmarks for HER2-targeted agents. As described in the Nature publication illustrating zanidatamab's mechanism of action, we believe its design is fundamentally different from other HER2 antibodies. By binding 2 distinct sites on the HER2 receptor simultaneously, zanidatamab cross-links neighboring HER2 proteins, leading to receptor clustering. The unique geometry and binding effectively blocks HER2-dependent cancer growth signaling. Additionally, zanidatamab activates the immune system to attack the tumor, including activation of ADCC, ADCP and CDC. We believe complement cascade activation is unique to zanidatamab among HER2-targeted therapies. Subgroup data from the HERIZON-GEA trial presented at ASCO shows PFS and OS benefits were consistent in patients across PD-L1 positive and PD-L1 negative disease. We believe the complement and other immune activation induced by zanidatamab further enhances the efficacy of immunotherapy and explains the efficacy we see irrespective of PD-L1 status. We believe the combination of its unique mechanism of action, along with impressive clinical efficacy and a manageable safety profile for this molecule to date are supportive of investing further in zanidatamab. Sam will discuss our expanded view on the value zanidatamab may offer to HER2-expressing cancer patients later in the call.

I'll now turn the call to Chumi for a discussion of our commercialization plans.

Thanks, Rob. The FDA approval of Ziihera is a landmark achievement and our team is ready to deliver this transformative therapy for GEA patients. I will start by outlining the significant unmet need for GEA patients on Slide 13. GEA, which includes cancers of the stomach, gastroesophageal junction and esophagus junction and esophagus is the fifth most common cancer worldwide. Almost all GEA patients, about 90% are symptomatic and usually present to a primary care provider or in the ER with complaints such as difficulty swallowing, painful swallowing, unexplained weight loss, blood in cough or abdominal pain. Because the vast majority of GEA patients are diagnosed at an advanced stage, immediate intervention is critical. Approximately 20% of patients are diagnosed with HER2-positive disease, which translates to an annual incidence of about 8,000 cases in the U.S. HER2-positive GEA is associated with high morbidity and mortality, and there remains a high unmet need for new treatment options. The overall prognosis for patients with GEA remains poor with a 5-year survival rate of less than 10% for metastatic GEA. This combination of high morbidity, mortality, poor prognosis and limited first-line treatment options underscore the urgent need for new therapies for these patients. The annual incidence of 8,000 HER2-positive GEA cases translates to a highly defined treatable patient population. When we look to patients who have unresectable disease, those who are eligible to receive treatment in the first line and those who received HER2 testing reach a market of 3,000 to 4,000 patients on an annual basis who are excellent candidates to receive Ziihera.

Our commercial investment strategy is focused on patient identification and GEA, ensuring no patient is left behind.

On Slide 14, I will highlight how we expect the treatment paradigm to evolve beyond legacy standards of care and we shape the management of HER2-positive GEA. For more than a decade, trastuzumab-based therapy has been a foundation of treatment for HER2-positive GEA and Ziihera represents a meaningful advance for these patients. In prior standards of care, which are shown on the left side of the slide, patients would need to be tested for PD-L1 status. Those who tested positive for PD-L1 were eligible for the newer regimen known as KEYNOTE-811, which added an IO to the ToGA regimen. While patients who tested negative for PD-L1 will continue to receive the trastuzumab-based ToGA regimen. Now with Ziihera, once patients have confirmed HER2-positivity, the treating physician is able to begin treatment with the HERIZON regimen without testing for patients PD-L1 status and without delay. Given the unprecedented survival outcome based seen from the HERIZON-GEA trial, we expect the Ziihera IO chemotherapy regimen to rapidly become the preferred clinical choice for eligible HER2-positive GEA patient.

Moving to Slide 15. Our launch strategy is built on rapid execution and operational leverage designed to swiftly establish Ziihera as a definitive HER2-targeted backbone. Critically, our success in BTC serves as a powerful commercial foundation for our next major growth phase in GEA. Because there is a significant direct overlap between existing BTC and GEA treating accounts, our commercial infrastructure is fully primed and highly optimized. With over 90% target physician overlap, our team will rapidly generate clinician excitement and demand. This enthusiasm is in rooted in zanidatamab exceptional clinical data, specifically an unprecedented median overall survival exceeding 2 years. Due to the high overlap across our solid tumor accounts, our field force has already established relationships with the highest volume prescribers. Our team is rightsized to capture the larger GEA market without requiring commercial expansion. The key component of our launch strategy leverage JazzCares' strength as a rare disease company, including identifying specific patient populations and building a precise commercial infrastructure to serve them. Our launch model is based on the blue print for how Jazz successfully commercializes therapies for rare and complex diseases. The key component of Ziihera launch is identifying the right patient at the right time to accelerate adoption of Ziihera. The HER2 testing infrastructure is already mature with 80% to 90% of patients undergoing biomarker testing at diagnosis, anywhere from 60% to 80% of HER2-positive patients go on to receive a HER2-targeted therapy depending on where the patient is being treated. While academic centers lead in adopting biomarker-driven therapies, we are actively closing this gap in the community setting.

Our launch in second-line BTC established a foundation for us to rapidly increase our presence in the community account and accelerate Ziihera adoption in GEA. We're executing our high-touch commercial model across academic and community networks, deploying specialized care educators and dedicated support systems to ensure seamless treatment initiation and long-term patient adherence.

To complement direct engagement, our nonpersonal promotion and digital campaign will increase awareness of Ziihera as a new treatment option. To support immediate clinical adoption at launch, we have submitted this data to key oncology pathways. Ordering is available for customers through leveraging our established permanent J-code and is also backed by our robust JazzCares patient support program. Rounding up the foundational component of our strategy is an emphasis on creating exceptional patient initiation and treatment experiences, which I will describe on the next slide.

We have made strategic investments that support sustained patient adherence to treatment, including the Nurse Educator Program and Patient Starter Kits. Details on these programs are outlined on Slide 16. The Nurse Educator Program is comprised of oncology-certified nurses who provide peer-to-peer proactive education on dosing and administration of Ziihera. The Patient Starter Kit includes educational resources around adverse event management with common over-the-counter loperamide. By supporting education around long-term adherence, we can help patients achieve the best possible outcomes. These materials were developed with feedback from patients, caregivers and advocacy groups and are designed to improve patient safety, comprehension and satisfaction. We remain committed to empowering patients and caregivers through every step of the treatment journey and are so excited to bring a therapy with such dramatic survival improvement to them.

I'll now turn the call over to Sam to review the commercial opportunity for Ziihera.

Thank you, Chumi. This approval is transformational for patients with HER2-positive GEA and marks an important inflection point for Ziihera. With approvals now in both BTC and GEA, Ziihera has evolved from a promising pipeline asset into a commercially launched medicine with the potential to become a foundational HER2-targeted treatment across multiple tumor types. Our previous $2 billion-plus peak sales potential was based on the foundational indications of first-line and second-line BTC, first-line metastatic GEA, metastatic breast cancer and our pan-tumor program. We worked diligently over the last 2 years to launch the registrational clinical trial that you can see outlined on Slide 18. One of the most exciting areas is breast cancer, the largest HER2-positive solid tumor market. We believe zanidatamab has the potential to play an important role following progression on Enhertu. We're evaluating this opportunity in our ongoing EmpowHER-303 trial, which we expect top line data from late next year or early 2028. At the same time, we are actively expanding our ambitions into earlier-stage breast cancer, where the opportunity is substantially larger through the EmpowHER breast cancer 208 trial, which was initiated over a year ago and the I-SPY program. We're also actively engaged in combination strategies that could further enhance the value of zanidatamab. These include collaborations such as our ongoing study with zongertinib Boehringer Ingelheim, zongertinib as well as continued development in our registrational pan-tumor program across multiple HER2-expressing cancers. With the zanidatamab clinical development program well underway, the question is, where will we take zanidatamab next to unlock its full potential, which I'll cover next on Slide 19. We have greater confidence in the molecule's ability to deliver meaningful outcomes across a much broader set of HER2-driven cancers, including earlier lines of therapy and larger tumor types. The HERIZON-GEA results significantly strengthen our conviction in zanidatamab's potential. Demonstrating unprecedented survival outcomes in a large Phase III randomized clinical trial provides important validation of both the molecule and its underlying biology, reducing development risk as we expand the program. Based on the strength of the HERIZON-GEA data and the growing body of evidence supporting zanidatamab's unique mechanism of action, we're increasing our peak sales expectation for Ziihera to $3 billion to $5 billion, up from our prior estimate of $2 billion-plus. Beyond breast cancer, we are advancing registrational opportunities in colorectal cancer and evaluating potential pathways in non-small cell lung cancer. Early clinical data have been highly encouraging, and we look forward to progressing the program. Taken together, we believe Ziihera has the potential to become a foundational HER2-directed therapy across multiple tumor types. Our updated peak sales range reflects both the progress we've made and the significant long-term opportunity we see ahead as we continue to expand the clinical and commercial potential of this asset.

I'll conclude on Slide 21. As we look ahead to the next decade and beyond, we see significant opportunity for growth driven by Ziihera's potential to redefine what is possible across HER2-expressing cancers. The approval of Ziihera in GEA proves our ability to identify, develop and bring highly differentiated, high-value assets to market, driving both clinical progress and long-term shareholder value. In addition, it's a validation of our vision to build a leading biotechnology company focused on innovative life-changing medicines for rare diseases. As we expand the zanidatamab development program, we will explore both Jazz-sponsored and collaborative clinical trials to realize the full potential of this unique medicine. We are laser-focused on delivering a strong launch in GEA and realizing the increased Ziihera peak sales opportunity of $3 billion to $5 billion through continued data generation, thoughtful global expansion and disciplined commercial execution. I'd like to take a moment to acknowledge and thank the patients, physicians, caregivers and Jazz team members for their commitment and dedication to bring Ziihera to this point. It's been an incredible effort over many years to reach FDA approval for GEA patients. And with that, I'll turn the call back to the operator to begin the Q&A session.

[Operator Instructions] Our first question today is coming from the line of Jessica Fye of JPMorgan.

Congrats on the approval. I'm curious, of the new $3 billion to $5 billion peak projection for Ziihera, how much of that is accounted for by BTC and GEA? And how much of that is from additional indications? And then if I can ask for forgiveness in advance on asking a second question. Can you talk about how you get to that 3,000 to 4,000 eligible frontline patients in the U.S. for zani? What cuts do you take to get to that number?

Jess, it's Sam. Thanks for your question. Yes, obviously, over the last couple of years, we've learned a lot about the potential for Ziihera, and we're very excited now with the approval of GEA to upgrade our peak potential for Ziihera to the $3 billion to $5 billion. As you may recall, the original estimate of $2 billion-plus included both first-line BTC, the GEA approval as well as the metastatic breast cancer and pan-tumor. The new $3 billion to $5 billion range, obviously goes beyond that now with the approval of GEA. We're excited about taking Ziihera into other HER2-expressing cancers, such as colorectal cancer, non-small cell cancer, early-stage GEA and early breast cancer. Whilst not providing a split between those indications that makes up the $3 billion to $5 billion peak, what I can say is that the GEA -- BTC and GEA are a significant contributor to that. And we're obviously now with the label, we're really excited to get going in GEA and start to deliver on the potential there.

Just to the second part of your question, we've obviously talked about the 8,000 patients before. Now as we look at the FDA-approved label, we're able to provide more specificity on what the exact kind of addressable patient population is of those 8,000. And to get to the 3,000 to 4,000, we're obviously looking at the unresectable disease patient population as well as those that are eligible to receive treatment in the first-line setting and those who receive HER2 testing. So from that, we go from the 8,000 to the 3,000 to 4,000.

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

Anything on the label that was a surprise to you? The commentary around the diarrhea, probably not. What about the IHC 3+ doublet kind of restriction? Anything there or that commentary?

Marc, this is Rob. Thanks for your question. To me, the label was very, very favorable. We're really pleased to have approval of zanidatamab is now the preferred regimen for HER2 GEA approval with tislelizumab and irrespective of PD-L1 status, we really feel that the triplet is appropriate for every patient unless there's a specific contraindication.

On the diarrhea, it's been addressed already. This is the known toxicity of zanidatamab when combined with certain chemotherapy. And we found in the conduct of the clinical trial that it's very manageable with very few patients actually discontinuing Ziihera due to diarrhea. Chumi touched on the education that's planned around this, which will be very important. And we think that some of that diarrhea is driven by capecitabine may even be more manageable with FOLFOX in the U.S. when given appropriate prophylaxis and attending to onset of diarrhea. We're very pleased that the triplet is approved, again, irrespective of PD-L1 status. And of course, that is for both IHC 2+ and 3+. Again, I think that this is a very poor prognosis disease. Many patients don't make it to the second-line therapy. It's clear that the addition of tislelizumab benefited patients, which is consistent with prior PD-1 therapies in gastric cancer. And so we think the triplet is really the new standard of care.

With regard to interpretation of data on IHC 2+, it's a very small subset. It's true from an epidemiology perspective, most patients are HER2-positive or 3+ in the trial was a very small subset. We think that the data are probably confounded by other factors as is evidenced by overperformance of the control arm where even in the control arm, 2 pluses did better than 3 pluses. So overall, very favorable label from our perspective, and we think that zanidatamab is now the HER2 agent of choice in this setting and the triplet really should be the standard of care for everyone who is eligible.

Our next question is coming from the line of Gregory Renza of Truist Securities.

Great. Let me add my congratulations on the approval as well. For Rob and Samantha, just circling back to the change in the -- your belief in the peak sales opportunity, certainly, a decisive statement. I'm going from, as you noted, Samantha, the $2-plus to $3 billion to $5 billion. We appreciate the color you provided. Just to add on that, just curious if you could comment a bit on how you're characterizing perhaps any change in the time horizon to peak or the time to getting to that peak potential to the $3 billion to $5 billion. And also, are there any maybe alterations in how you're looking at the geographic spread that has also informed your conviction today on those numbers? Congratulations again.

I can, first of all, comment on the peak sales potential. Yes, we've already -- always said $2 billion plus. And now we're being more concrete around what that plus actually represents. Obviously, with this GEA approval, it discharges some of the risk around some of the other studies that we have ongoing. We know that we have our development program in breast cancer, which is obviously one of the largest opportunities that we're now very excited about. Rob can speak a little bit about some of the timings associated with that, and obviously moving into early breast cancer as well, which will be a significant contributor to that overall peak potential for the program.

So maybe, Rob, if I hand over to you to kind of say a little bit about the time horizon for some of those study readouts.

Yes, happy to. I'll just very quickly maybe give a broad description. So remember, we're approved in second-line BTC, but we have a frontline BTC that's ongoing and progressing very well, where there's no HER2 therapy approved in that space. So combining with PD-L1 in that setting, we think the prospects of that being a positive study are very, very high. We now have the definitive new standard of care in frontline GEA. We're very interested in exploring other aspects of gastric cancer. I think there is a potential in early-stage gastric cancer where, again, there's no approved HER2 therapy. As Sam mentioned, we've made meaningful progress on a Phase III trial in the later-line breast cancer setting post Enhertu, which was kind of an obvious first place to go with zanidatamab in breast cancer given how Enhertu is changing that treatment landscape. And there won't be any -- this will really be the only pivotal trial that looked specifically post Enhertu. And there, again, it's a head-to-head comparison with Herceptin, but we have broader ambitions in breast cancer as Sam mentioned, we have ongoing Phase II work in neoadjuvant breast cancer in our Study 208 as well as collaborations with I-SPY and MD Anderson, and we'll look to interpret those data and potentially move to a pivotal trial in neoadjuvant, adjuvant breast. We have collaborations with both Boehringer Ingelheim as well as Iambic on novel TKI combinations with zanidatamab, starting in breast cancer, but potentially in other settings. And the importance there is that, that combination could be quite powerful, allow us to get to even earlier lines in breast cancer and difficult-to-treat populations such as brain mets. And then we have aspirations beyond that. You may have seen that we have breakthrough designation now in colorectal cancer. We'll be working with FDA to define a path to approval with colorectal cancer. We have an ongoing pan-tumor trial, which ultimately could give us a tumor-agnostic indication. That trial is also enrolling non-small cell lung cancer patients who are overexpressing HER2, and there may ultimately be a path there as well. So a lot of opportunity now given the results that we have so far with zanidatamab.

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

So it was good to see the broad label. I was curious about the extent to which Ziihera could be used with pembro rather than tisle. Do you think there's going to be any kind of interchangeability in the marketplace? And how do physicians approach when they've been using pembro? Just some curiosity about that. And then also the 3,000 to 4,000 eligible patient population, is there an opportunity to moving it towards the 8,000? Or is the 3,000 to 4,000 quite set?

Yes. So the study was conducted with tislelizumab, which is already approved in the U.S. And so we think there's a little obstacle to combining with tislelizumab. However, as you said, multiple other PD-1s have shown efficacy in gastric cancer. We do have an ongoing trial combining with pembrolizumab, which should provide some, let's say, safety and preliminary efficacy such that if there were some compelling reason to use a PD-1 agent other than tislelizumab, we think zanidatamab would certainly be compatible.

Annabel, It's Sam. The 3 to 4 patient population, this patient population that we're talking about here, that is reflected in that $3 billion to $5 billion, [ overall ] peak estimate that we've provided. Within that, obviously, we're looking at the kind of unresectable disease. There's also those that are treated with -- that are -- that get a test. We will be focusing on ensuring that patients that are tested that are -- first of all, they're tested for HER2-positive, that's obviously been seen. But those patients that are tested and are positive for HER2, then they are treated with zani. So these are all the areas that we'll be focused on during the launch phase.

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

Mine was just, would you expect physicians to prioritize the doublet in elderly patients? Some of the language in the label seem to suggest that like the diarrhea profile, more severe cases was less with the doublet. So curious if you -- it's a meaningful size subgroup within GEA, if you think the doublet would get traction there? And how do you think community docs will navigate some of the prophylactic measures with the diarrhea? I don't know if there's any analogs you can point us to that give you a high degree of comfort that -- how that will be managed by community oncologists.

Sure. So with regard to the older population, I do think that every eligible patient unless there's a specific contraindication should get the triplet. Remember, this is still a very lethal disease. It's clear that tislelizumab added to the benefit irrespective of PD-L1 status. And you can even see as you look toward the latter parts of that curve, there's some encouragement there that, that might persist. We believe that the mechanism of action potentially synergizes with the PD-1. And so this is a disease where you don't want to sequence the therapy. You really want to give these best therapies upfront where there may be synergy and you get the full benefit. In terms of toxicity, as it was observed in younger than 65 or older than 65, interpret that with some caution, you start to get to small subgroups where other factors may be at play. And I would just point out specifically with regard to diarrhea, these are easily distinguished. The zanidatamab diarrhea comes on early, whereas tislelizumab diarrhea is more immune-related and tends to be more delayed. There are diagnostic evaluations that really can distinguish the 2. So -- and I'll let others comment potentially on differences in community practice. But as I said, we conducted a very large global trial where we think the diarrhea is managed very, very well. Yes, there's needed education around starting with prophylaxis, ensuring the patients alert doctors promptly if they have onset of diarrhea because more can be done in terms of supportive care, in terms of upping the antidiarrheal therapy. The label pretty clearly says to first modify chemotherapy so that you can maintain exposure to Ziihera, which is really critical for the survival benefit. And so these various things that we know about how to manage will be subject of education for any new prescriber, whether that be tertiary care centers or in the community. And I think everyone will be well equipped to manage this well. But maybe Sam or Chumi would want to add to that answer.

Yes. I would just add that, of course, the benefits of using Ziihera in this patient population are clear from the data that we have, that we're familiar with now. And in the clinical trial, discontinuation rate of Ziihera, [ choosing ] diarrhea was low, less than 5%. So what we want to do now is ensure that those results can be replicated in the real world. And we will be investing significantly to ensure that patients, doctors are supported to ensure that patients can stay on treatment and get the full benefit of Ziihera. And maybe I'll just ask Chumi to comment here a little bit around some of the investments that we're making to achieve those goals.

Yes. Thank you, Sam. So we've invested in education around management of diarrhea and we made some strategic investments that support sustained patient adherence, which is obviously important. We have a clinical nurse educator team that will provide support to nurses on patient initiation and management so that they have a first [ rate ] experience in peer-to-peer education speaker programs that are targeted specifically at the community and will proactively educate on the evolving treatment paradigm as well as the compelling efficacy and data. By supporting this education around long-term adherence, we can help patients achieve the best possible outcomes. We're prepared to do that.

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

On the approval. I wanted to ask more broadly on the development strategy. You guys are running the basket study for potentially -- and you talked about how it would potentially be registrational for tumor-agnostic label, but you're also exploring a potential registrational study in colorectal and in non-small cell. And I guess those would also be included in the basket study. So I guess what I'm asking is, how are you thinking about the differences that specific studies in colorectal, non-small cell could add to the opportunity? I guess, how you're thinking about what those clinical trials would be enrolling in terms of patients? Just any sort of differences in future labels that you'd be aiming for patient segments?

Sure. I'm happy to take that question. So the basket study or the pan-tumor trial was really meant to allow us to enroll the patients that we would needed ultimately to get a tumor-agnostic label. And we are progressing toward that goal. And we continue to think that, that is potentially a pivotal trial for that purpose. It's a place where we can get additional data in refractory colorectal cancer patients as well as non-small cell lung cancer patients in addition to any patient across a whole range of rare tumors who over express HER2. So there may be an opportunity for our tumor-agnostic indication in addition to having enough patients in any one indication such as colorectal or even non-small cell lung cancer, where you may get a specific label in that regard as well. Remember, for colorectal cancer patients, we had some Phase I data. I think there were 28 patients in the Phase I. So we're adding to that in the Study 206 pan-tumor, and on the basis of the combination of those from Phase I and from the 206 Study, we received breakthrough designation. And the next step now is to agree with the FDA on path to an approval for colorectal cancer. But you're right, it is an opportunity for a pan-tumor or tumor-agnostic indication as well as to generate data that could give us specific indications. And then, of course, there's the opportunity to go beyond that. That would be in a refractory setting, but there's always the possibility of then expanding into earlier lines as well.

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

This is Alex on for David. Looking beyond the U.S., you've cited a combined annual incidence of, I believe, 63,000 across the U.S., EU and Japan. Can you please provide more color on the EU specifically and the number of annual cases there? And just a general broad refresher on how you're thinking about the EU opportunity?

Yes. Thanks for the question. Yes, we've said 63,000 patients for GEA and that reflects globally the U.S., Europe and Japan. And we do -- we are excited about taking zanidatamab obviously more broadly with this GEA indication. We're anticipating an EMA approval before the end of this year. And we've also -- as part of Project Orbis, there has been some -- the FDA filing has been also simultaneously completed in the U.K. and in Health Canada. So also anticipating approvals there in the foreseeable future. So yes, excited about the potential for GEA beyond just the U.S. and [indiscernible] markets.

Next question is coming from the line of Gary Nachman of Canaccord Genuity.

Congrats on the approval. So any commentary on what you think uptake should look like for the first few quarters of the GEA launch? How much pent-up demand is there within the 3,000 to 4,000 treatable patients that was waiting for this approval? And how smooth reimbursement will be using the existing J-code?

And then based on the GEA approval and label, would you consider modifying anything in the breast cancer and other future studies?

Thank you very much for the question. Yes, we're really excited about the label approval today, very excited about the label itself and the opportunity that, that gives us with Ziihera in this indication. As you know, we've been established in the field now with DTC and with our solid tumor team in general across Zepzelca as well. And so that gives us a major foothold that was established. Chumi mentioned the strong overlap between prescribers, which means those relationships have already been developed. A lot of the friction that you might anticipate with a new launch doesn't really exist here because of the fact that we have the permanent J-code in place, reimbursement established as well. So maybe I'll just speak to -- I'll just hand over to Chumi, who can speak a little bit about our plans here to really accelerate the launch of Ziihera. I mean we believe this data is really important for patients, and we believe that it's going to be very important for us to hit the ground running and ensure that patients can benefit from this treatment as soon as possible and our plan and ambition really reflects that. So Chumi, perhaps you can add a little bit more depth and color as to how we plan to do that.

Yes. Sure, Sam. We're really, really excited about the label that we've gotten and are ready to go. Our team is rightsized to capture the larger GEA market without requiring major expansion. We did add to MSLs last year. And so we're ready to go. Not only do we have 90% overlap with DTC, but we've also been as you know, very successful with that. And it's the same team that has a strong presence in the community accounts and academic accounts. And so we're very established amongst the high value prescribers. And so we are ready to go. We've got the payer access [indiscernible] has a J-code. And in addition to that, our state-of-the-art JazzCares support services, along with flexible ordering and fulfillment options will ensure that providers can access higher efficiently and without delay.

I think part of the question is that we've been -- Yes, part of the question was also, do we learn anything there that impacts our thinking on breast cancer. And I would just say we're satisfied with the design of the breast cancer trial that's ongoing. We certainly learned a lot from the GEA trial, though. And one thing was when you put zani up against Herceptin directly in the context of GEA at least, and I think you can infer results in other context as well, it beats definitively. The other is that we think this mechanism of action with zani probably synergizes with immunotherapy. If you think of all the trials that have been done with PD-1 agents, in gastric cancer, they've all had restricted indications to patients whose tumors are PD-L1 positive. This is the first trial showing activity in PD-L1 negative patients, really suggesting that immune activation occurring with zanidatamab due to its unique mechanism of action is probably synergizing with immunotherapy. And so that does make us think that wherever we can go head-to-head with Herceptin, wherever we can combine with the PD-L1 or PD-1 antagonist like frontline BTC, like early gastric cancer, other settings, that could be a pretty good formula.

And perhaps just before we close this question, I think the other element of this was whether we expect a kind of bolus of patients that would be waiting for treatment. That's not something that we anticipate in this space, typically when patients get a diagnosis, they get treated right away. So yes, that shouldn't be part of the expectation here. And I might also just add that on the previous question when we were talking about the EU, the expectation is that we will make a submission to the EU by the end of the year and not approval. So apologies there. So I just wanted to clarify that.

Our next question is coming from the line of Sean Laaman of Morgan Stanley.

Congratulations and I hope everyone is well. Obviously, a big ramp to get to the new peak sales. But what early commercial data point do you believe would give investors confidence that the peak sales estimates may prove indeed reasonable? And how are you thinking about guiding? What sort of metrics do you think you might unfold to investors as we go quarter-to-quarter during the launch?

Yes. Thanks for the question. Yes, I mean, in relation to the confidence, I mean, I think we're very confident about our potential to realize the full potential of Ziihera. We've seen a really very strong uptake in BTC achieving standard of care in that space. And we've also demonstrated our ability to execute in the community with the launch of Zepzelca lurbinectedin. So we're -- we've got strength in this area. We've got experience in this area, and we're very confident about being able to execute here, too. In terms of what we'll be reporting here will be quarterly sales. And maybe I'll just hand over to John here just to comment a little bit further on the guidance side of things.

Sure. Thanks, Sam. Yes, Sean, I think the revenue number, as Sam is saying, is really the one to watch as the GEA launch gets off the ground. And then we'll be looking closely at the metrics and evaluating if there's good information we can provide to the Street to help you assess how the launch is going and how Ziihera is being accepted commercially and clinically. I wouldn't want to commit to anything specific right now, but we want to make sure that you've got good visibility as we do to how things are going, and we're excited about the GEA launch.

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

Congrats on the approval. I just wanted to ask about if you have any -- your latest visibility on the NCCN review process and whether we should be expecting Category 1 recommendations for the doublet and the triplet. And is that recommendation in any way a gating factor to see more brisk uptake of the Ziihera-GEA?

I can start by commenting on the process. We obviously don't control the time lines for NCCN. We know they have a regular meeting every year in August. We provided data every step of the way, including at the time of the abstract and post an oral presentation at ASCO GI and then the New England Journal of Medicine paper. And now we have approval. And so we're very confident in the label that we have and the data that support that label, and we do think that should come through. Let's go Category 1 on NCCN. This is a drug that has a survival advantage showing more than 7 months difference in the triplet arm at a median level of the first [ year ] analysis.

Yes. And I might just add, I think given the strength of the data, we would anticipate NCCN Category 1 listing. Had that NCCN approval come through forward earlier than the approval, then that might have paved the way for patients to have access sooner than the approval. But now that we have the approval and we have the label that we're thrilled about. We know the strength of this data. We have the J-code already in place, and we're not really -- we're not anticipating any friction here when it comes to access. So -- and in fact, our sales teams have been trained on the label and they're in front of customers as of this afternoon. So everything is in place for us to execute, I think, extremely well.

Next question is coming from the line of Ash Verma of UBS.

This is Natalie on for Ash. Congrats again on the label. So maybe just to build off of some of the prior questions. Could you comment a bit more on the breakdown of patients in the community? And what are some of your expectations for community growth?

Thanks for the question. Yes, perhaps I'll hand to Chumi to talk around our community strategy.

Yes. Thank you, Sam, and thank you for the question. So the split between academic and community, about 30% of GEA is treated in the academic centers and about 70% of GEA is treated in the community. So as we launch a lot of our investment and focus of the team is in the community setting. We have great relationships in the academic setting based on BTC and a lot of focus of what we're doing is peer-to-peer education. We're working with the key community centers and both our MSL teams as well as our sales teams are focused on education in the community and building upon relationships that we have due to Zepzelca and BTC. So we're ready to go there and focus there.

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

This is Jacob on for Joe. We were just wondering now that the doublet is approved in IHC 3+ disease. What specifically do you think the second interim OS analysis could potentially change labeling NCCN guidance or maybe even commercially? And then do you think a statistically significant OS outcome here could support a label update or a broader treatment recommendation? It kind of seems like you're maybe leaning more toward the triplet, right now where possible.

Yes. I mean as we're reiterating that we're expecting that next interim this quarter. And certainly, there's likely to be -- there's the potential for there to be useful information that would then result in the label update. But I would just reinforce that at the first interim, the data were quite mature and the results are quite definitive. It wasn't necessarily static because we put a relatively small alpha against it. But if you look at the -- the hazard ratios for overall survival and even the median compared to the control arm, it was a clinically meaningful difference with pretty narrow confidence intervals there. So I think it definitively shows that zani beat Herceptin. And I'm not sure that the next interim, even if it's static, changes my view on that. I think it's a favorable result. And to your point, we do think that the triplet is going to benefit patients most for all the reasons that we said before. It can be used irrespective of PD-L1 status. It's a very poor prognosis disease where you really want to give your best therapy upfront. And in this case, we think there's potentially synergy between zani and a PD-1 antagonist like tislelizumab. And so you want to combine them to get the greatest benefit for a population that where previously maybe half of the patients wouldn't have gotten to second-line therapy.

Yes. I would just kind of reinforce that from a commercial perspective. We do believe that the Ziihera in combination with tislelizumab and chemotherapy is the preferred choice for all patients, except those for whom it's not indicated or trastuzumab may be contraindicated. And of course, in that patient population, that's IHC 2+ and 3+ across PD-L1 status as well. So commercially, that's where our focus will be, that's where patients are going to get most benefit. So the Arm B OS readout, we have everything in the label that we need right now to be successful. The OS readout to come, obviously, will be very interesting to see. And we would anticipate that the Arm C with tislelizumab would continue to strengthen as well. So we're very excited with the label that we have. We believe that's going to give us every opportunity to really execute well commercially and ensure that patients can really make a really significant meaningful benefit from this new treatment option.

This does conclude today's Q&A session. I would now like to turn the call back over to Sam for closing remarks. Please go ahead.

Thank you, operator, and thank you, everybody, for your questions today. We really hope that this overview of zanidatamab has conveyed our excitement about the potential for zani to become the HER2-targeted agent of choice. I'd like to just close by thanking all of our Jazz colleagues for their commitment and dedication to bring Ziihera to GEA patients in need. Thank you all very much.

This is today's program. And thank you so much for participating. You may now disconnect.

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

I will now hand the conference over to your first speaker today, John Bluth, VP and Head of Investor Relations. Please go ahead.

Thank you, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its second 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 second quarter ended June 30, 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.

Now I'd like to turn the call over to Renee.

Thanks, John. Good afternoon, everyone, and thank you for joining today's conference call.

We delivered another outstanding quarter, generating record revenue of $1.2 billion representing 16% year-over-year growth. The momentum we've built in the first half of the year provides us with confidence to raise our full year revenue guidance. Our results reflect an intense focus on aligned execution across our diversified portfolio, sustained demand of our commercial products and progress in advancing our long-term priorities for value creation.

As we approach a significant milestone with the August 25 PDUFA date for zanidatamab in first-line HER2-positive metastatic GEA our commercial, medical and market access teams are fully prepared to successfully launch zanidatamab. We're entering a new phase of growth created by the opportunity to deliver clinically meaningful outcomes for patients facing this highly aggressive, difficult-to-treat disease.

Our consistent execution reflects the focused strategy we outlined at the beginning of the year, expand our leadership in key therapeutic areas, advanced differentiated innovation and create durable long-term value. Across the business, our teams are delivering key therapies to patients, advancing zanidatamab, and leveraging our financial strength to invest in both internal R&D and external innovation.

An example of this approach is our preclinical research collaboration with AbCellera which leverages their T cell engager platform to discover novel multi-specific antibodies. This agreement directly complements our oncology expertise and supports our refined rare disease strategy. These exceptional results from the quarter position us to sustain our momentum while delivering meaningful benefits for patients and driving robust returns for our shareholders.

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

Thank you, Renee. Our commercial teams delivered another impressive quarter of revenue, with 16% growth across the portfolio and double-digit growth from each of our key promoted brands. This performance is a result of focused investments and targeted impactful execution, which is driving sustained momentum across our increasingly diversified portfolio.

I'll begin on Slide 7 with rare sleep. Xywav's profile is the only low sodium oxybate on the market continues to resonate with physicians and patients. Xywav net product sales increased 13% to $471 million in the second quarter of 2026 compared to the second quarter of 2025. Supported by targeted health care provider and patient-focused digital campaigns, our field execution continues to expand the narcolepsy and idiopathic hypersomnia markets, and deliver sustained new patient adds.

These efforts emphasize Xywav's differentiated low sodium profile and the efficacy it provides by treating underlying disrupted nighttime sleep and addressing daytime symptoms for patients living with narcolepsy and idiopathic hypersomnia.

Demand for Xywav remains robust with approximately 525 net patient additions in the quarter. This brings our total active patients to approximately 17,125 representing more than 12% year-over-year growth. This momentum is supported by our targeted investments in high-touch patient support services, such as our field nurse educator program, which delivered differentiated support to help patients achieve optimal dosing and sustained treatment.

This first half performance underscores the durability of our sleep franchise with limited impact from high sodium generics. Whilst we will closely monitor second half market dynamics, including generic availability and potential new product launches, our confidence in Xywav's foundational role is unwavering. Its clinical profile remains differentiated as the only low sodium oxybate and the only FDA-approved option for IH patients.

Moving to Slide 8 and Epidiolex. Epidiolex delivered another outstanding quarter with net product sales growing 16% year-over-year to $292 million, driven primarily by robust underlying demand, this momentum is fueled by our field team's ongoing success in educating HCPs and caregivers on Epidiolex' broad spectrum efficacy and it's meaningful beyond seizure benefits for new and existing patients.

Concurrently, we are actively expanding the Epidiolex franchise, while Rob will cover our clinical expansion into new treatment resistant seizures, I want to highlight a critical life cycle initiative our novel capsule formulation, designed to unlock additional utilization within our approved indications, the capsule targets deeper penetration in certain segments of the adult patient population. By offering this convenient alternative alongside our oral solution formulation, we aim to improve accessibility and compliance for adult patients while firmly reinforcing our long-term leadership in the anti-seizure market.

Turning to our oncology portfolio. We are extremely pleased with the ongoing launch of Ziihera in BTC, as shown on Slide 9. In the second quarter of 2026, Ziihera generated $15 million in net product sales. Since launching in second-line BTC, we have rapidly established clinical leadership, achieving more than 50% of the addressable market share in the U.S. This clinical momentum is driven by deepening utilization in academic centers and expanding adoption across community settings, supported by highly consistent, positive real-world prescriber experiences.

Critically, our success in BTC serves as a powerful commercial foundation for our next major growth phase in GEA because there is significant direct overlap between existing BTC and GEA treating accounts our commercial infrastructure is fully primed.

On Slide 10, you can see how our launch readiness framework is designed to drive rapid uptake. Our commercial footprint is highly optimized with over 90% target physician overlap, allowing our team to rapidly generate clinician excitement and demand. And this enthusiasm is rooted in zanidatamab's exceptional clinical data specifically an unprecedented median overall survival exceeding 2 years, establishing it as the potential preferred backbone in HER2-positive GEA.

To support immediate clinical adoption at launch, we've submitted this data to key oncology pathways, and we'll leverage our already established permanent J-code to minimize reimbursement barriers. Backed by our robust [indiscernible] patient support program, we are fully prepared to deliver seamless access to patients upon approval.

Turning to Slide 11 and Modeyso. Modeyso generated $48 million in net product sales in the second quarter of 2026, representing remarkable progress since our launch in August of last year. Driven by highly coordinated, disciplined execution, more than 600 patients have now been treated with Modeyso through the end of the second quarter.

To sustain this upward trajectory, we initiated additional nonpersonal promotion and peer-to-peer speaker programs in the second quarter. These initiatives are designed to educate community-based physicians and expand our reach to ensure timely referral of patients to academic centers of excellence.

On the diagnostic front, while biomarker testing is already high in high-grade gliomas we are actively working to establish reflexive testing across all of the owners. This systematic approach is critical to ensure every H3 K27M patients is identified early and referred to targeted care. To support this, updated NCCN guidelines now endorse liquid biopsy for the H3 K27M biomarker. This represents a major milestone that broadens diagnostic pathways, reduces patient risk and accelerates time to treatment.

Finally, Modeyso continues to benefit from robust highly favorable payer coverage. Combined with our dedicated patient support services, we are exceptionally well positioned to maintain the strong commercial momentum.

Moving to Slide 12 and Zepzelca. We are very pleased with Zepzelca's performance this quarter, achieving $106 million in net product sales, a 42% year-over-year increase. This robust growth was driven by highly positive prescriber feedback and rapid adoption in the first-line maintenance setting, which more than offset the anticipated tapering of our historical second-line business. The strength of our IMforte trial data clearly demonstrates that Zepzelca's greatest clinical value is in early intervention in combination with a PD-L1 inhibitor in the first-line maintenance setting, a consensus recently reinforced by its elevation to a category 1 listing in the NCCN guidelines. Because metastatic small cell lung cancer progresses so rapidly, reaching patients earlier in their journey is critical. Later, Rob will provide an update on the second line indication.

Overall, we are very pleased with the commercial performance across our portfolio in the second quarter, and we remain focused on sustaining this momentum throughout the remainder of 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 a very exciting time with Jazz driven in part by the August 25 PDUFA data map. The Phase III Horizon GEA 01 trial results were recently published in the New England Journal of Medicine, further characterizing the efficacy and safety profile of zanidatamab in combination with chemotherapy with and without a PD-1 inhibitor to tislelizumab.

Publication in the New England Journal of Medicine underscores the clinical significance of these results, and we believe will support awareness and adoption of zanidatamab among oncologists treating GEA patients. We also presented subgroup data at ASCO, confirming that the zani and tisle combination delivers a consistent survival benefit irrespective of PD-L1 tumor expression, a 26.4 month median overall survival was observed with the zanidatamab plus tislelizumab arm, which was more than 7 months longer than the control arm with trastuzumab. The benefit was seen for all HER2-positive patients, irrespective of tumor PD-L1 status and represents a remarkable advance for this patient population.

Zanidatamab plus chemotherapy showed a clinically meaningful survival benefit with a median OS of more than 2 years and a strong trend towards statistical significance at the time of the first interim OS analysis. We look forward to the upcoming top line results from the second interim OS analysis of this [indiscernible] arm, which are expected in 3Q '26.

In addition, we have submitted the New England Journal of Medicine Managed Group for potential inclusion in the NCCN guidelines. Our belief in zanidatamab increases and it was recently granted breakthrough therapy designation for adults with previously treated, locally advanced unresectable or metastatic HER2-positive colorectal cancer. We look forward to sharing more on our development plans for colorectal cancer in the near term.

Turning to Slide 15. Our R&D programs remain focused on building the next generation of growth drivers through internal innovation and external partnerships. We are leveraging our deep expertise in rare epilepsies to broaden our pipeline and extend the potential benefits of Epidiolex, also known as cannabidiol to more patients with treatment-resistant seizures. We are initiating 3 new clinical trials, including a Phase IV trial in adults with LGS a Phase III trial assessing the antiseizure efficacy in a broad group of developmental and epileptic encephalopathies and a seamless Phase II/III trial that will explore the capsule formulation in juvenile myoclonic epilepsy.

These new trials build on the Phase Ib trial in focal onset seizures that was initiated at the end of last year and the Phase I trial of JZP047, a novel molecular entity discovered by Jazz being developed in absence epilepsy. In addition, we submitted an NDA to the FDA for a novel capsule formulation to broaden utilization of Epidiolex in currently approved indications of LGS, DS and TSC to improve flexibility and provide a new administration option for patients.

Moving to oncology and Zepzelca. Based on the results of the Lagoon trial, and in alignment with FDA in 3Q '26, we will submit for FDA's review and subsequent action of labeling supplement to remove the second line indication. The first-line maintenance indication will not be affected.

Lastly, on Modeyso, our Phase III ACTION trial is progressing based on the latest estimate of event accrual, we now anticipate that the overall survival interim analysis will be in the first half of 2027. This trial is designed to confirm the benefit of Modeyso and support regulatory approval as frontline therapy directly following radiation. We are making meaningful progress across our pipeline and in-house R&D efforts. And we look forward to sharing more updates as our programs advance.

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

Thanks, Rob. Before diving into the financials for the quarter, I'd like to underscore our consistent progress delivering on our rare disease strategy. Our commercial organization is firing on all cylinders, and we're making targeted investments to continue our momentum. Our R&D organization is working with urgency to generate practice-changing clinical data, highlighted by the medium publication of the zani first-line GEA results, and speed new medicines to market while also expanding indications for existing medicines to benefit even more patients, and we're deploying capital in a disciplined manner to enhance our growth prospects, most recently with the AbCellera deal.

Turning to the financial results for the quarter. 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 quarterly revenue of $1.21 billion, an increase of 16% over the second quarter of 2025. Driven by 32% growth in our oncology portfolio, 13% growth in Xywav and 16% growth in Epidiolex.

Moving down the P&L. Our non-GAAP adjusted gross margin declined slightly year-on-year, due to higher sales of Zepzelca and Modeyso, which carry third-party royalties. Non-GAAP adjusted SG&A and R&D expenses, both grew 11%, with the increase in SG&A driven by higher expenses for Modeyso and Ziihera first-line GEA, and to a lesser extent, by investments in key commercial capabilities and digital and AI. While the increase in R&D was driven by higher expenses related to clinical trial costs primarily related to zanidatamab.

Our non-GAAP adjusted effective tax rate this quarter was moderately higher than our full year 2026 guidance due to shifts in the expected geographic mix of income and expenses. 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 $5.71, which included IPR&D charges totaling $0.94.

Beyond the income statement, I'd highlight that we generated operating cash flow of $824 million in the first half of the year. And during the second quarter, we paid off our 2026 convertible notes. With our strong financial position, we're able to continue to invest in our currently marketed products and our existing pipeline as well as in corporate development.

Turning to Slide 18 and our 2026 financial guidance. I'll focus my comments on those guidance elements that have changed since our last earnings call. We now expect total revenues in the range of $4.60 billion to $4.75 billion. This significant upward revision is largely driven by the outstanding execution of our Xywav field teams driving home the unique benefits of Xywav offers is the only low sodium oxybate. To date, uptake of high sodium generics has been quite limited, and we continue to post strong net patient adds.

We now anticipate double-digit growth for Xywav in 2026 and rare sleep revenue of between $2.025 billion and $2.125 billion. Strong first half results of our rare oncology and epilepsy portfolio further support our revised total revenue guidance range. On the expense side, we've modestly increased our SG&A expense guidance. This reflects deliberate strategic investments to build upon momentum in Xywav and Epidiolex as well as to drive implementation of our rare disease strategy and our corporate development efforts.

Finally, our updated share count guidance is 69 million to 70 million shares, reflecting the increase in our stock price since our last earnings call and its accounting effect on our convertible notes and employee stock compensation plans.

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

Thank you, Phil. I'll conclude our prepared remarks on Slide 20. Our second quarter results demonstrated the strength and continued diversification of our product portfolio, delivering record quarterly revenue, including a 32% increase from our oncology products compared to 2Q '25 and consistent execution across our commercial and R&D pipeline.

Importantly, we entered the second half of the year with significant momentum, highlighted by the anticipated zanidatamab approval and launch in GEA and multiple upcoming clinical readouts. Building on our proven scientific capabilities and strong financial position, we are making a meaningful impact for patients. Over the past 12 months, we have embarked on a period of rapid and deliberate transformation.

I am incredibly proud of the execution by the entire Jazz team during this time and deeply grateful for the trust you have placed in our shared vision.

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

[Operator Instructions] Now first question coming from the line of Marc Goodman with Leerink.

Yes. Could you guys give us a little more color on Epidiolex. Just give us a sense of was there any inventory in the U.S. or anything strange in the quarter? I mean, what was really just driving it? Were there new indication? Just give us a sense of what's happening here because the quarter was much better than expected.

Marc, this is Sam. Yes, thanks for the question. Yes, very pleased with the continued momentum that we've seen for Epidiolex a 16% revenue growth, taking us to $292 million for the quarter. This is 12% volume growth which again, just reflects really good strong demand in both the pediatric and the adult settings, reinforcing our position as the #1 granted anti [indiscernible] medication and refractory epilepsy.

I think some of this growth is coming from -- continues to come from our focus on the long-term care setting. As you know, we've generated some good data there beyond seizure benefits really resonate with adult, and we continue to see good headroom for growth actually in that segment as well. There were no really significant unusual inventory movements. But I'll hand over to Phil. If you want to comment further on that topic.

Yes. Thanks, Sam. Just to note, Mark, ex U.S., you may recall that in the second quarter last year, we had talked about some onetime pricing adjustments that are made in a couple of the ex U.S. markets that did depress second quarter 2025 revenue that led to some of the favorability on the compare in the second quarter of this year for ex U.S. revenue. We also did have a decent effect in this first half of the year coming from FX that was most pronounced in the first quarter and came down pretty significantly here in the second quarter, but did also help drive a little bit of the ex U.S. revenue growth.

Our next question coming from the line of Jessica Fye with JPMorgan.

I wanted to ask about zani and just hoping you could speak to your confidence in approval heading into the upcoming PDUFA there has been some talk about the possibility of maybe approval before the PDUFA date, we're getting pretty close now. So just wanted to hear your confidence there. And then maybe related to zani, can you speak to your confidence in the zani doublet hitting on OS with the upcoming interim?

Nice question, Jess. So we've been productively engaged with the FDA, and it does feel like we're in the home stretch. We're highly confident in the approval. I would still say on or before the PDUFA date, and we are certainly ready to launch. On your second question around the second interim for the doublet, certainly, we have -- we had a great result at the very first interim. And certainly, we have more power at this next turn. So looking forward to those results in 3Q of this year.

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

Maybe one for Phil. Just -- when you look at the strength of Xywav in the first half, how do you see that carrying over into next year? Should investors look at like the outperformance is more or less just the delayed generics and more of a headwind in 2027? Or do you think that this is -- the strength that offers a rebasing of numbers going into 2027 for Xywav?

Yes. Appreciate the question. Definitely extremely pleased with the performance of our field teams driving Xywav. It really is a pretty astounding and amazing story. And really based on the unique benefits that Xywav offers is the only low sodium oxybate. We've been seeing this resonate with physicians as well as patients. I think we've continued to see that during this year. Probably leading to even slower uptake of generics than we might have originally anticipated, which is leading to some of the raises we have for the guidance this year.

I would say that continues to put us in a really strong position as we think about the go-forward discussions that we might have with payers as well. Given that the market continues to highly value the unique position that only as Xywav occupies. So not ready to sort of give specific guidance on '27 yet. We'll do that when we get to the fourth quarter '26 call early next year, but the momentum we've got gives us increasing confidence in the position that Xywav have in this market on a go-forward basis.

Our next question coming from the line of Ash Verma with UBS.

Congrats on the progress here. Maybe just on the GE market dynamic, can you talk about in terms of how many patients are in the major cabinet centers versus the large community practice network? And if you think that the adoption is going to look different 1 way or the other in either of these channels.

Yes. Thanks for the question, Ash. Yes, we do believe that for the GA launch obviously, having a strong foundation of support from those academic centers is key. And of course, the data really has been well received by those physicians following the publication in new English Journal of Medicine, and they're easily anticipating the launch. But what will be very important with this launch and something we really appreciate is how important it will be for the community physicians to really understand the data and to quickly adopt -- hear as the new standard of care in GEA. This is something that we're quite well prepared for because it pretty much mirrors the situation with Zepzelca. So we have a team already out there who very well positioned to a very strong overlap, as you know, between Zepzelca and Ziihera. So they're well positioned to communicate the benefits of Ziihera through community positions and we anticipate good strong uptake there for the reasons that we've talked about previously, the overlap, the fact that we have the permanent J-code already established, and we have those relationships already in place.

Our next question coming from the line of Joe Thome with TD Cowen.

Can you talk a little bit about the breakdown between frontline and second-line Zepzelca patients that are presenting at this point? Just trying to understand a little bit how much the second-line label update will impact sort of your thoughts on the long-term value of [indiscernible] kind of your peak sales estimates there?

Yes. Thanks for the question. I'll take that one. Yes, I mean, we're very, very pleased, obviously, since we launched Zepzelca in the first-line maintenance segment in October last year. We've seen really strong adoption of Zepzelca with those patients. And that's really what's driven the growth that we've seen over the last few quarters. 42% growth this quarter, taking on $206 million. And that growth is really all being down to in that first line segment. We estimate now that between 30% to 40% of our overall U.S. sales are coming from that first line maintenance segment. And of course, that's growing. And that is reinforced by the recent NCCN category listing elevated to category [indiscernible] as a preferred regimen in first-line maintenance in combination with Tecentriq.

So whilst we have been seeing a gradual decline in that second line business, as a result of competition, but also as patients get initiated on to that well in the frontline segment, they're not going to get retreated in that second line segment. We can expect the second line business to erode. That's what we were anticipating. Of course, with the announcement today, we may expect that to accelerate. But of course, all of that factored into the guidance that we've provided for this year. Rob, would you like to add anything from your perspective on that?

Yes. I mean I would just say that we designed the [indiscernible] trial because we really felt that it was important to preempt progression in this pretty aggressive disease. And had a strong hypothesis that Zepzelca would synergize with a PD-L1 inhibitor like atezolizumab, and that is what we observed in the fray. So we think frontline maintenance is the best place to use to Zepzelca for patients to get the best benefit and the longest treatment duration. We think there is a synergy with PD-L1 antagonist, and there was important data published at ASCO showing just that, looking at the impact of tumor-associated macrophages of Zepzelca and explaining the potential synergy with the PD-L1 agent. So we do think frontline is the best place to use Zepzelca.

Our next question in queue coming from the line of Sean Laaman with Morgan Stanley.

Congratulations on the number and hope everyone is well. My question is on the durability of Xywav. So it seems that most of the net patient adds came in IH. And I guess just given the biology of the disease, we have normal levels of orexin and then you do have a pretty competitive bar there on [indiscernible] medical literature in terms of MWT. How do you think that evolves the mix of Xywav for patients on IH and how defendable or otherwise, do you think it may be as [indiscernible] agonist advance.

Yes, thanks for the question. Yes, of course, we're very pleased with the durability that we've seen for Xywav. We did, as you mentioned, we had really good solid patient adds this quarter, 200 for narcolepsy, 325 for idiopathic hypersomnia in total 25 net patient adds is actually the highest number of ads that we've had for a year. So very happy to see that continued momentum.

Obviously, the brand is proving itself to be very durable in the face of multisource generics. That's perhaps not surprising given the differentiation factors for Xywav haven't changed with the availability of multisource generics. We're still the only low sodium oxybate on the market, the only products approved for IH. Obviously, as we look ahead, we are anticipating the launch of the orexin. And I'll maybe get Rob to comment a little bit on how he's seeing the potential combinability of orexins with Xywav. Rob?

Yes. Thanks, Sam. Across the [ Hyperzone ] NT1, NT2IH, the root cause really is disrupted nighttime sleep. And Xywav is the only approach to address the disruptive nighttime sleeping. So we think it's a cornerstone of therapy there. It's been the case that patients will also use daytime stimulating agents. And we think that really offers another opportunity to complement the potential benefit of oxybate and specifically Xywav.

Our next question in queue coming from the line of Mohit Bansal with Wells Fargo.

This is [ Will Zang ] on for Mohit. So I guess, like looking at zani's Phase III trial in breast cancer, I just want to understand, given that you guys are developing in this like post TDXT posted HER2 set, what is kind of the patient pool? What is the size of the patient population that you're looking to address your sense and HER2 still be getting is in the early phases of this launch into the first-line breast cancer setting.

Yes. So the trial is positioned in patients who have been treated with HER2, the current treatment paradigm that's typically third-line plus patients. I'll remind you that we have data showing the zanidatamab, given its unique mechanism of action is active even in patients who've progressed on in HER2. And that comes from monotherapy data. It comes from a combination data with standard of care, staying in the HER2-positive, HER-positive population that we published and also with novel agents like the ALX agent.

We think this is roughly 150,000 patients annually. And we also feel that it's a significant unmet need has in her to progressively moves to the front line that zanidatamab would be, I think, unique in having data demonstrating its activity versus standard of care in patients who progressed on a HER2 regardless of the line of tariff. So we're eager to see those results. We've said in the past that we expect to see the trial completed enrollment mid-2027. And we could see results depending on how the events progress late 2027 or early 2028.

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

I wanted to ask on the Epidiolex strategy from here, maybe how the pieces there fit together? You guys are running a number of additional studies, LGS in adults, DE, GME? And there's also this new capsule formulation. I guess what I'm trying to understand is how are -- to what extent does this growing the opportunity versus defending it from future branded entrants as the DE space sort of heats up competitively? And then is this new capsule formulation, something that's going to extend the IP runway as well?

Yes. Thanks. I'll start and then also welcome comments from Sam and Rob in terms of both the broader commercial opportunity and some of what we are investing in on the clinical side. But if you step back and think about Epidiolex as a growth driver for the company, with the visibility of long durability into the very late 2030s now with this franchise we believe we have multiple opportunities to invest. We talked today about multiple clinical programs underway, and we also believe having the capsule formulation allows us greater potential penetration into the adult market for certain patients who are more suitable for the capital formulation.

And if we step back and think about the impact that this business development transaction of bringing Epidiolex into the company has had for us, it's created now a major growth driver we paid a little over $7 billion for what is the franchise that is growing nicely over $1 billion a year with the opportunity to grow in multiple formulations through clinical data and also internationally. It's a really nice business for us to be in and also continue to build around when we think about future business development transactions. Sam, do you want to comment further on the capsule?

Yes, happy to. Yes, we're very, very excited about the potential for Epidiolex to continue its strong momentum into the future. We have seen and we continue to execute on our strategy to grow Epidiolex in the adult segment. We continue to see growth in keeping patients on treatment for longer that persistency is really very material in terms of the long-term outlook. And we also identify an opportunity for patients to restart Epidiolex who may be a previously discontinued treatment. And when you look at the capsule formulation, the capsule formulation is going to enable us to do all of those things even better, particularly for those adolescent and adult patients where the oral liquid solution is a less convenient option for them.

So we believe the capture will enable us to capture naive patients, improve persistency in existing patients and encourage restarts for patients that may be started on the oral solid dose on the liquid and it wasn't the best treatment for them. So we do believe when you take all of those together, this is a material incremental opportunity that will drive more patients benefiting from Epidiolex.

And maybe to hit your IP question right before Rob jumps in. The capsule launch does not have any impact on IP. It does not have any impact on our ANDA agreements that extend the durability, as I mentioned, out to the 2030s, the very late 2030s our patent estate contains method of use patents that are relevant to all approved indications, and that's relevant to both the existing oral solution as well as the new capsule formulation. But Rob, do you want to cover now the clinical programs?

Yes. So we're excited to be initiating a number of new clinical trials Epidiolex, we're convinced of its broad activity across different seizure types based on prior data we have for the current indications in the EAP. And so as you know, about a year ago, we initiated a Phase II trial of topline here. We just announced a trial we initiated in tuminile myoclonic epilepsy that will be with the capsule formulation, and that's a Phase II/III seamless design, so potentially pivotal.

We also are initiating a trial in a broad set of DEs that could lead to a broader label there that would be pivotal and doing some more work in adult LGS patients to really try to better characterize its efficacy there and support its use from adult prescribers. So confident in the activity that Epidiolex has its ability to combine and as has already been said, because of the long -- congenity that we're initiating new trials in this space. And then since I have the mic, I just want to make sure my comments earlier on breast cancer for Ziihera understood, 150,000 really represents the pool of metastatic patients globally. So obviously, it's a subset of that who would have progressed still are eligible for treatment after in HER2.

Our next question in queue coming from the line of David Amsellem with Piper Sandler.

So I have a long-term question on the oxybate franchise, namely Xywav in IH. So obviously, we have the data in hand for [indiscernible]. And just wondering how you're thinking about the trajectory of IH? It's obviously growing nicely. There's good headroom here. That's definitely not lost on me, but the question is, once you do have that competition emerging in '28, how do you think about your growth trajectory longer term? And then even beyond that with potential availability of orexin. So if you could just comment on how you're thinking about the next several years for your IH part of your sleep business, that would be helpful.

I can certainly start, and then maybe hand over to Rob. Yes, I mean the differentiation for Xywav is twofold. And perhaps 1 of the most kind of important things about Xywav is the low sodium. And of course, that's going to be a component of its differentiation that will go beyond just another product having an IAH indication.

And this is a message that really does resonate with prescribers. We know that patients who are diagnosed with IH or narcolepsy, the majority of them do have a cardiometabolic or cardiovascular comorbidity. And so increasingly, I think physicians and patients recognize the importance of having a low sodium option. And that differentiation is obviously pretty durable. So -- in relation to the orexin question, maybe I'll hand that over to Rob.

Thanks. I was just going to add, again, that we are different Xywav differentiated on the basis of low sodium. And while it's well understood that not only narcolepsy but IH patients have a significant risk of negative cardiometabolic outcomes. We also demonstrated that in the Xywav study that after initiation of high sodium oxybate, you see a change in blood pressure, which is clinically meaningful. And so patients benefiting from Xywav now, I think that will be pretty sticky.

Did I miss another aspect of the question on narcolepsy that you want to me to address, Sam?

I think there was a question just around the competition versus the longer-term availability of.

Yes. I mean, again, I think I answered this earlier. Whether it be IH in narcolepsy, the root cause of the daytime sleepiness and symptoms such as cataplexy have to do a disruptive nighttime sleep and only oxybate and Xywav really the safest proximate could address that group cause. And so we continue to think that, that will have an important role in treating patients, even if they would additionally benefit from daytime wake promoting agents?

And just to build one last point here. With respect to the IH market, we are still very early in our overall penetration. We think there's probably 37,000-plus patients diagnosed and seeking treatment for IH. And while we've made significant progress and headway we do believe there's a lot of room still to grow here, and we believe that Xywav as we've seen with narcolepsy, including the patient support services supporting the overall journey that patients go through with a new diagnosis of idiopathic hypersomnia. We do believe that Xywav will continue to compete well in this market.

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

I had a question on Ziihera as you think about potential for indications beyond breast cancer, can you talk about what type of updates we could expect with regards to CRC or non-small cell lung cancer and how you might go about pursuing those indications?

Sure. So we have the ongoing basket trial, which is the 206 study. And in that trial, we continue to enroll patients with second-line colorectal cancer and non-small cell lung cancer. We had previously published on colorectal cancer, and those for some of the data that we brought to FDA, including -- and in addition, data from the EMERGE-206 trial that led to the breakthrough designation for colorectal cancer. So we'll continue to generate data in both of those indications through that study, and we'll work with FDA now that we have to identify the path forward ultimately for approval in colorectal cancer.

More broadly, we're very excited about the potential of zanidatamab. We have the ongoing frontline B2C trial that we're optimistic about. As you know, we're about to launch in GEA, contemplating other areas in gastric cancer, such as early gastric cancer where there's no approved HER2 therapy. Of course, we have the ongoing late-stage metastatic breast cancer trial as well as other Phase II trials looking to determine how else we might use that in combinations, sometimes novel combinations in the breast cancer setting as well as the new indications such as CRC and non-small cell lung cancer, as you mentioned. So overall, we do you think this is a pipeline and a product and we're pursuing every opportunity to export.

Our next question coming from the line of Gary Nachman with Canaccord.

So for Ziihera and GEA just back to that, if approved, how long before you think the NCCN guidelines will be updated since you already submitted the data for that? And how much would that impact the uptake? And I'm also curious, has there been any real off-label use in first-line GEA since the data came out late last year. Maybe just generally, a bit more on how you're thinking about the pace of the uptake in GEA, including with reimbursement because you obviously can leverage the BTC indication and have a lot in place already?

I can start on NCCN. We've been providing NCCN and all the data we have as soon as we have it, we share the data that went into the abstract and then we immediately share the New England Journal Publication. Obviously, we don't control their time lines, but we do think they have everything they need to adopt that into the guidelines potentially even before approval, but obviously, that's up to better.

Yes. And so just I'll follow up with the -- your question in relation to our kind of readiness to launch. I mean, we are ready to launch in GEA, we sized our team specifically with a GEA launch in mind. And made some investments to ensure that we can cover all of the customer groups that we want to cover very rapidly at launch. BTC has served for us more service for us is a powerful foundation for the next major growth phase in GEA. We have -- there's a number of features around our presence in B2C that make us very confident that we will be able to launch successfully and rapidly. We have more than 90% physician overlap between GEA treating centers. We obviously have access already established with the permanent J-code already acted from the BTC approval.

We've submitted the data to oncology pathways. And we have onboarded a team of clinical nurse educators who are ready to support smooth, efficient access and patient onboarding really leveraging our [indiscernible] care program. So we are ready, and we think our readiness combined with the data, the compelling nature of the data, which you're all familiar with by now, means that we should see really very rapid uptake, and we're committed to ensuring that who need this product can get it as soon as possible.

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

This is Anastasia for Akash. So on the post-INHER2 trial, I know you compared our arm is the plus physician's choice chemo, but it looks like the NCCN guidelines list [indiscernible] plus tras and [indiscernible] is the preferred second third-line regimen. Can you talk us through how you chose the comparator arm and what you consider the box for success in the trial as well as what is considered clinically meaningful. Also just verifying, you're still on track to complete enrollment in the first half of '27?

On the second part of the question, yes, we're on track to complete enrollment by midyear 2027. When we have results will depend on the events, but we haven't changed our guidance on that for end of 2027, 2028. In terms of the design of the trial, most of the data with other HER2 agents, or generated before the availability of the HER2. So that's really the motivation for this trial. It's unclear what to use once patients have progressed on in HER2. The trial is set up to be third line plus trial is a global trial.

So in some places, that will mean that patients they have gotten to cat previously. But in some parts of the world, such as South Korea, tucatinib's not commonly used. And so it will be a trial where you'd expect a third, fourth or even possibly top line patients.

While that's a poor prognosis group. We had prior data suggestion that zanidatamab can be active in that setting. And again, this is a head-to-head against herceptin and so we continue to be confident in zani's ability to beat what would be the standard of care in certain sets.

Our next question in queue coming from the line up. Etzer Darout with Barclays.

Great. Just a follow-up on comments on Xywav and guidance from Phil earlier. And just Wondering how much of that change is in the steep franchise revenue guidance is revised expectations on generics? In 2026? And maybe related to that, if you could provide any additional color on the additional investments for Xywav and Epidiolex reflected in the SG&A guidance? That would be helpful.

Yes. This is Phil. Thanks for the question. Maybe I'll take the first part and then turn it over to Sam for color behind some of the additional investments to drive even further momentum and revenue growth for Xywav and Epidiolex.

So the revised guidance really comes down to extremely strong execution in the field that's led to this unique benefit that Xywav has resonating with physicians and patients, which we believe is most likely leading to the very slow uptake that we're seeing of generic high sodium oxybate. We had said all along, we didn't expect really much of any impact in the first half of the year, and that impact has played out as we had expected.

However, based on the pace of the introduction of the high sodium generics, we're now expecting a much more muted impact in the back half of the year as well that is behind the guidance raise for Xywav where before we had expected the product to be flat to up mid-single digits this year, and now we're expecting double-digit growth for the full year. So really pleased with the momentum that we have and look for that to continue. Sam?

Yes. And in terms of the investments that we're making, obviously, given the strong resilience of Xywav and momentum, we are continuing to invest in some of the media spend that has been particularly effective in ensuring that patients diagnosed patients get treated with Xywav as well as some investments, continued investment in the patient support program.

For Epidiolex, we have continued to invest and upgraded our investment in ensuring that we can fully penetrate the LTC adult segments, where we've started to see some good inroads. And also, we do see an opportunity to drive persistence, and we have invested to expand our JazzCares program so that more patients can get enrolled onto the JazzCares program. We know those patients generally do better on treatment. And in addition, of course, we're starting to prepare for the oral solid dose launch as well. So that's the nature of some of the additional investments that are outlined in the guidance.

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

This is Luke on for Brian. Just one quick one on business development strategy. Can you provide any color on particular areas of interest within rare disease or with regard to development stage you'd be looking for? Or would you say you're fairly agnostic?

Yes. This is Renee. Thanks for the question. So we won't comment on specific deals for obvious reasons, but I would say we do remain highly engaged on the BD front. I'll remind you that we hired a new CEO earlier this year to drive those efforts, and we do continue to expect to announce 1 or more deals still in 2026.

In terms of the areas that we're interested in, we really do focus on where we believe there's a significant unmet need and where we believe we can have a meaningful impact with our unique, either expertise, global footprint or current other operations that we have underway. We generally will look for an efficiency of commercial call point 1 where the support services that we do offer to our patients can also be relevant and valued. We are focused on strengthening our current areas of rare epilepsy, rare sleep, rare oncology. We think there's a lot of substrate there. But we are also looking into other areas of rare disease, and we'll delay on actually providing much commentary there because they're so many different areas that we could go into that I wouldn't want to be too specific there in terms of inadvertently commenting on specific deals we might be interested in.

In terms of the stage, we were really excited to announce the AbCellera deal this last quarter. That is a preclinical collaboration looking at next-gen T cell engagers, so very early in our pipeline, but it directly aligns with our overall rare disease strategy, really expanding our focus on GI cancers. We are also, though, looking at later pipeline deals as well as commercial and near commercial transactions. It really depends on the specific asset and the type of deal that we are interested

in. Importantly, we have a strong track record of doing deals that have generated meaningful value. I mentioned Epidiolex, the GW earlier. Last year, we did the Modeyso Chimerix transaction. That was near commercial, obviously. And then we talked about quite a bit on this call about zani also came into our business via business development, which we're incredibly pleased by.

And I'll just close with a reminder that we're in an incredibly strong financial position to be able to execute on BD, we generated $824 million in cash flow in the first half of this year. $2.2 billion of cash on the balance sheet. So supports our ability to execute in BD in addition to the investments that we've talked about throughout the call today behind our commercial brands as well as our pipeline.

And ladies and gentlemen, that's all the time we have our Q&A session. I will now turn the call back over to Renee for any closing comments.

Great. Thank you, operator. Well, I'd like to close today's call by thanking all of our employees as well as our partners and stakeholders for their continued confidence and support. We look forward to sharing additional updates on the potential approval of zanidatamab and GEA as well as other progress in our business, looking forward to sharing those updates with you over the remainder of the year. Thank you for joining us today, and we can close the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

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.