Alrighty, I think we're going to go ahead and get started. Thank you all for joining us in the room and online for the third day of TD Cowen's 45th Annual Healthcare Conference. I am Joe Thome, one of the Senior Biotech Analysts here on the team at TD Cowen. It's my pleasure to have with us today the team from Jazz Pharmaceuticals for a fireside chat. We have EVP and CFO Phil Johnson, and EVP Global Head of R&D and CMO Rob Iannone. So thank you both for joining us. Maybe just to kick things off, obviously some news this morning, but it would be great just to kind of get a high-level overview of where the company sits and what investors should be looking at this year, and then we can dive into the specifics.
Fantastic. Thanks, Joe. It's really an exciting time at Jazz and really pleased to be here at the conference, not only have this session, but to meet with investors, to talk about Jazz, answer their questions, and help them make some informed investment decisions. Before I get started, I do need to do some of the work here to let you know. Please do consult our SEC filings, our recent earnings call for risk associated with our business. If we do refer to 2025 guidance in this session, we'll be referring to the guidance we gave at our recent earnings call. And then we may talk about non-GAAP measures as well.
Please do refer to our earnings materials for reconciliation to the corresponding GAAP measures as well. Before I get into the state of the business, which is in a really strong position, let's talk a little bit about the announcement we had this morning, well-timed to be able to be here with you today. I know you got some good knowledge of that company and its lead molecule as well. Chimerix, their lead asset, or dordaviprone, is targeted to H3K27M mutation in glioma that typically affects very young pediatric patients or young adult patients. Devastating disease with very poor prognosis.
I think around something like maybe 12 to 15 months patients survive from time of diagnosis. There's really been no advances here since radiation therapy 50 to 60 years ago. Huge unmet need. Looking forward to hopefully closing this transaction in the second quarter and then working aggressively with our new colleagues at Chimerix on getting this product approved and then out to patients and physicians.
This is a great fit with our oncology business. It can leverage some of the capabilities that we've already developed, particularly the commercial capabilities, provides us a near-term launch and also an asset that can be very durable as well with patent life extending into 2037 and potentially beyond with patent term extension. Please do consult the overall press release. We just put out the joint press release with Chimerix for additional details, and then we'll be, I'm sure, answering some questions here during the session. In terms of the state of the business, as I said, coming off a really strong 2024, we had record revenues of $4.1 billion in the year.
Each of our promoted brands also had record years, really strong growth with Xywav, growing 16% for the year and 19% in the fourth quarter. Really strong new patient adds in the fourth quarter, 525. So that business continues to perform extremely well, even with authorized generic competition and branded competition. Epidiolex also performed extremely well last year, growing in the teens, positioned to be a blockbuster this year. And we had really good news with the settlements with our ANDA filers and provided some clarity for the street for how long we'll have exclusivity for that product, which I think was welcome news.
Maybe it's a surprise to some that that would go out to the very late 2030s. And then, on sort of newer products coming to market, had great progress last year with the approval of and then getting initial patients treated with Ziihera for second-line biliary tract cancer. I know Rob will talk more in his remarks about the progress we're making with Ziihera and the great potential we see to help patients and also to generate significant revenues for Jazz and value for shareholders. So with that, maybe turn to Rob for some of your thoughts.
Yeah, thanks, Phil. I would love to start with the Chimerix announcement for this morning. As Phil mentioned, this is a very high unmet need cancer. I'm a pediatric oncologist by training. Even though I look young, I finished my training in 2001, and there really has been no progress in this area. So I know from treating these patients that it's been a very sad situation to have only radiation and surgery as the effective therapy. There was a breakthrough here in identifying the H3K27M mutation as causal in a group of these diffuse high-grade gliomas.
Just want to spend a moment explaining how that works because I think that underlies the rationale why we think this is going to be a very promising drug. That mutation results in hypomethylation. So there are growth factors, growth signaling that are essentially shut off in normal cells through a methylation process. And because of this mutation, you see then lack of methylation or so-called hypomethylation that then releases the growth signaling so that that becomes then the growth driver for this tumor. What's been shown with dordaviprone is it reverses that hypomethylation and causes remethylation of those growth genes that should be suppressed in normal tissue.
And that's been the mechanism of action. The clinical data bear that out. They've studied over 400 patients. And amongst those, there was a large proportion who had this mutation. And it's clear that the mutation is a marker for response to this therapy. There's been use in essentially frontline as well as second line. So patients who are just completing their radiation therapy then move on to get dordaviprone, very well tolerated in that setting, or even some data in combination therapy settings. In the pivotal trial, which was curated to identify those patients who truly had documented progression, for example.
And then had a response and a durable response, because that is the criteria for an accelerated approval in the US that you show objective responses that are durable. So the pivotal program will be a subset of that larger sample set. And it's passed the validation period. It's been given priority review with a PDUFA date of this August 18th. So we think this is potentially a meaningful targeted therapy for these patients who have a very poor prognosis and literally no alternatives.
Perfect.
I do want to tell you, I mean, that's the news of the day, and I wanted to touch on that, but we've got a lot of other exciting stuff. So if you give me another two or three minutes, I'll just hit a couple of highlights and then we'll jump into the Q&A. So I do want to talk about Zepzelca. You all know this is our drug that's approved in second line. It's now the preferred treatment choice second line small cell lung cancer. We put in place a frontline trial soon after we did this in-licensing deal. And we were very thrilled to see in the fall that at the time of the PFS analysis and the interim OS analysis, we were stat-sig on both.
And we've said that it was clinically meaningful in both and should become the new standard of care in frontline. We continue to be on track to complete that submission this half of this year. We haven't said yet where this is going to be published, but we're moving quickly to publish this, present it at a major congress, and publish it contemporaneously, and then to move quickly to get this adopted into NCCN because we do think it's practice changing. Very excited about that. Ziihera has had a number of really important milestones.
Recently, of course, we had approval for BTC, and now we have some launch under our belt, which we feel is going very well. Docs really want to use this for their BTC patients because of the transformative efficacy that we've seen. It's also helpful that we're now in the marketplace on formularies. Docs who are prescribing for BTC will be the very same docs who will be prescribing for GEA when that trial ultimately reads out. We are expecting approval in Europe for BTC. We've said 2Q this year, so imminent, and we're reiterating that we're on track for that.
We slightly revised timelines on the readout for the GEA trial based on the fact that it is an events-driven trial. The first readout is PFS, so it's based on progression events. We will take an early look at OS at that point, and then we count events for OS, and we do a second OS, and then a final OS. We said we're closing enrollment imminently, and with more mature events projections, we now have more confidence around when this should read out, so we've said second half of this year. We are still waiting, counting events as they come in.
And so we certainly wanted to leave open the possibility that that could be pulled into 3Q, which is essentially a quarter off what we had said previously. It's not on the basis of enrollment that's gone as good or better than projected. It really does have to do with events. And we're extremely excited about turning that card over because we believe that Ziihera, every time we've looked at data, it's performed, outperformed, whether that be in BTC or in GEA with the two frontline phase two trials that independently are showing 15.2 and 16.7 months of median PFS compared to historical references, which should be about the eight-month range.
But also in breast cancer, and we're seeing activity as monotherapy. We're seeing activity in combinations. We're seeing activity in patients who've progressed on Herceptin. It gives us a lot of confidence that head-to-head with Herceptin, like in the gastric trial, we should be positive. We also have two other pivotal programs. We are very excited that we've kicked off our breast cancer program. There's a real opportunity here. You go from approximately 12,000 BTC patients, 63,000 GEA patients, 150,000 breast cancer patients, US, Europe, Japan.
Breast cancer obviously is a very big population. For those who don't know the field, you might say, "Isn't that pretty crowded?" I would say it's evolved in a way that there's a real opportunity for Ziihera there because in HER2 now is entrenched in second line. It's likely to move to frontline based on the ongoing trial. For all the other HER2 agents, there really are no data showing efficacy in patients who've progressed on HER2. And there's reasons for some of those to think that they wouldn't perform very well in that setting.
We now have a growing body of data showing efficacy after HER2, being comparable. Recently published at San Antonio Breast Cancer Symposium in a cohort of patients who all had had HER2, showing very strong data. So we think we could be first, and right now that's sort of a third line plus, but if HER2 moves to frontline, it could wind up being a second line plus in a population of patients who tend to survive to their next line of therapy. So very excited that that ultimately would play out to its favor. And we lastly started a pivotal trial in a cohort, several cohorts of patients that would support a tumor agnostic indication.
So for anyone who has IHC3 plus HER2, regardless of tumor type, without an approved alternative therapy, would then be eligible. And that trial is ongoing as well. Those are the big highlights, Joe.
Perfect. And as I'm sure everyone in the room is aware, Chimerix was our top Q1 pick for the regulatory review. So we also like the asset. The deal is going to close in Q2. The PDUFA is in August. So maybe can you talk a little bit about your confidence that the drug will be approved this cycle? And obviously, there's the phase three ongoing to move it frontline. How do you think about the odds of success to move it in frontline in H3K27? Yeah.
So for me, we've looked at, again, very large experience. We've looked at the data, both objective response rates, seeing some very durable responses, looking at patients who did receive it in frontline where you'd expect a very short progression-free interval and survival. Single-arm data showing very encouraging results there. So we think it's a meaningful potential treatment for patients. We're pleased that the FDA recognized that with priority review. There's been no hint that there would be a need for an ad board, an ODAC.
And so that for a fairly straightforward package, that August 18th PDUFA date seems reasonable or even beatable. Whether this would get used in frontline, so of course, we would never promote off-label, and we do expect that initial label to be in the recurrent setting. However, we've just said very high unmet medical need. There really are no alternatives to this therapy. Patients universally progress on a pretty tight timeline. And so there was a lot of interest in participating in a trial where they could give this immediately following radiation therapy as part of the frontline therapy.
And that was really the inspiration for the confirmatory trial, the so-called action trial that's ongoing, which is a frontline trial and would ultimately update the label, but just showing the appetite to have that as really a first response rather than waiting for patients to progress who universally do and are then at a pretty challenging situation. Progression occurs typically with symptomatic complications given the location of these tumors in the midline of the brain.
Perfect. And we do get probably the most questions on zanidatamab and Ziihera and GEA for the upcoming readout. Can you talk a little bit about what will be deemed in your mind or clinicians' eyes clinically meaningful in terms of an extension on PFS? And do you need to hit in both Arm B and Arm C in the upcoming trial?
Sure. So for those who may not be familiar with the trial, it's newly diagnosed gastroesophageal adenocarcinoma who are HER2 positive by the typical ASCO-CAP criteria, which is IHC2 plus and amplified or IHC3 plus. The great majority of these patients tend to be 3 plus. In the most recent trial, that was about 80%. It's designed as a three-arm trial where the standard of care remains Herceptin chemotherapy. That's arm A. Arm B is zanidatamab replacing Herceptin plus the backbone chemotherapy.
And then arm C adds to that tislelizumab, which we believe is a best-in-class PD-1 inhibitor. And we know that for patients who overexpress PD-L1, they're likely to derive some benefit from a PD-1 inhibitor. There's been a lot of experience with this population of patients. Three prior clinical trials showing the control arm to perform pretty similarly. I mentioned the best was probably eight months. The very early trial that got its approval was more like 6.7 months median PFS. The most recent precedent is KEYNOTE-811, which actually got an accelerated approval based on response rate.
But when the PFS data read out, that was about a median of two months. Now, ultimately, they had survival data, but the approval was based on response rate and a median of about two months. In our trial, like I said, we certainly don't necessarily expect to replicate what we've seen in phase two, but I am encouraged that it's two independent phase twos that are showing 15.2 months and then incrementally better when you add atezolizumab. So pretty promising. And as you know, we upsized the trial to ensure that we have adequate power for the overall survival analysis that will come later.
Maybe on that overall survival analysis, when we see the data in the back half of the year, maybe how mature will OS be and kind of how are you going to be using that when potentially taking the PFS data of the FDA?
Yeah. I'm going to answer that, but I realized I left one of your questions on the table, which is, what do you need to get approval for both? So I gave that detailed study design because certainly you need to beat the control arm to get approval. So arm B has to beat A and be stat-sig, clinically meaningful to get approval. Arm C has to beat the control arm, arm A, stat-sig, and be clinically meaningful. Now, for contribution to components, you wouldn't want to add a therapy if it's not also adding incremental efficacy. And so arm C has to be incrementally better than arm B.
Yes for efficacy, but also just an overall benefit risk when you're talking about whatever additional toxicity you might have from that. That traditionally hasn't had to be a statistical evaluation versus more of a consideration of the totality of the data, especially when you're going to want to look at subgroups like PD-L1. And then coming back to your other question was.
In terms of how mature the OS is going to be and how you're going to use OS when the PFS is done.
So the first analysis is PFS driven by PFS events. Now, one of the consequences of having pushed out a little bit beyond protocol assumptions is we probably have more power for OS than we thought we would. Having said that, what's important is that we preserve the power for the study for the longer term. So we do have a shot. The purpose of that first OS is really to support the approval based on PFS to show that there's not a detriment, that there's a trend in the right direction. The second OS analysis has about the power that the original trial design would have had at its final.
And so then you start to get into sort of a more meaningful probability of success. And then you have a final analysis that we think is comparably powered to other modern trials. Now, having said that, powering is just a construct that relates to how big is the effect size. And so like in the Zepzelca trial where we weren't expecting a stat-sig OS result, you can see it if the effect's big enough. So we'll see. That's the nice thing about having multiple shots there.
And can you talk a little bit about the relative size of the GEA market versus your initial launch indication of second-line BTC?
Yeah. So BTC is about 12,000 patients first and second line worldwide, when we talk about US, Europe, and Japan, with about 3,000 in the US. GEA is substantially larger, frontline 63,000. And in frontline, you tend to get a longer duration of therapy, of course. And then when you get to breast cancer, 150,000. And even if you're in second, third, fourth line, those patients do tend to make it to subsequent lines more so than, let's say, difficult-to-treat lung cancers. And so we think that becomes one of the biggest market drivers for us.
Similar to BTC, where there's the 12,000 Rob mentioned across those various geographies with 3,000 in the US. I also think GEA is similar with the 63,000 you mentioned across those major geographies and roughly eight, I believe, in the US. In the ASCO data in BTC last year, we did see that Ziihera does show maybe a slightly larger benefit in the IHC3 plus population versus 2 plus, and the label followed that. When you think about GEA, do you expect the same thing? What proportion of patients in the trial do you anticipate will have IHC3 plus disease?
We don't have data from the trial to track, but we know it's a great majority that are 3 plus, probably similar to BTC. Is that 80%? I'm not quite sure, but it's a great majority of 3 plus anyhow. But I would say I would caution around conclusions around IHC 2 plus. Again, I would never promote off-label or encourage this, but if I were the treating physician and I had a second-line BTC patient with an amplified 2 plus, I would use it. We just don't have enough data to be sure it doesn't work there. Certainly, when you're in a frontline setting where you're also with combination therapy for a tolerated drug, I think there's a reason to give it a shot to have some additive benefit.
So I don't anticipate that our label would be restricted in frontline GEA. I actually anticipate when we read out the frontline BTC, we'll probably broaden the label.
And maybe can you talk a little bit about the opportunity in breast cancer and your work here? Obviously, you've shown some interesting data positive and HER2. Kind of how are you thinking about zanidatamab in that setting?
Yeah. I mean, this is something that I think if you're not working in the field, you may have missed this, but I would say I had prior experience in breast cancer really going back for Keytruda days, but when I was at Immunomedics as their CMO, obviously, we worked with many breast cancer experts. I would say that the day this deal closed, I was on the phone all day with breast cancer docs saying, "We want to work with this drug based on the experience that they had."
They were observing a couple of things, very well tolerated, especially as monotherapy, highly active, not in a direct comparison, but more than you'd expect even from the combination of Herceptin and Perjeta. They were perceiving that while there's a lot of excitement around Enhertu, it's not curative. There's going to be a major scientific gap in terms of how do you treat a patient who's progressed on Enhertu. Remember, Enhertu is built on the Herceptin scaffold. So you're essentially giving Herceptin with a warhead, especially anticipating that the frontline Enhertu trial is, remember, a combination of Enhertu-Perjeta versus Enhertu versus the so-called Cleopatra regimen, which is Herceptin-Perjeta chemotherapy.
So you may be in a situation where patients are getting Enhertu, Herceptin-based, plus Perjeta, and then progress. And so you wouldn't just give the frontline therapy next, or at least not without having data to show that it works. And then there's a whole host of other things you could give. Would you give T-DM1, which is another ADC? Well, Enhertu kind of blew T-DM1 out of the water head-to-head. Would you give tucatinib, which is certainly relied upon for brain mets, but no data in that setting after Enhertu? And so the message to us was, there's a big gap here. We know your drug is working.
We have an accumulating body of data to show it's actually working no matter what you've given before, Herceptin-Perjeta, tucatinib, T-DM1, now a growing body of literature on Enhertu itself, which makes sense because Enhertu resistance is probably from resistance to the Topo I warhead. They said, "We want this drug as a choice for after Enhertu." And there's been tremendous enthusiasm for doing that trial at a time where no one seems to be working in that space. There are novel ADCs that would obviously be testing after Enhertu as a salvage, but none in the pivotal space.
And so it was serendipitous that we had the opportunity to get into it. We have the data to do it. And ultimately, the design of the trial is patient comes in, they're assigned their chemotherapy, they're randomized to either get zanidatamab or Herceptin, and patients who all progressed on Herceptin and then progressed on a Herceptin-based ADC. It seems like a low bar to win. And based on the data, we're confident that it's going to win handily and be the only asset that has data in that space. And I certainly think that if we're head-to-head in Herceptin, not naive patients with gastric and look good there, that it's going to have to look good in breast cancer.
Perfect. And maybe we'll jump over to the sleep franchise. Maybe start on the narcolepsy side of things. What are you seeing in terms of obviously generic Xyrem and potential competition from Lumryz as it relates to your Xywav franchise? How sticky are you able to keep your oxybate side of things, and what's anticipated in the current guidance?
Yeah. So as we mentioned before, we do expect Epidiolex to grow this year. I'm sorry, Xywave to grow this year. We gave our guidance. We didn't break that out between narcolepsy and idiopathic hypersomnia. Clearly, we've said consistently we see the biggest growth opportunity with idiopathic hypersomnia. As I mentioned earlier, we've been really pleased with how well narcolepsy has held up, not just with the AG, but also with Lumryz coming in as well. We do think this really speaks to the benefit that patients and physicians see to low sodium in a patient population that has an increased risk relative to the general population of cardiovascular events.
And we've continued to build out not only the messaging to physicians on this point, messaging to payers, but also bringing additional services that have really helped with persistency and getting patients up to a really good therapeutic dose where they're getting good benefit from the drug through our nurse navigator program that's been highly successful. So we really feel good about the position that we are in. We did say for 2025, our guidance does assume that authorized generics continue for the full year of 2025. And there is uncertainty about what will happen in 2026.
That is the year that generics can come in. Technically, even Hikma could elect to come in now. They could have elected to come in last year as well. Certainly, if we do have generics coming in and Hikma would not be in the AG, that AG revenue would go away. We'd expect remaining Xyrem revenue to come down significantly. Xywav is the question mark to the extent that the market, including payers, are really valuing the low sodium content that we have. We think that can be a stickier franchise. And we'll look forward to making strong progress this year, growing that franchise to position ourselves well for 2026 and beyond.
When you think about IH, how penetrated into this market are you? Can you kind of talk about how easy it's been to identify and treat this proportion of patients?
You know, the rule was nothing for this condition before. So this is a market that we're building over time. And it took us quite a while to build narcolepsy as well. So I think it was 3,900 patients that we had on Xywave in idiopathic hypersomnia coming out of 2024. There's probably at least 27,000, I think, from the claims data we've seen of patients who are diagnosed and seeking treatment. And then we have anecdotal data from physicians saying in their practice, they actually think they have as many IH patients as they do narcolepsy patients. So we see significant room here in the US to continue to grow in IH.
We have heard.
I just, I know you don't have much time, but I do want to just come back from a medical perspective. To me, Xywave has orphan exclusivity because of the high cardiovascular risk in narcolepsy patients and the FDA statement that Xywave is safer for all narcolepsy patients because of that underlying risk. So for me, the benefits of low sodium should be the main driver of treatment choice, even if all other things are equal. And nobody should be taking that amount of sodium who doesn't have to, especially a patient with narcolepsy. Having said that, Xywave has other advantages.
It can be tailored and optimized by virtue of its split dose. For many people, it's not intuitive. Why would you want to take a drug twice if you can only take it once? In this case, actually, it's important that you have the flexibility. When I say tailored, it's because people's lifestyles vary day to day. They can't have two prescriptions, one for Lumryz, one for Xywav. So on a Friday night where you're out late and you've got an early morning soccer game with your child, maybe you've got to tailor it to fit that schedule versus on a Sunday, Saturday, and a Sunday, you say, "I really want to just sleep as well as I can," and you tailor that.
Optimizing. It's clear from the studies we've done associating PK exposure of oxybate to PSG findings that you don't optimize with a PK curve that looks like Lumryz. If you gave Xywav once, as you can do, it's effective but may not be optimized for a particular patient. Being able to wake up, take that second dose to ensure that you get the maximal effect for the next period of night really ultimately gives you the best sleep. And this is the root cause of narcolepsy. You have to correct the underlying sleep in order to have relief of symptoms during the day, which is of course sleepiness, cataplexy, but other related symptoms. So it can be tailored and optimized in a way where it's also the superior drug, not just the safer drug.
Perfect. And with that, we are at time. So congrats on all the great progress and looking forward to more.
Thanks for having us, Joe. Appreciate it.