Good afternoon, ladies and gentlemen. My name is Abby and I'll be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals Fourth Quarter 2023 Earnings Conference Call. Today’s conference is being recorded and all lines have been placed on mute to prevent any background noise. [Operator Instructions]. Thank you. And I’ll now turn the conference over to Andrea Flynn, Head of Investor Relations. Ms. Flynn, you may begin.

Thank you, operator, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its fourth quarter and fully year 2023 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also refer to the press release we issued earlier today, which is also posted to our website. On the call today are Bruce Cozadd, Chairman and Chief Executive Officer; Renee Gala, President and Chief Operating Officer; and Rob Iannone, Executive Vice President, Global Head of R&D; 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 and commercialization milestones and goals, 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 today's press release, in our slide deck and the risks and uncertainties described in our SEC filings which identify certain factors that may cause the company's actual events, performance and results to differ materially from those contained in the forward-looking statements made on today's webcast. We undertake no duty or obligation to update our forward-looking statements. As read on slide 3, we'll 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 Bruce.

Thanks, Andrea. Good afternoon, everyone. Thank you for joining us today to discuss our fourth quarter and full year 2023 results and our excitement about 2024. I'll start on slide 5. 2023 was a highly productive year for Jazz. Thanks to the passion and innovation of our talented employees around the world, we helped more patients generate more than $3.8 billion in revenues and advanced multiple pipeline programs. We believe these accomplishments position us well for success in 2024 as we focus on commercial execution and accelerating top line growth, delivering on key pipeline catalysts, and remaining active in assessing corporate development opportunities to drive growth and value creation. Before we move on, I want to highlight our announcement from last week that Philip Johnson is joining Jazz as our Chief Financial Officer effective March 1st. Phil comes to Jazz from Eli Lilly, where over the course of almost three decades, he led several finance functions and was most recently Group Vice President of Finance and Treasurer. As we move into 2024, we are excited to add Phil's industry experience, leadership, and strategic approach to our executive team. Turning to slide 6, our performance in 2023 is reflective of the strong execution that's transformed our business over the past several years. Highlighting a few commercial accomplishments in 2023, combined revenue from our key growth drivers, Xywav, Epidiolex, and Rylaze increased 27% year-over-year. We drove more than $1.9 billion in revenue from our sleep therapeutic area, reinforcing our confidence in its durability. Epidiolex continues to grow, reflecting strong underlying demand and the execution by our commercial team. Epidiolex is now annualizing at more than $900 million and on track to deliver on its blockbuster potential. Our oncology therapeutic area surpassed $1 billion in revenue for the year, with Rylaze leading the…

Thanks, Bruce. We had a strong fourth quarter, generating quarterly revenue of more than a $1 billion for the first time. This capped off a successful 2023, in which we achieved year-over-year double-digit growth across each of our key products, Xywav, Epidiolex, and Rylaze. I'll start on slide 9 with our sleep therapeutic area. Total revenue from sleep, which includes Xywav and Xyrem sales, plus royalties from high-sodium oxybate authorized generics, or AGs, was $483 million in the fourth quarter of 2023, and exceeded $1.9 billion for the full year. We believe we are well positioned to achieve our Vision 2025 goal of $2 billion in sleep revenue. Xywav revenue was $337 million for the fourth quarter of 2023, and approximately $1.3 billion for the full year 2023, which represented year-over-year annual growth of 33%. We have increasing visibility into oxybate market dynamics since the entry of branded and AG high-sodium oxybate in 2023. We remain confident in the durability of our sleep therapeutic area, and Xywav in particular as the only low-sodium oxybate and the only therapy approved to treat idiopathic hypersomnia, or IH, we expect Xywav to remain the oxybate choice, including the number-one treatment for narcolepsy. Exiting 2023, there were approximately 9, 525 narcolepsy patients taking Xywav. Our focus is on educating patients and prescribers around the lifelong burden of high sodium intake for narcolepsy patients. Based on positive feedback from the field about the benefits of reducing sodium intake, we believe that the majority of patients and healthcare providers will continue to prioritize long-term health when evaluating oxybate therapy. Looking at IH, annual revenue from this indication doubled from 2022 to 2023, and we continue to view IH as a source of sustained growth for Xywav. Exiting 2023, there were approximately 2, 775 active IH patients…

Thanks, Renee. 2024 represents an exciting time for us on the R&D front. And we anticipate multiple and meaningful catalysts across oncology and neuroscience. On slide 14, we've provided an overview of the key clinical programs in our diversified pipeline. And I'll highlight several milestones we expect to reach in the near term. Starting with oncology and zanidatamab, we anticipate completing our rolling BLA submission for accelerated approval of zanidatamab in second line biliary tract cancer, or BTC, in the first half of this year. And I'm excited to report that we recently initiated our first line BTC trial. Additionally, we are targeting late this year to report top line data from the ongoing Phase III first line gastroesophageal adenocarcinoma, or GEA trial. If positive, we expect this trial would support a registration. I'll speak more to our zanidatamab development plan in just a moment. We're also pleased with the progress of the Zepzelca first line trial, which completed enrollment in January of this year. Top line progression-free survival data for Zepzelca in combination with Tecentriq and first line extensive stage small cell lung cancer is expected at the end of 2024 or early 2025. If approved, this indication would enable more patients with small cell lung cancer to potentially benefit from longer duration of therapy with Zepzelca. Turning to neuroscience, we expect top line data from our Phase three III trial of Epidyolex in Japan in the second half of 2024. We also have ongoing trials for Suvecaltamide or JZP385 to both essential tremor and Parkinson's disease tremor with top line data from the ET trial expected late in the first half of 2024. If trial findings are positive, we believe this trial could serve as part of a pivotal regulatory package. Slide 15 provides more detail on our…

Thanks, Rob. I'll start with our top line results on slide 18. As a reminder, our full financial results are available in our press release and 10-K. In the fourth quarter of 2023, we achieved more than $1 billion in total revenues. And for full year 2023, we recorded more than $3.8 billion in total revenues, representing 5% growth over full year 2022. We were pleased to deliver growth, despite headwinds from the introduction of both branded and AG high sodium oxybate competition, with our full year results driven by continued growth in both neuroscience and oncology, including double digit growth from each of our three key growth drivers. Turning to slide 19, our full year 2023 non-GAAP adjusted net income was approximately $1.3 billion and we reported non-GAAP adjusted EPS of $18.29. We continue to generate significant cash from our business, demonstrating the strength and diversity of our global portfolio. We recorded approximately $1.1 billion of cash from operations for the full year 2023 and ended the year with $1.6 billion in cash on hand. Our strong overall financial position and operating cash flows mean we have significant flexibility to invest in priority commercial and R&D programs, as well as corporate development opportunities. We are pleased to share our full year financial guidance for 2024, beginning on slide 20. Our 2024 total revenue guidance range of $4 billion to $4.2 billion represents 7% year-over-year top line growth at the midpoint. We expect double digit percentage revenue growth of Xywav, Epidiolex and Rylaze combined to drive total revenue growth this year. Our 2024 neuroscience revenue guidance of $2.8 billion to $2.95 billion reflects the expected growth of Xywav and IH and Epidiolex offset by the expected decline in Xyrem. I'll note this guidance is inclusive of AG royalties, which we…

[Operator Instructions] And we will take our first question from Jessica Fye with JP Morgan.

Hey there. Good afternoon. Thanks for taking my question. We're seeing worries about Xywav’s position in narcolepsy, despite what looks like sleep neuro guidance, slightly ahead of consensus. Can you talk about what you're seeing competitively in narcolepsy right now, and maybe set expectations for what you think the outlook is for Xywav in that setting? Thank you.

Yes, hi, Jess. Thanks for the question. Renee, maybe I'll turn that one over to you.

Sure, yes, happy to comment. Thanks, Jess. So at a high level, as we look at Xywav for 2024, as we noted on the call, we do expect it to be an important growth driver, one of three, as we look at where we expect growth on the top line across the year. We do see Xywav continuing to resonate as a differentiated therapy, as the only low. sodium oxybate, the number one treatment of narcolepsy, and then, of course, the only drug approved for IH. What we're seeing in terms of the market is we are seeing the majority of new to oxybate patients starting on Xywav. We do believe it will remain the oxybate of choice. And that said, as we're looking at Q4, as we've said, we do expect some patients to try Lumryz given there are now many more patients on Xywav than Xyrem, naturally, we would expect some impact there. So, as we look at exiting the fourth quarter, we had more than 9, 500 narcolepsy patients ending the year. Keep in mind also that our patient number is a net number, so it reflects the adds from the quarter less in a discontinuation that we had. Also, in the fourth quarter, we did see an increase in our non-revenue bottles as we continue to refine our patient support services program. We are seeing an increase in programs that essentially seek to take advantage of our affordability programs, this increase with seasonal, and we don't expect it to continue given how we're refining those programs. And then finally, keep in mind within the fourth quarter, as we continue to add new patients in both IH and narcolepsy, those patients need to titrate, so the revenue is lower upon starting, meaning that a patient that is starting therapy may not be as valuable upon starting therapy as a patient that's discontinuing. And then I'll just say that as we look forward, we do believe that every high sodium patient is a potential Xywav patient. In particular, as we see decreasing commercial coverage for Xyrem, we expect those patients to shift therapy, either to authorize generics, which of course we receive a significant royalty on, or to fix that high sodium branded therapy, or importantly to Xywav, which will be an additional driver of growth in 2024 for narcolepsy, with probably more of our growth coming from an idiopathic hypersomnia.

And we will take our next question from Marc Goodman with Leerink Partners.

Yes, can you give us a little color just on the oncology portfolio? I mean, you have products, Defitelio, Vyxeos, Zepzelca, Erwinia I'm sorry, Rylaze, I still say that, Bruce, I apologize. Any color you can give us just on the quarters, I mean, Defitelio and Vyxeos is obviously much higher than expected. The other two products flattish quarter-to-quarter, so anything you can provide would be helpful. Thanks.

Yes, Marc, you're not the only one that occasionally refers to a prior product name. I'll say for some of our products, we do see significant quarter-to-quarter variability, particularly in the sort of very rare diseases. This has been true of Defitelio for years, so I wouldn't read too much in on the Defitelio, Vyxeos side. We've been more focused on the growth in Zepzelca, but particularly on our strong performance with Rylaze, and maybe I'll turn it over to Renee to comment a little bit on Rylaze.

Yes, thanks, Bruce, and thanks for the question, Marc. I would say certainly echoing the variability with respect to Rylaze in particular, we did see some seasonality at the end of the fourth quarter going into the holidays. This is a relatively small market in terms of the rare population here with respect to the use that we see in Rylaze. Importantly, we do see Rylaze as a growth driver in 2024. Just a reminder, due to supply constraints with Erwinia, we were never really able to fully understand the market potential for that product, but we're continuing to see strong demand overall in the fourth quarter, and we also began a rolling launch in Europe late in the year. That is not an area, as we think about Europe, that we expect to see a strong contributor to growth in 2024, but we're pleased we were able to get that underway. And then with respect to Zepzelca, we've established this as the number one treatment for second line small cell lung cancer, and we do see future growth opportunity in first line as we look at reading out that study either late this year or early the next year. We continue to hear positive feedback from HCPs on the clinical benefit, the ease of use as I mentioned and seeing additional use there but we do as Bruce said have some variability quarter- to-quarter in that area as well.

And we will take our next question from Jason Gerberry with Bank of America.

Hi, good evening. Thanks for taking my question. My question just how you foresee with zani the frontline GEA differentiating in the PD-1 negative subpopulation if you aren't stratifying patients on the basis of PD -1 status. So is the thought here that as long as that subpopulation doesn't produce a discordant result versus the all comer group that that should facilitate a broader label than Merck secured with this KEYNOTE-811 regimen. Just kind of wondering how you can kind of paint that picture. Thanks.

Thanks, Jason for the question. Rob, you want to weigh in on that?

Yes, the PD -1 biomarker wouldn't have any predictive value for zanidatamab or any other HER2 therapies. But we think we can clearly define a benefit in the PD -1 positive or negative subgroups. Of course, we have two experimental arms. Part one where zani is combined with standard of care chemo. And we also have an arm where we add PD-1 antagonists to that atezolizumab from BeiGene. And so we have an opportunity to address both the PD-1 negative group where the standard of care continues to be Herceptin chemo and the PD-1 positive group where PD-1s have been shown to benefit patients. And we think in that segment we have the superior HER2 drug. We don't think that there will be a differential based on which PD-1 is used.

And we will take our next question from Ami Fadia with Needham & Company.

Hi, good afternoon. Thanks for taking my question. Going back to the Oxybate market, can you talk about the market dynamics here, particularly with the entry of Lumryz? How has that impacted the total number of patients on oxybate? Do you believe that they are expanding the market or predominantly taking share? And how do you envision that evolving in 2024 in your guidance? And maybe just related to that, in IH, can you elaborate on where the increased salesforce will focus on to drive additional prescribing debt? Thanks.

Thanks Ami, for those questions. Renee, I'll turn that one over to you.

Sure, yes, and thank you, Ami. With respect to what we're seeing in narcolepsy, as I'd mentioned, new to oxybate patients today, we see the vast majority of those starting on Xywav. Now based on as we look at 2024 for example, we expect to see a continued decline of Xyrem. We said we expect AG royalties to exceed $200 million and we expect to see Xywav as an important growth driver. But that growth will likely be greater in IH versus narcolepsy as I mentioned before, but the narcolepsy business is very important to us. As we think about what's happening in terms of narcolepsy, given that there are fewer patients that are on Xyrem today versus what are on Xywav, it would be natural to expect some impact to Xywav from patients starting on branded fixed-dose high sodium Lumryz. We do continue though, to see as we look forward this opportunity for some growth within narcolepsy related to some market expansion. I think there's very little of that that we're seeing right now and just given if you are looking at on market opportunity it would be much easier to go after patients that are already experienced on oxybate. Now with respect to IH, as we look at what's happening with that market, we continue to see an opportunity to continue to educate on the entire condition of IH and the benefit of restorative sleep in terms of the improvement on that overall condition. We are looking at opportunities where we have both experienced oxybate prescribers but those who are not currently doing it a lot of prescribing for IH as well as broader opportunities to focus on prescribers that are less familiar with oxybate in general but have a number of patients within their practice on IH.

And we will take our next question from Ashish Verma with UBS.

Hi, thanks for taking my question. So I wanted to just like get your latest thoughts on what you're thinking about bridging to 2025 vision of $5 billion in sales. Do you think you need the development to get there? And is it possible that you could reconsider the target metrics for 2025 at some point? And then second question, so for Zepzelca on competitive front, there is a drug from Amgen, Tarlatamab, if you can comment on how do you think the small cell lung cancer space might evolve? Thanks.

Thanks. Yes, Ash, thanks for the questions. On the Vision 2025 target for revenue specifically, we had identified that as we came into 2022 as coming about $2 billion from oxybate. And I'll remind you that we had excellent progress with Xywav in particular in 2023, and we continue to expect additional growth in 2024. Last year, we had over $1.9 billion as we moved toward the $2 billion target. Epidiolex, we said, would be a blockbuster product north of $1 billion in revenue. We're currently annualizing based on the last quarter at over $900 million and still showing this growth both in the US and outside the US with Epidiolex. So we believe we're solidly on track for that. And we also said our oncology business would contribute north of a $1 billion in 2025, Epidiolex and oncology together contributing $2.5 billion. And we're very pleased obviously to see our oncology business grow to more than a $1 billion in 2023. And we've again, projected nice growth of that business, as you can see from our guidance for 2024. So for the organic piece, $4.5 billion, we feel that we are on track for Vision 2025. We of course did include a placeholder of $500 million in 2025 revenues that could come from corporate development transactions done after we announced Vision 2025. Of course, that could include some revenue contributions from zanidatamab where we said we'll finish our rolling ELA submission in the first half of this year. And we're projecting that launch come in 2025 or sooner. We're not suggesting that would make up all of that $500 million in 2025. But we are in strong financial position with our cash and our cash flow to be active on the corporate development side. And we continue to review targets that would make interesting additions to our business. I'll point out we're not going to do a deal just to do a deal. We're going to do a deal if it's a good use of our capital, it furthers our strategy as an additional growth driver and provides sustainability over not just 2025, but as we look through the period 2025 to 2030. So long answer asked to a short question, but we're making excellent progress toward Vision 2025. And on the Zepzelca side, maybe Rob, I'll turn that one over to you.

Happy to, Bruce. As Tarlatamab is a very different mechanism of action than Zepzelca. The data that will support, that have supported a BLA are in the third line versus Zepzelca in the second line. And the safety profile for Tarlatamab is really quite different with a high risk of CRS and serious CRS, even in including neurological effects. And that safety profile may well be a significant challenge, especially for community practitioners where many small cell lung cancer patients are treated. In contrast, Zepzelca has a very favorable safety profile, can be easily given as an infusion once every three weeks. And that really makes it an ideal candidate for add-on therapy in the frontline setting. And as in partner with Genentech, we are running a frontline trial in small cell lung cancer. We expect top line PFS results as early as the end of this year. And that will allow a greater proportion of patients to receive therapy for a longer time.

And to build on that further, so as we look at that opportunity in first line, we also appreciate, as Rob had mentioned, the ease of use for Zepzelca currently in second line, just given the tolerability profile, the patient experience, the clinical activity, these patients that are coming in with second line small cell lung cancer generally have quite a poor health prognosis. So they've already relapsed at this point, and so having a drug that's very easy to use is quite important in the treatment decision.

And we will take our next question from Joseph Thome with TB Cowen.

Hi there. Good evening. Congrats on the progress, and thank you for taking my question. Maybe just one on zanidatamab. How should we think about continued investment in the program overall, and you outlined the breast cancer opportunity and other HER2 expressing cancers. I guess, what's sort of the decision point to make that additional investment to start additional studies, either in breast cancer or some of these other cancers? Is it the first kind of approval in BTC? Is it if it works in GEA, or are you looking more at the landscape overall in competition? How should we think about the appetite to expand that? Thank you.

Yes, I'll start. And then, Renee or Rob, if you want to add anything in, you certainly can. While we don't give R&D guidance by program, you saw our R&D guidance for the full year represents about the same percentage of total revenues as we reported for 2023. With zanidatamab having contributed a lot to the growth in R&D, 2023 over 2022, we have a little bit more of an apples-to -apples comparison between 2023 and 2024. I will say our guidance does assume activity in breast as well as BTC and GEA. And we'll certainly, at our R&D day in March be explaining a little bit more about our specific plans. But Rob, let me know if you want to say more now.

Yes, only that we know, of course, we're already working in areas outside of BTC and GEA. We've published data in the metastatic breast cancer setting, both HER2-positive and the combined HER2-ER-positive patients early in metastatic setting. So we already have data. And as Bruce mentioned, we are planning for additional work in breast cancer even now.

And we will take our next question from Gregory Renza from RBC Capital Markets.

Hey, good afternoon, good evening, Bruce and team. And congrats on the progress and thanks for taking my question. Maybe, Bruce, just adding on to some of the color that you've provided around Vision ‘25 and that $500 million potentially through corporate development. Just curious if you could comment a bit on where you see valuations for some of the areas in which you're looking externally. Certainly, 2023, as you've noted, maybe put Jazz just based on where the markets were in a position of strength. I'm just curious how you see 2024 to date for competition, for attractiveness of assets that are in Jazz's power alley. Thanks so much.

Greg, thanks for the question. We have quite a bit of experience on the corp dev side having done a number of these transactions over the years and feel like there's a great set of opportunities out there across neuroscience and oncology, as well as some rare disease spaces that would build on capabilities we already have in-house based on a lot of our activities over recent years. Being active in all of those spaces, looking at on-market and near-market products, including some in late stage development, I think gives us the ability to find things at valuations that work for us. There can be pockets of areas where it seems like everyone's looking at the same time, valuations may be a little high to earn a good return. If that's true, that's why we look at other areas, as well, so with our team, with our strong financial position, we're confident we'll continue to find opportunities to put capital to work to drive that growth and sustainable growth over a longer period of time.

And we will take our next question from Annabel Samimy with Stifel.

Hi, thanks for taking my question. On zani, I know that you're still in the rolling BLA process, but can you talk about your launch plans there, how you might be preparing for it in terms of sales, which are type of investment you need to make in the launch of the infrastructure to appropriately target GEA cancers versus lung cancers, and could that potentially impact, say, Zepzelca? And then, I guess, sort of related, on the operating margin, Vision 2025, I guess, was supposed to be five points over where the guidance was set back in 2022. I think you're still at 43%, and that would have been 48%, so are you backing off of that operating margin guidance, given the number of investments that you have to make here? Or just if you can give a little color there, that would be great. Thanks.

Yes. Annabel, maybe I'll take the second part of your question first, and then we'll come back to zanidatamab commercial launch thinking. When we set that target, it was coming off of 43% margin back in 2021. I'll point out we essentially achieve that increase in margin as we moved through 2022, that's given us great flexibility to make the kinds of investments we wanted to make in the R&D portfolio and behind our key growth drivers on the commercial side. So we're glad to be making those investments today. We obviously haven't given guidance for 2025 specifically yet, I will point out as we've pointed out before that whether or not we do a corporate development transaction and spread our expenses over a greater revenue base does impact our margins. So, we built that into our thinking as well but for now, we think the investments we're making are investments that will lead to high return for our shareholders. Renee, you want to talk about zanidatamab?

Sure, yes, thanks for the question. So with respect to how we're thinking about BTC, we believe we have the ability to really effectively cover our BTC launch, which could happen as early as later this year, we'll be ready certainly, but we're looking at more than likely 2025. So the way we're thinking about the launch is we should be able to leverage our current field force that is out in the field right now with Zepzelca with a relatively small augment to that field force. The key is to enter the market with BTC to help HCPs get important experience with zanidatamab. We do expect to have our GEA data as early as the end of this year, that's what we're targeting. And so by being in a position where we have our HCPs getting experience with zani, it's a more seamless transition when you're thinking about GEA. Also, if we're looking at an SBLA process for GEA, that's of course a bit faster as well. So we think it's a relatively small expansion to the footprint in the US. And we're also looking at zani as a global brand, an important global brand for us. So after the US, we're also looking at Europe as well as Japan. And while the BTC opportunity holistically from an epidemiology perspective is smaller, it's a high unmet need in terms of the severity of the cancer. And so we're looking at a build strategy. Start with BTC, where we have around 12, 000 patients worldwide, build into GEA with 63, 000. And when I say worldwide, I need the US, Europe, and Japanese markets. And then as we expand into breasts, we're looking at a much larger population of more than 150, 000 patients. So that's how we're looking at the broader opportunity.

And we will take our next question from David Amsellem with Piper Sandler.

Hey, thanks. Can you talk a little more about Epidiolex and what drove the performance? Are you seeing double digit volume growth, both US and x-US? And was there any stocking benefit that we should be aware of? Thank you.

Thanks for the question, David. Renee, maybe I'll turn that one over to you.

Sure. Yes, happy to comment. So as we look at Epidiolex, as we've said in the past, we tend to see a more gradual buildup over the second half of the year. And then that works off over the first half of the year. We saw a very small amount of that in the fourth quarter in terms of buildup. But we are seeing continuing demand growth. And we're seeing that across both the US as well as in Europe. We've said in the past what continues to resonate with physicians, providers, patient is really the understanding of some of the beyond seizure benefits as well as the synergistic effect we're seeing with clobazam. We see continued opportunity in the adult segment. That's an area we're starting to focus a bit more on. And that we expect to be a driver of growth in 2024. And then more broadly, as we look at how Epidiolex is viewed in the market as the number one branded treatment, it continues to be seen as a very well characterized and tolerated drug, which means that lends itself well to polypharmacy. That's the norm in this area. And the data that we continue to generate both as I just described in terms of with clobazam and the data beyond seizures and just further understanding of these effects that you're seeing is creating greater demand from our physicians stating they intend to use it earlier in their process of this polypharmacy with patients. We are seeing growth outside the U.S. as well as I mentioned, so we're continuing to both launch in new geographies and then add indications within existing geographies, and so that growth is proceeding nicely as well.

And we will take our next question from June Lee with Truist Securities.

Thanks for the update and for taking our questions. When you do report top line data from Suvecaltamide essential tremor, well, you have a Go-No-Go decision when you report a top line, or is that something that you still have to consult with the FDA in an end of Phase II meeting before being able to comment on a Go-No-Go decision? And is the advancement into Parkinson's disease dependent on the outcome of ET, or are they independent events? And just quickly, anything you can share on the latest on orexin program. Thank you.

Okay, so the first part of the question was around essential tremor, and I would say in general our practice has been to share top line data on a timely basis. Whether we comment precisely at that time on next steps, remains to be seen and remains to be, it remains dependent on the data. But in general, our view is we know what we need to move this program forward, so I'm not sure that barring a surprise in the data, that would involve a different regulatory interaction. Rob, anything else you want to add on ET or on orexin?

I would just say that with regard to ET, I agree with you that, we'll see the data and we're not expecting to have to talk to FDA before providing some guidance on that. It certainly is positioned as a pivotal trial. We're very excited about it given the high unmet need. There hasn't been an approved drug in 50 years and what's available there is pretty poor. We think we have a differentiated mechanism action and a best in class calcium channel modulator. Certainly this trial was built to be part of a pivotal program, so I think it'll be quite informative when we do see the data. I don't think Parkinson's disease tremor is a direct read through, but certainly strong data and essential tremor would give us more confidence in this target overall. And then finally on the question of orexin, there are no updates there. We're on pause while we're examining the safety findings that we previously characterized.

And we will take our next question from Gary Nachman with Raymond James

Hi, good afternoon. So on zani, just what's the timeline for expanding further into breast cancer? Will you be doing that in parallel with BTC and GEA? And then, regarding increasing the size of the GEA trial, just describe what you hope to see from that interim OS data. And next year, is it possible that GEA could contribute to the sales of zani and not just BTC? Thank you.

Rob, I'm going to turn this one over to you.

Yes, so similar to the answer I gave previously, we have been working in breast cancer already, both in the metastatic setting for HER2 positive cancer, and then we published recently on HER2 Positive, ER Positive Breast Cancer at San Antonio last year. We published on early stage disease. So we have been working in breast cancer and publishing on those data, and we are progressing further development plans in those areas. It's not dependent on any other readout. With regard to the changes to the GEA study, again, we made those changes to ensure better power for the overall, final overall survival endpoint. We plan to read out the progression-free survival based on the original sample size, so that it has no impact on the overall timeline. And we know from health authority interactions that in this setting, PFS is adequate to support approval. It's usual and typical to do an interim analysis, albeit early on OS at the time that you're looking at PFS. And generally health authorities just want to be sure that something funky is not happening, that you're not seeing somehow a detriment in the OS. But there's not an expectation that OS on that first interim would be well-powered. Then of course we have the second interim analysis, which is occurring around the time that it would have on the original trial, which is why we believe we sort of have our cake and eat it too, if this change. And then on the mature OS data, we'd have more power.

And then with respect to –

I mean, in terms of, sorry, I didn't get to the -- didn't address the question on revenue in 2025. There's a scenario where we are, given what we've shared around BTC, that we are on the market for BTC. And as we read out the data for GEA, we certainly have a faster path as a supplemental in the US to get an update to the label. But we certainly will also publish and seek compendia listing even while we are progressing the supplemental BLA.

And we will take our next question from Akash Tiwari with Jefferies.

Hi, this is Avee on for Akash. Thanks for taking our question. Just a quick one on zani in GEA. So given the mechanism similarity between Herceptin Pergola combo and zani, why do you think their Phase III GEA trial, JACOB, failed? It doesn't seem to be like HER2 expression related, given the treatment arm enrolled roughly similar HER3 population compared to the comparator arm, which is Herceptin plus chemo. So is there anything you are doing differently in your trial? Thanks.

Rob, you want to take that?

Yes, happy to, Bruce. So first of all, while the epitopes on zanidatamab do correspond to the same epitopes that Herceptin and pergola independently bind. The reason zanidatamab is differentiated is that when they occur, when they're positioned on the same antibody, what you get is binding of the two FAB fragments of the antibody on different receptors. And it causes receptor clustering, which enhances interference of signaling, whether that be through HER2 or interference of dimerization with HER3 and therefore interference of signaling with HER3, internalization and marking the cells for immune destruction. A lot of this experimental data was published in Nature Communications and includes some really nice data showing this clustering effect that occurs with the bipartopic antibody and showing that it induces complement dependent incited toxicity, which is unique amongst any HER2 antibodies, and also some experimental data comparing head-to-head to just combining those two antibodies separately. So we think we actually have a differentiated drug that will be more effective than giving the combination. And our clinical data, by the way, support that. So we have activity in patients who have progressed on the combination of Herceptin and Pergola with breast cancer. So I think our preclinical data show the differentiated mechanism, and the clinical data are showing better results, whether it be in breast cancer or also in BTC, where we seem to have better results than when you give Herceptin, Pergola to BTC patients.

And we will take our next question from Charles Duncan with Cancer Fitzgerald.

Your line is open. Hi, this is Acia, on for Charles. We have a question on Epidiolex. So given the Phase III readout in the second half of this year, can you talk a little bit about the addressable market and opportunity in Japan compared to the opportunity in the US. And also you did mention additional market launches this year so I was wondering if you can provide a bit more color on this. Thank you.

Yes, Renee, let me turn that one over to you.

Sure, yes, I'm happy to jump in there. So for Japan, we're excited to be able to have made the progress that we have in that geography. There's about 20, 000 patients across three different indications that we think provide quite an important opportunity in Japan obviously is the second largest pharmaceutical market in the world. We have now the opportunity, not only with Epidiolex, but also zanidatamab to be able to have meaningful opportunities in that market. So we do expect the top line results in the second half of this year, and we're pleased also with the progress we've made to be able to see changes to the Cannabis Control Act underway, which will enable that eventual launch. And then in terms of outside the US, as we think about the progress that we're making there, we're already approved in more than 35 different countries. We do have some additional launches and reimbursements anticipated through the end of 2024, and I would think of that as gradual updates as we go. We are already approved and reimbursed in the five main large markets in Europe. So what we've been doing over the course of ‘23 and ‘24 is really focused on ensuring we have the full indication set available in each of the countries. We're continuing to be able to execute partnership agreements to ensure that either if we're not going direct, we're making the product available through our partners, and we'll expect that to continue over the course of 2024. And given we're now in a place where we're annualizing at more than $900 million, we see the product as being very much on track for blockbuster status.

And we will take our next question from Jeff Hung with Morgan Stanley.

Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our question. On the high sodium authorized generics, what evidence generation is needed to support the long-term health messaging and drive patients towards the switch to low sodium? Or do you think that the majority of the narcolepsy and IH community are more or less aligned with the benefits given the need for lifelong treatment? Thank you.

Yes, I would say the evidence surrounding the impact of sodium on cardiovascular health pretty incontrovertible. I certainly underlined the original Orphan Drug Exclusivity Decision by FDA determining that Xywav was clinically superior to Xyrem on the basis of that lower sodium and the same thing could be said for Lumryz which has the same sodium level as Xyrem. That doesn't mean there aren't opportunities to bring out more data as we have already, including with our presentation at the neurology meeting last year that within a period of 180 days of starting high sodium oxybate therapy, we saw patients have a significantly increased either diagnosis of hypertension or getting antihypertensive med. So even in a short period of time, you see that impact on people, even if they aren't already diagnosed as being hypertension patients, which is again why that original determination was that Xywav would be a safer product in all narcolepsy patients who are known to be at high cardiovascular risk to begin with.

And we will take our next question from Joel Beatty with Baird.

Hi, thanks for taking the question. For zanidatamab, how much of the $2 billion in peak sales potential projection comes from breast cancer? And are you able to give a sense of when we might see data in that setting from the I-SPY2 and MD Anderson collaboration trials?

I'll take the first part of that and Rob, hand the data part of it over to you. We have not provided a breakdown of the opportunity set for zanidatamab which we believe is extensive and certainly in our slides you can see that while we have made the most commentary thus far on BTC and GEA and breast cancer, it certainly has potential beyond those indications as well, which is why we say north of $2 billion, we haven't fully quantified how big the product could be as we determine where else to take it. We've got our near-term priorities work out and looking forward to sharing a little more information at our R&D day. But on timing of data, Rob, maybe I'll turn that one over to you.

Yes, for the MD Anderson Neoadjuvant study, some data were already published. You may be aware of that December at San Antonio. That trial is ongoing and I would expect some updates. They haven't indicated exactly when the updates will be published. On I-SPY, which is a little bit late, it started a little bit after that trial, really depends on the enrollment rate and the results and when that might graduate from that phase. And so we don't have any specifics at this point. But we are pleased that the trials are ongoing and we're excited to see how that may inform next steps in that early stage space where we think zani is particularly well positioned to provide a better tolerated option for women with curative breast cancer.

And, ladies and gentlemen, we have no further questions at this time. I will now turn the call back to Mr. Bruce Cozadd for closing remarks.

Thank you, operator. I'd like to close today's call by recognizing our Jazz colleagues for their efforts and thank our partners and shareholders for their continued confidence and support. Thank you all for joining us today.

Ladies and gentlemen, this concludes today's call. And we thank you for your participation. You may now disconnect.