Jazz Pharmaceuticals plc (JAZZ) Q4 2024 Earnings Report, Transcript and Summary

Thank you for standing by. My name is Jeannie, and I will be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals Fourth Quarter 2024 Webcast. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. [Operator Instructions] Thank you. I would now like to turn the call over to Jeff Macdonald, Executive Director, Investor Relations. You may begin.

Thank you, operator. Good afternoon, everyone. Today, Jazz Pharmaceuticals reported its fourth quarter and full year 2024 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website as is the press release we issued earlier today. On the call are Bruce Cozadd, Chairman and Chief Executive Officer; Renée Galá, President and Chief Operating Officer; Rob Iannone, Executive Vice President, Global Head of R&D; and Phil Johnson, Chief Financial Officer. On slide two, 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 under the caption Risk Factors in our annual report on Form 10-K for the fiscal year ended December 31, 2023, our quarterly report on Form 10-Q for the quarter ended September 30, 2024, and our subsequent filings with the SEC including our annual report on Form 10-K for the fiscal year ended December 31, 2024, which identifies certain risk 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 these forward-looking statements. As noted on slide three, 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 a slide presentation available on the Investors section of our website. I'll now turn the call over to Bruce.

Thanks, Jeff. Good afternoon, everyone. Thank you for joining us today to discuss Jazz's fourth quarter and full-year 2024 results. I'll start on slide five. I'm very pleased to report that 2024 was another record year for Jazz. Our strong commercial execution resulted in more than $4 billion in total annual revenue and fourth quarter revenue of nearly $1.1 billion, our highest ever. Importantly, we helped more patients who benefit from our highly differentiated therapies in areas with limited or no therapeutic options. These achievements reflect the tenacity and dedication of our talented employees around the world. On the R&D front, we achieved several important development and regulatory milestones in 2024, headlined by the accelerated approval of Ziihera in the U.S. for the treatment of second-line HER2-positive biliary tract cancer or BTC, in November. In addition, we believe the positive results from the Phase III Zepzelca clinical trial in first-line maintenance for small cell lung cancer will support expansion into an earlier line of treatment, potentially benefiting a broader patient population. We plan to further diversify our commercial and pipeline portfolios through strategic corporate development, which remains a key focus for Jazz. As part of our ongoing search, we're evaluating neuroscience and oncology assets, while also contemplating other rare and orphan diseases. In addition, durability of revenue, efficiency of commercial call points and alignment with our expanded R&D capabilities are part of our considerations as we assess opportunities to maximize long-term shareholder value through corporate development. Turning to slide six. I'm pleased to confirm we achieved our 2024 guidance, delivering top line growth at the upper end of our range and $1.37 billion in adjusted net income on a non-GAAP basis. Phil will discuss our 2024 financial results and 2025 guidance in more detail later in the call. On the commercial front, our sleep, epilepsy and oncology portfolios are each annualizing at over $1 billion based on fourth quarter net product sales. Xyway remains the number one branded treatment for narcolepsy based on revenue and the only FDA-approved therapy to treat idiopathic hypersomnia or IH. We've been pleased with our execution across narcolepsy and IH as our team has navigated the entry of high sodium fixed dose, branded oxybate, an authorized generic or AG competition since their introduction in 2023. Epidiolex net product revenues grew 15% in 2024 compared to 2023, and it is poised to reach blockbuster status this year. Oncology revenues grew 9% in 2024 to a record of more than $1.1 billion even with changes to pediatric protocols, which temporarily impacted Rylaze's revenue in the second-half of 2024. Renée will discuss our commercial performance in greater detail. Overall, our 2024 total revenue grew 6% compared to 2023, reflecting our stron76nhjg execution of the commercial strategies we are implementing. We continue to advance promising opportunities in our pipeline. We look forward to the data readout from the HERIZON-GEA-01 Phase III trial, evaluating zanidatamab in first-line gastroesophageal adenocarcinoma, or GEA. While we had previously provided an estimate of the second quarter of this year for top line and progression-free survival readout, based on our more mature projections of events accrued to-date, we now expect data readout in the second-half of this year. Rob will share additional color on this trial a bit later in the call. The first-line BTC confirmatory trial, Phase III breast cancer trial and Phase II pan-tumor trial are all progressing well. In addition, we plan to submit a supplemental new drug application or sNDA, for Zepzelca as maintenance therapy in first-line extensive-stage small cell lung cancer in the first-half of 2025. We remain focused on driving growth while maintaining a disciplined and strategic approach to capital allocation. Our financial strength and cash flow enable us to invest in our commercial portfolio, pipeline and future corporate development opportunities. Before we move on, as previously shared, I'll be retiring from my role as CEO this year. It's been a privilege to lead Jazz through the growth and significant diversification that has transformed the business into the fully integrated biopharma company it is today. Importantly, we remain committed to reaching more patients by making strategic investments through corporate development, a focus that will continue during the CEO transition period. After a successor is appointed, I'll continue serving as Chairman of the Board of Directors, providing ongoing leadership and strategic guidance. I'm confident Jazz's next leader will continue delivering for patients, employees, partners and shareholders. I'll now turn the call over to Renée to discuss our commercial performance, after which Rob will cover our R&D pipeline. Phil will then provide a financial overview and review our 2025 guidance, and then we'll open the call for Q&A. Renée? Renée Galá: Thanks, Bruce. Before I cover individual commercial products, I'd like to thank the Jazz team for their tremendous efforts across the year, which resulted in each of our promoted commercial products achieving their highest ever annual revenues in 2024. Beginning on slide eight and our Sleep portfolio, our focused efforts to educate physicians and patients on the benefits of Xywav, including the importance of meaningfully reducing sodium intake continue to resonate in the market. We view every high sodium oxybate patient as one who could benefit from low sodiums Xywavs as people living with narcolepsy are at a 2 times to 3 times higher risk of cardiovascular comorbidities such as stroke and heart failure than the general population. In addition, results from the RHYTHM study demonstrated patients with IH experienced a higher likelihood of comorbid conditions across multiple clinical categories, including cardiovascular conditions. There were approximately 14,150 patients taking Xywav exiting 2024, representing approximately 1,850 net patient adds compared to the end of 2023. In the fourth quarter, there was a meaningful increase of approximately 525 net patient adds comprised of 175 narcolepsy patients and 350 IH patients. Total sweep revenue, which includes Xywav and Xyrem net product sales, plus royalties from high sodium oxybate AG was $506 million in the fourth quarter and exceeded $1.9 billion for the full-year. Xywav's net product sales grew 16% year-over-year to approximately $1.5 billion in 2024 and were $401 million in the fourth quarter of 2024. The initiatives we implemented at the end of 2023 and throughout 2024, including field force expansion, digital and media campaigns and the field nurse educator program coupled with our JazzCares services contributed to both patient demand and persistency across narcolepsy and. We believe the IH market we are building with the first and only FDA-approved therapy to treat IH represents the most opportunity for patient growth and is a durable segment of our Sleep portfolio. Our field team continues to expand the breadth and depth of HCP's prescribing Xyway for IH by highlighting the significant unmet patient needs and the benefits of treating multiple symptoms of IH with Xywav. On slide nine, we turn to Epidiolex with net product sales of $275 million in the fourth quarter, representing a 14% increase, compared to the same quarter in 2023. For the full-year 2024, Epidiolex revenue was approximately $972 million, up 15% year-over-year, primarily driven by underlying demand. Key drivers of demand growth in the U.S. included continued positive response to data on the benefits of Epidiolex beyond seizure control, reaching adult patients and long-term care facilities, along with broad quality access. In December, we presented nurse reported responses to the become survey in long-term care facilities that showed Epidiolex treatment was associated with an overall reduction in seizure frequency and improvements in patients' abilities such as communication, cognition and emotional functioning. We expect this continued data generation and increase penetration in the adult patient setting and long-term care facilities will drive demand. Growth in the adult patient setting is supported in part by data showing many LGS patients reach adulthood without a specific LGS diagnosis and by providing health care professionals with clear diagnostic tools to identify adult LGS patients. Further, we believe Epidiolex is a durable, long-lived asset, and I'm pleased to share we recently settled with all 10 current ANDA filers. Under the settlement agreements, we granted each of those ANDA filers a license to manufacture, market and sell its own generic version of Epidiolex beginning in the very late 2030s or earlier under certain circumstances. We're pleased with the momentum and growth of Epidiolex and expect it to reach blockbuster status in 2025. Moving to oncology on slide 10. Rylaze's net product sales were approximately $101 million for the fourth quarter 2024 and approximately $411 million for the full-year, representing a 4% year-over-year increase, compared to full-year 2023. In our third quarter earnings, we reported a temporary negative impact to Rylaze revenue due to an update to Children's Oncology Group pediatric treatment protocols for acute lymphoblastic leukemia or ALL. This update impacts the timing of asparaginase administration pushing back the use of Rylaze by 10 weeks. It's important to note the protocol changes do not change the recommended total number of asparaginase doses, and we don't anticipate an impact to underlying demand for Rylaze. Revenues are still expected to normalize early this year. We see the most opportunity for growth in the adolescent and young adult or AYA market, and we are continuing to educate oncologists who treat these patients on the benefits of asparaginase therapy. On slide 11, I'll discuss Zepzelca. Net product sales for the full-year 2024 were approximately $320 million, up 11% year-over-year. In the fourth quarter, Zepzelca net product sales increased 6% year-over-year to approximately $78 million. Zepzelca remains the treatment of choice for second-line small cell lung cancer, and we continue to hear positive feedback from physicians on its clinical benefit and ease of use and administration for patients in their health care practices. Expansion into first-line maintenance therapy for extensive stage small cell lung cancer represents an opportunity to extend the duration of treatment while reaching patients earlier in their disease progression. We plan to submit an sNDA for Zepzelca in this indication in the first half of this year. Moving to slide 12 to cover Ziihera. We had an exciting fourth quarter with the FDA approval of Ziihera. The first and only dual HER2 targeted bispecific antibody approved for HER2-positive second-line BTC in the U.S. Our experienced oncology team swiftly initiated the commercial launch of Ziihera following approval and I'm pleased to share that the first BTC patient was treated with Ziihera in December. We recognized approximately $1 million of net product sales in 4Q '24. The initial reception from HCPs has been positive, and we have the right capabilities and infrastructure to deliver a successful launch of Ziihera in second-line HER2-positive BTC. Physicians currently diagnosing and treating BTC patients significantly overlap with our existing Zepzelca call universe, positioning us to leverage our current footprint to help accelerate the launch and uptake of Ziihera for second-line HER2-positive BTC. Ziihera has the potential to deliver greater efficacy outcomes, compared to the current standard of care for BTC, while providing better tolerability and safety to maximize patient outcomes and benefit. Although BTC represents a small patient population, this initial launch will help establish Ziihera with health care professionals and allow them to get meaningful experience with it. With that, I'll turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

Thanks, Renée. I'll begin on slide 14. We achieved an important milestone for patients and our company in 2024 with the FDA approval of zanidatamab in second-line BTC along with the initiation of our first-line BTC confirmatory trial. Beyond BTC, we significantly advanced zanidatamab development, including our ongoing first-line GEA trial and the initiation of the Phase III EmpowHER breast cancer trial and Phase II pan-tumor trial. As Bruce mentioned earlier, we are now expecting the top line PFS readout from our Phase III frontline GEA trial evaluating zanidatamab with standard of care chemotherapy with and without the addition of a PD-1 agent in the second-half of 2025. Recruitment for this trial is on track, and we expect to complete enrollment within the next few weeks. As a reminder, this is an event-driven trial, and our updated estimate is based on a more mature projection of progression events relative to the initial protocol assumptions. While we, as the sponsor remain blinded to the results of the trial, we are encouraged by the positive results from two independent Phase II trials zanidatamab in first-line GEA that have demonstrated increased median PFS, duration of response and confirmed objective response rates. If positive, we expect the PFS data from this trial will support registration. Moving to other programs. In October 2024, we reported highly encouraging results from the Phase III IMforte trial of Zepzelca in combination with atezolizumab compared to atezolizumab alone when administered as maintenance therapy in first-line extensive-stage small cell lung cancer. The combination demonstrated statistically significant and clinically meaningful improvements in the primary endpoints of overall survival and progression-free survival. The results have the potential to be practice-changing and we look forward to presenting the data at a medical meeting this year, which is an important step toward potential inclusion in NCCN guidelines and compendial listings. As Renée mentioned, we plan to submit an NDA to FDA in the first-half of 2025 to expand the Zepzelca label to include first-line maintenance. The Epidiolex trial in Japan remains ongoing as we collect long-term safety data, which was included in the trial design for 26- and 52-week analyses. Numeric improvements were observed in the primary and several secondary endpoints, and we expect to have substantive discussions with PMDA by mid-2025. Turning to slide 15. I'll review the unique clinical profile of Ziihera for zanidatamab and why we believe it has the potential to become the HER2-targeted agent of choice. Zanidatamab has demonstrated activity in multiple HER2-expressing cancers. Its biparatopic binding results in multiple mechanisms of action, all resulting in tumor cell death. Zani has been shown to interfere with HER2 signaling, which also disrupts heterodimerization of HER2 and HER3, further inhibiting tumor cell signaling and growth. Zanidatamab also causes receptor clustering and internalization, inducing immune destruction through ADCC, ADCP and CDC. We think that zanidatamab induces complement-dependent cytotoxicity at a level that is highly differentiated in the category. Zanidatamab's profile includes established safety and tolerability, ease of administration, single-agent activity without chemotherapy, and it combines well with other therapies, including chemotherapy. We believe zanidatamab has the potential, the best-in-class HER2 targeted therapy for multiple HER2-positive solid tumors. Importantly, Ziihera was added to the NCCN and ESMO guidelines for biliary tract cancer after approval as part of an off-cycle review, highlighting the meaningful advance Ziihera represents for HER2-positive BTC patients. Slide 16 highlights the potential for zanidatamab in BTC and beyond. In addition to FDA approval for BTC, the European Medicines Agency validated the marketing authorization application for zanidatamab in second-line BTC in 2024, and we await potential approval as early as 2Q 2025. We've already discussed the opportunity we are pursuing in GEA. Additionally, we initiated the Phase III EmpowHER trial, which is designed to evaluate zanidatamab in combination with chemotherapy in breast cancer patients who have progressed on or are intolerant to in HER2. With this ongoing Phase III trial, we have the opportunity to be the first HER2-targeted therapy to demonstrate efficacy and safety in breast cancer patients post in HER2. We also have multiple ongoing trials in early-stage breast cancer, including through our collaboration with MD Anderson Cancer Center and the I-SPY program. Zanidatamab monotherapy has shown promising activity across a range of tumor types. And we initiated a Phase II pan-tumor trial to generate additional data across a variety of HER2 expressing solid tumors. Overall, we are incredibly excited about the opportunity that zanidatamab represents for patients with HER2-expressing tumors. Now I will turn the call over to Phil for a financial update. Phil?

Thanks, Rob. I'll start with our top line results on slide 18. As a reminder, our full financial results are available in today's press release and in our 10-K, which will be filed tomorrow morning. In the fourth quarter of 2024, we achieved nearly $1.1 billion in total revenues. We were pleased to deliver this top line growth, which was driven by increased Xyway of Epidiolex and oncology revenues. And for full-year 2024, we recorded approximately $4.1 billion in total revenues, representing 6% growth over 2023. This marks our 20th consecutive year of top line growth. And as you've seen in our guidance, we expect 2025 to be our 21st consecutive year. Turning to slide 19. Our full-year 2024 non-GAAP adjusted net income was approximately $1.37 billion and we reported non-GAAP adjusted EPS of $20.90. We continue to generate significant cash from our business, demonstrating the strength and diversity of our portfolio. We recorded approximately $1.4 billion of cash from operations for the full-year 2024 and ended the year with $3 billion in cash on hand. Consistent with our prior communications, in January, we made a voluntary repayment of $750 million to reduce the principal amount of our Term Loan B. During 2024, we continue to utilize our share repurchase authorization and spent approximately $311 million repurchasing shares. Going forward, if not used for corporate development investments to enhance our future growth prospects, we expect a significant portion of free cash flow to go toward debt paydown, share repurchases or some combination thereof. Finally, our overall financial position and robust operating cash flows provides significant flexibility to invest in value-driving commercial and R&D programs as well as in promising corporate development opportunities. We're pleased to share our full year financial guidance for 2025, beginning on Slide 20. Our 2025 total revenue guidance range of $4.15 billion to $4.4 billion represents 5% year-over-year top line growth at the midpoint, driven by our diversified commercial portfolio, spanning Sleep, epilepsy and oncology. Top line growth in 2025 is underpinned by our expectation of continued growth of Xywav, Epidiolex reaching blockbuster status and the assumption that high sodium oxybate AG royalty revenue will continue for the full year. As a reminder, if Hikma and others enter the market with true generics, our AG royalty revenue will go away and we could have rapid erosion of remaining Xyrem revenue. While we believe we'll be well positioned with the Xywav, given it's not rated to all other high sodium oxybate, including generics, the impact of true generic Xyrem on Xywav revenue is uncertain and will depend on a number of factors, such as the continued recognition by HCPs, patients and payers of the value of low sodium. Other dynamics we anticipate throughout the year include a continued decline of Xyrem revenue and normalization of Rylaze's revenue early this year. We anticipate modest revenues from Ziihera given the small BTC patient population, although a successful BTC launch is key to providing HCPs with valuable experience with Ziihera ahead of a potential launch in GEA. Finally, while we don't provide quarterly guidance, I do want to note our first quarter revenues have historically been affected by several factors, including reauthorizations and inventory build in the latter part of the prior year, which can contribute to lower revenues in the first quarter compared to other quarters. Now I'd like to draw your attention to several items on Slide 21. With regard to operating expenses, our non-GAAP adjusted SG&A guidance range is $1.25 billion to $1.31 billion. The increase in non-GAAP adjusted SG&A reflects continued investment in our lead commercial products. We remain focused on operational excellence and continued execution of the commercial initiatives from last year to further drive growth of our diversified portfolio. Our non-GAAP adjusted R&D guidance range of $720 million to $770 million represents an 8% decrease from 2024. We're continuing to focus investments on priority programs, including the broad zanidatamab development program that has the potential to positively impact many patients and deliver significant shareholder value. The decrease from 2024 is primarily driven by a reduction in clinical studies and outside service costs relating to JZP-385 and continued portfolio prioritization. On the bottom line, we expect adjusted net income in 2025 to be $1.4 billion to $1.5 billion. This reflects our expectation of continued strong commercial performance and disciplined expense management while continuing to invest in our highly differentiated commercial portfolio and pipeline. I'll now turn the call back to Bruce for closing remarks.

I'll conclude our prepared remarks on Slide 23. 2024 was a record year for our promoted commercial products, and we expect to deliver continued strong execution in 2025. Epidiolex remains poised to reach blockbuster status in 2025 and we expect Xywav to remain the number one branded narcolepsy treatment with continued growth in IH. Ziihera represents a significant growth opportunity with an estimated $2 billion plus in peak sales potential. We look forward to submitting the sNDA for Zepzelca with the potential to help more patients for a longer duration and extend survival. Our proven strength in commercial and pipeline execution and corporate development are supported by our continued focus on operational excellence and strategic capital allocation. I'm confident Jazz is well positioned to deliver our 21st consecutive year of top line growth in 2025, drive meaningful shareholder value with data readouts such as the Phase III GEA trial and pursue strategic corporate development opportunities to deliver long-term sustainable growth. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

Thank you. We will now begin the Q&A session. [Operator Instructions] And your first question comes from the line of Marc Goodman with Leerink. Please go ahead.

Hey Rob, can you talk about the orexin 441? Any type of comment you can make? Have you figured out the safety margin? Is your low dose kind of doing what you wanted to do? Any comments there would be helpful. And then just on the settlement with Epidiolex, is there any reason you're being so cagey? Can you actually give us the date?

So Marc, this is Bruce. Maybe I'll jump in on your second question first. We actually think saying our Epidiolex settlements with all 10 ANDA filers go out to the very late 2030s is being pretty specific. I'll remind you those agreements have confidentiality provisions, which limit what else we can say. So that's all we're going to have to say at the moment is very late 2030s. Rob, I'll kick it over to you for a 441 update.

Thanks, Bruce. So Mark, we don't have an update on the trial that we said we are initiating. This is a trial with 441 in NT1 patients, small number we thought about 10% or so. But so far, no updates on that. But we do think that even in a small number of patients that will help us define a better therapeutic index. So no updates at this time.

Your next question comes from the line of Jessica Fye with JPMorgan. Please go ahead.

Hey guys, good afternoon. Thanks for taking my question. For the HERIZON-GEA trial, I think you said you'll complete enrollment in the next few weeks. So just to confirm, is that for the upsized 918 patient target enrollment? Can you remind us when you completed enrollment of the originally planned 714 patients? And then I guess while I made on this trial, Rob, when you see the event rate maturing differently than initially projected as it seems to be here, do you take that as positive, neutral or negative for probability of success?

Go ahead, Rob.

Okay. Yes. So we are referring to the 918 when we say we'll be completing enrollment in the coming weeks. We haven't said when the 714 was enrolled. As you know, we are blinded to the results of the trial. And so we can't say what's driving the slower accrual of events, whether that's coming from control arm or the experimental arms. Generally speaking, it certainly could be a good thing that the experimental arms are having a significant effect and pushing that out. But we don't see the data. So we don't know for sure. I would say that the control arm certainly could be behaving differently than prior trials. However, we've seen three Phase III trials in this setting, and the control arm has been pretty consistent across those. So I don't expect a big surprise on the control arm. But again, we are blinded to that information. We have an external vendor who is tracking events and gives us periodic updates. But as we've said, we're confident in the second-half of this year, depending on how the events continue to roll in, that certainly could come in 3Q.

Your next question comes from the line of Jason Gerberry with Bank of America. Please go ahead.

Hey guys, thanks for taking my question. Mine just on M&A. You guys seem to be flagging that again this year. And I guess it's been a dominant part of the Jazz investor discussion for a while now, but you really haven't like swung the bat in a big way since GW. And so just kind of curious maybe why that is, ultimately, if you can reflect on that? And then with this Epidiolex patent settlement in place and not having a runway on a $1 billion franchise plus well into next decade. Just how does that alter how you guys think about M&A having that longevity of assets now?

So Jason, this is Bruce. I'll jump in with a little historical perspective, and then maybe I can have Phil give you a more forward-looking view. Just as a reminder, we completed the GW acquisition in May of 2021 and levered up to some degree to do that and spend some time after that, bringing leverage back down quickly and considerably. And during that period, we were needless to say, not pursuing larger transactions as we had forecast. To say we haven't done anything, I think, would forget that we did the zanidatamab transaction, which while it had a smaller upfront certainly has been a major focus for us in terms of value creation potential for the company, and we remain excited about it. Phil, maybe you could take the part of the question that refers to what we're expecting going forward. Phil?

Sorry, I have a bad connection here. So I was trying to get on to a handheld not use the speaker on to me a second. So Jason, as Bruce mentioned, we've delevered substantially from the time of the GW deal. I think we closed effectively at about 4.9 times net leverage at that point in time. As of the end of 2024 that was down to 1.8 times. So we certainly have significant financial resources bolstered by the strong cash flow that we generate as well to engage in M&A and licensing activities for the various sizes. We do have active efforts looking at each of our verticals to continue to build our growth prospects in those that would include epilepsies where the very long runway with Epidiolex has been and continues to be a strong point, I think, for the overall Jazz story, as well as making it in even more attractive area for us to be investing in. So certainly, we do look at opportunities to build out that franchise. Further, as Bruce mentioned in his prepared remarks, we do look at areas that would be either adjacencies to, and in some cases, newer areas that share characteristics with where we've been successful in the past. Often, we use our more orphan indications more focused call points, the ability to add significant value with services in addition to just product and leverage those capabilities that we've built and honed over the years. So continued very active looking. I certainly would not take the lack of announcing a large deal as lack of activity or interest in doing things and certainly, we've commented in the past, seen no expectation of those activities slowing down as we move into the coming quarters. So stay tuned. We're active and looking. I do feel there's opportunities of value to Jazz and if patients don't see valuations at this point in time being a significant impediment to be transacting in the areas where we're looking. So I hope that gives you some color.

Your next question comes from the line of Annabel Samimy with Stifel. Please go ahead.

Hi. Thanks for taking my question. Just quickly on Zepzelca, just curious if there was any strange trend at the end of the year, we saw it compressing a little bit. And then what can we expect from Zepzelca this year? I know you're filing the sNDA? The approval is not expected to expect until 2026, but could we be seeing some entity and guideline -- compendia listing for this specific indication? Renée Galá: Yes. Thanks for the question. This is Renée. So in terms of what we've seen with Zepzelca, we have continued to see strong performance. I would say typically from Q3 to Q4, we do have a dynamic where there are less buying days for our distributor in Q4, compared to Q3. We had a similar dynamic in 2023, so that did have some impact. I will note, though, that as we mentioned on the call, our sales increased 11% to $320 million in 2024. That was the highest year ever for Zepzelca and that is with a competitive entrant in the market with [Imdelltra] (ph). As we look at 2025, we mentioned we plan to file in the first half of this year for our first-line extensive stage with our first-line extensive-stage data, we will not be promoting, of course, in the first line until we have that approval. We would hope to get on treatment guidelines as soon as we have the data out and available and in a peer-reviewed journal, which we're working diligently on. And then I would also say that the benefit, of course, in the first line is to be able to reach patients earlier in their overall treatment journey. We do believe there's a larger group of patients to access 27,000 in first-line versus 17,000 in the second-line and about 70% of those first-line patients are extensive stage. There's also longer duration of treatment in the first-line. So we do expect to see growth in Zepzelca, but again, we won't be promoting in the first-line until we have an actual approval. And then if I just step back and think about Zepzelca's positioning in the second-line, while we would expect to see Imdelltra as a new competitive entrant to see some gain in the second line, I'd also say we continue to receive a lot of positive feedback from physicians on Zepzelca. In terms of its clinical benefit, the ease of use, it does not require extended monitoring or an inpatient stay, which is, of course, different from Imdelltra. So we do expect to continue to see some strength in Zepzelca, and we look forward to having the ability to promote in the first line.

Your next question comes from the line of Andrea Newkirk with Goldman Sachs. Please go ahead.

Good afternoon. Thanks for taking our questions. Bruce, I was just wondering if you might be willing to provide an update on the CEO search and the background are fit that the Board is looking for? And then in the context of this ongoing transition. As a follow-up to the M&A or BD question earlier, how should we think about that strategy and the timing for a potential transaction to occur this year?

Yes. Thanks for the question. So I'm not going to give a detailed update on the CEO selection process other than to say as was true when this was announced back in December, we're going to take our time and get it right. We're not in a hurry. We want to make the right choice and the right choice is dictated by where the company is today and where we want to take it. I will say, we're just starting to reach out in the marketplace, and we're getting positive feedback that the position is an attractive one in terms of where the company is positioned today, we're obviously coming off a very strong 2024 and are excited about our prospects for 2025. On the M&A BD side, we're really well positioned right now. We've got strong operating results. Our commercial teams, our R&D teams are executing well across the board. So from an operational perspective, we feel ready to take on additional programs and more products. And as Phil mentioned, from a financial perspective, whether it's our balance sheet, our cash on hand, our cash flow, again, we feel very well positioned to really take advantage of our infrastructure, leverage it and continue to add growth opportunities to our business.

Your next question comes from the line of Troy Langford with TD Cowen. Please go ahead.

Hi. Congrats on the results this quarter and thanks for taking our question. Just a really quick one on the opportunity for Ziihera and breast cancer. About how many breast cancer patients total do you think would fall into that and HER2 progression or intolerance bucket that Ziihera could potentially address? Should it succeed in the Phase III trial?

So Renée, I don't know if you want to make an overarching comment about the opportunity we see for zanidatamab, including in breast cancer. And then Rob, maybe you could talk a little bit more about how we see this fitting into the breast cancer treatment landscape. Renée Galá: Sure. Thanks, Bruce. So as we step back and look at the broader market opportunity, we do see this as a $2-plus billion opportunity overall when we look at the indications we're focused on right now. That includes BTC, GEA, breast cancer as well as pan-tumor. Now BTC, we've said consistently that we expect the revenues to be quite modest there given the very small patient population. But as we get into larger indications, such as GEA, we look at 63,000 patients across the U.S., Europe and Japan as compared to 12,000 for BTC. And then as we progress into breast cancer, we're looking at more than 150,000 patients across those same geographies. So while we haven't broken that up into the different elements, we do feel quite confident that there is a much broader opportunity to go after there. Rob?

Yes. I would just add that HER2-positive breast cancer patients in the metastatic setting tend to get multiple lines of therapy. Currently, that's the Cleopatra regimen followed by in HER2. There is an ongoing frontline in HER2 trial and there's optimism that, that will ultimately become the standard-of-care in frontline. So whether it be third line plus or second line plus, we think with positive results from the trial that we have ongoing that Ziihera would become the treatment of choice after patients have progressed on HER2. And we think that captures high proportion of patients given that these patients tend to be able to go on to subsequent lines of therapy.

Your next question comes from the line of Akash Tewari with Jefferies. Please go ahead.

Hi, this is Amy on for Akash. Thanks so much for taking your question. How should we think about the pricing strategy for zani depending on whether the doublet or triplet arm hits in HERIZON-GEA, if pricing remained consistent, how would the outcome of these arms impact your peak sales estimates?

Renée? Renée Galá: Yes, I'm happy to jump in there. So we have priced Ziihera for BTC with a 28-day cycle WAC cost of approximately $35,550. Now when we priced it for BTC, there was also a view of thinking about GEA coming shortly thereafter. We haven't given specificity around GEA. I'll say the cycle there is 21-days versus the 28-day cycle for BTC and then the weight-based dosing is slightly different for BTC. We're looking at more of an average median weight of a patient when we give the 28-day cycle price. But with respect to GEA, what we're looking at is a threshold above and below a certain weight, you would be going with a certain dosing. We're not looking specifically at the doublet and triplet arm and giving specific guidance with respect to the pricing or the peak. What we're really focused on is ensuring that we're able to capture a meaningful opportunity with GEA. And then as Rob had mentioned, also a much larger opportunity with breast cancer.

Your next question comes from the line of Mohit Bansal with Wells Fargo. Please go ahead.

Great. Thank you very much for taking my question and congrats on the progress. Rob, if you could help me understand the [ARM C] [ph] of GEA trial in a little bit detail. It seems like in the context of commercial aspect, it is a pretty important ARM given that majority of the patients that we believe are high patients. But again, this ARM is not power to show benefit over ARM B, so it seems like you are looking at just any benefit over Herceptin. That may be enough. So in that context, could you help us understand like how would you look at Arm C and how should investors like us look at ARM C when the data come out in the context of market opportunity? Thank you.

Yes. So for starters, I would say that the proportion of patients for whom the standard of care remains Herceptin chemo, we think is quite high. The KEYNOTE-811 trial, we don't think represents the true epidemiology. It's likely that, that trial was enriched for PD-L1 positive, “PD-L1 positive” patients given the ubiquitous PD-L1 testing during when that trial was conducted. We also think there's a question around how to define PD-L1 positive. Are all patients with one DPS score of one or higher, truly benefiting? Or would that optimal cutoff be higher? And if it's higher, it really does drive that proportion of patients who truly benefit from a PD-1 down quite a bit. Having said that, we think Ziihera has the opportunity to be the HER2 agent of choice regardless of PD-L1 status. ARM B will demonstrate that in Ziihera combined with chemotherapy and ARM C has the opportunity to demonstrate that in combination additionally with tisielizumab. We haven't spoken to the specific power of a comparison to ARM C versus B, and we don't necessarily think of that as being required. I mean certainly for the ARM C regimen of both Ziihera and tisielizumab and combo with chemo to be approved, it has to be better than ARM A. And it also has to be, from a broad benefit/risk perspective, better than giving Ziihera alone with chemotherapy. And so we'll have an opportunity to look at all of those data as part of this trial. And again, we think Ziihera will be regardless of PD-L1 status of the HER2 of choice.

Your next question comes from the line of David Amsellem with Piper Sandler. Please go ahead.

Thanks. So how are you thinking about Zepzelca's exclusivity runway particularly with the label expansion opportunity in first-line? So that's number one. And then secondly, to the extent that your own orexin program doesn't pan out, I guess my question here is, how badly do you need to be in the orexin game, so to speak? In other words, would you continue to pursue other orexin? Or do you feel like there's other areas in terms of M&A and Biz Dev, that you would then turn your focus on? Just trying to get a better sense of how you're thinking about your Sleep franchise to the extent there isn't an orexin that moves forward in your pipeline? Thanks.

Renée, do you want to start on the Zepzelca question? Renée Galá: Sure, happy to do that. So with respect to exclusivity, we have a composition of matter patent that extends to December 2029. And then we have additional patent applications that could extend that IP protection further. I don't think we have any comments beyond that to offer today, but stay tuned.

And then on your specific question on the orexin space, we continue to watch as we all do data emerging from different agents in terms of what we're seeing as the benefits of orexin therapy, certainly an exciting new mechanism of action across these serious sleep disorders, particularly with the daytime benefit, a little less clear right now, whether the benefits at night are positive or whether there are, in fact, potential concerns with what it would do to nighttime sleep. We certainly believe there is a role for ongoing use of oxybate as a nighttime agent that helps consolidate sleep and produce additional daytime benefits, absolutely seen with other daytime agents that are currently available or have been studied. In terms of do we need to be in that space, we're, of course, interested in the SLEEP space where we are a leader. We're also interested in other potential areas across neuroscience, oncology, as we've talked about, a rare disease where we've got relevant capabilities. So I don't want to narrow us down to only one area, but we're looking broadly across each of these areas for opportunities that we think would be a good fit, meeting and need good fit with our capabilities on the commercial side, efficient call point, good durability and an opportunity to diversify and produce sustainable growth over the longer term.

Your next question comes from the line of Ami Fadia with Needham. Please go ahead.

Good evening. Thanks for taking my question. Perhaps to switch gears to the oxybate franchise. Can you talk about some of the dynamics in the narcolepsy market and how you're seeing rise impact either your business or the overall market? Are you seeing switches from Xyrem or Xywav or any switch facts? And then also as the AGs have the ability to launch their own generics at the end of the year, how should we think about sort of shoring up the Xyrem revenues, switching them to Xyway or -- and maybe just sort of what type of payer dynamics you expect once additional generics come to market and how that might impact Xywav? Thank you.

Yes. I mean, that was a multipart question for sure. But Renée, maybe you could talk about just what we're seeing in the oxybate space and in particular, how we think Xywav has continued to be positioned. Renée Galá: Yes, absolutely. Happy to step through that. So I'd say just looking at our full-year results and the fourth quarter results that we had, we're really pleased with what we're seeing with Xywav. We had record revenues in the fourth quarter, 19% year-over-year, with 525 patient adds, that includes, of course, narcolepsy and IH. And when you look at where our adds are coming from in narcolepsy. That's coming from both new to oxybate patients, as well as patients switching from high sodium oxybate, and that's across all the high sodium oxybates. In terms of how we think about AG. So when we look at 2026, you heard Phil earlier say that our assumptions with respect to our 2025 guidance, include the fact that we will be receiving royalty revenues from AGs throughout 2025. So if we're thinking about the market in that way, and of course, we don't know if any authorized generics will decide to launch early, that would be if Hikma were to decide specifically to launch early, that would invite or other generics into the market before early 2026. And in that case, for full generics, they would need to have their own REMS because right now, the authorized generics are distributed through our REMS. So as we look at 2026, what that then looks like is a situation where our ability to continue to drive revenues with Xywav is dependent on the continued appreciation of the differentiation of low sodium and the importance of that to long-term health. In 2026, if we see full generics on the market since royalty revenues would cease to exist. And then we would also expect further erosion of Xyrem, which we do not actively promote and have not actively promoted since we launched Xywav. We continue to educate on the benefits of reducing sodium, including generating important data in this area, with Xywav being the only low sodium oxybate and therefore, the only one that doesn't carry a warning related to high sodium oxybate -- high sodium intake we can see clearly that physicians and patients are choosing that long-term health benefit as well as the flexible dosing that comes with Xywav. Maintaining strong payer coverage, of course, is important throughout this. We have the vast majority of our patients that are commercial today. And we had great coverage with more than 90% of commercial lives covered. And so we will continue to educate on the benefits of reducing sodium and continue to generate data. And we have already shared data that makes it clear that with both narcolepsy and idiopathic hypersomnia, there's an increased prevalence of cardiovascular comorbidities, including heart failure and stroke compared to the general population. Those findings came from both CB bond and CB Rhythm studies. So stepping back, we'll be continuing to focus on strengthening the differentiation of Xywav with physicians, customers and payers. We do believe we're well positioned for 2026. Xywav is not AB rated relative to generics. And as we look at the market with narcolepsy and idiopathic hypersomnia, we see the most opportunity for growth with idiopathic hypersomnia. We're continuing to build that market, but we're still early, very low penetration currently and definitely additional room for growth.

And I'll just jump in to remind people that percentage of our revenues coming from the high sodium business, the old Xyrem branded sales and AG royalties has continued to decline over time now probably in the latest quarter, maybe dipping below 10% for the first time.

Your next question comes from the line of Gary Nachman with Raymond James. Please go ahead.

Thanks. Good afternoon. On the 2025 guidance, you didn't break down the revenue components specifically this time. So can you give us more of a sense of how you expect the neuro and oncology franchises to trend relative to the overall revenue growth of 5% that you said this year? And then just the R&D, as you're scaling back in expenses relative to last year, down 8%, just talk more about the reprioritization of the pipeline? And what's the right level of spend going forward for R&D as a percentage of revenue? Thank you.

Phil, you want to jump in on that?

Yes. Gary, I'm happy to. So on revenue, what might be helpful as you think about the pushes and pulls for the year sort of step through the various products and we start with the larger ones first, working that way down. So Xywav, as Renée had mentioned, really strong momentum, growing 18% in the full year last year, 19% in the fourth quarter, really strong net patient adds 525 in the fourth quarter. So well positioned for continued growth there. Similarly, Epidiolex, really strong momentum, again, 15% growth for the full-year, 14% in the fourth quarter, and we're well positioned to reach blockbuster status in 2025. I'm very pleased with the long longevity of that franchise moving forward. Rylaze, about 4% growth for the full year, relatively flat in the fourth quarter, reflecting that negative impact that we mentioned in the second half of 2024 coming from the COG protocol change where we continue to expect revenue to normalize early this year. Zepzelca, again, 11% growth for the full year, that did dip down to 6% in the fourth quarter in part for the number of days that we had for shipping, as Renée mentioned. We feel really good about prospects for Zepzelca when we get the first line maintenance indication include the treatment guidelines and get it into the label when approved by FDA. And in the interim, we may see some weakness in Zepzelca sales of Imdelltra gained share in that second line plus setting. Defitelio really strong growth, particularly in the second-half of the year in the U.S. As we mentioned in the past, we're monitoring that situation to understand how much of that uptick you saw in the second-half is sustainable, providing a new base for the product and how much of that may be transitory this really relates to use of atezolizumab to prepare patients for their procedures that can lead to an increased incidence of VOD. So again, we'll see in coming quarters if that's durable. And then on the sodium oxybate front, as Renée mentioned, you think about the AG royalty revenue, that nearly tripled in 2024, compared to 2023. That was largely due to the significant increase in the royalty rate in late 2023, as well as additional volume coming through that channel in 2024. With that royalty rate increase now fully annualized growth from that royalty revenue should moderate accordingly in 2025. And then finally, Xyrem, revenue was less than half in 2024, what it was in 2023 with revenue coming down 59%. So mathematically, the drag from lower Xyrem revenue has to moderate in 2025, and be a bit of a buoy, if you will, less of a drag on growth this year than it was last year. So that gives us some color across the portfolio. In terms of R&D spend, you mentioned at the very end of your question, Gary, the sort of percent of revenue, we're not necessarily thinking of it in that way. We do think we have some very good opportunities, particularly with zanidatamab that make a lot of sense to invest behind. And when we've got those great investment opportunities, we will fund those and that will cause the funding level as a percent of revenue to moderate up or down depending on how many of the opportunities that we have. And mentioning of the context in the prior answer to questions on some of the prioritization on R&D, really reflects some of the readouts we had last year, 385 to a certain extent, 150 as well, where those are programs are no longer investing behind given those outcomes. We do expect to be active in corporate development activities that certainly would add to our portfolio and could bring in promising additional assets to invest behind, so that can lead to additional uptick. And then we'll see as we go forward with the data readouts for the zanidatamab, and we more fully talked about the full program of how to invest in that asset to drive the most value for Jazz and impact the most patient sort of additional investments that will come there. But those will be some of the pushes and pulls on that site.

Your next question comes from the line of Gregory Renza with RBC Capital Markets.

Hi, guys. It's Anish on for Greg. Thanks for the updates this quarter and for taking our questions. As you look at Ziihera's Phase III GA top line now guided for the second half, how should we be thinking about time lines for subsequent analyses, including the second and third interim overall survival analysis? And quickly on Epidiolex, what levers can be pulled or hangups remove to enhance uptake across the treatment segments? Thanks so much.

Rob, why don't you start on the zanidatamab readout timing? And then Renée, you can comment on Epidiolex.

Yes. So the projected readout that we just provided is based on progression events. And at the time of that PFS analysis, we would have the first interim analysis for overall survival. So as you've seen -- as you see that time line get pushed out, of course, that also allows for greater maturity and overall survival. So we'd expect more maturity of that first interim than we might have had if the readout or sooner. Again, we're not referring specifically to the pace of overall survival events. So this new projection has no implications for the second survival analysis or the final. There are 3 in total. Renée Galá: And then I'll jump in on the Epidiolex question. So I would say we're really pleased with the growth that we're seeing. We do have quite a bit of runway now that we're really excited about. In closing the GW transaction, we were quite confident in the durability and long live nature of this asset, and we're pleased to be at a point now where we can have greater clarity on what that looks like. So as we look at what driving the increased growth right now and what we'll continue to lean into. Epidiolex is highly differentiated, and that's supported by the data that we've generated for both seizure and non-seizure benefits and that data really resonates with physicians as well as with caregivers. We have great momentum in the adult and long-term care setting, and that's an area we're making investments in the breadth and quality of our access continues to improve, and that's having a positive impact as we see pull-through -- persistency has always been a hallmark of this brand, and we're seeing great impact even additional benefit to persistency through nurse navigator programs, and we're also piloting new programs within this area where we're seeing some early success, highly targeted consumer ads and also things like we've added virtual account manager position. So this is an area where we continue to learn, and we're really thrilled with the results that we're seeing.

Your next question comes from the line of Joon Lee with Truist Securities. Please go ahead.

Congrats on the quarter and thanks for taking the questions. This is [indiscernible] for Joon Lee. Just a couple from us. I know you haven't updated us completely on the 441 program. But what are you thinking in terms of the amount of dose reduction? And just going off David's question earlier around how much longer could the pending patents for Zepzelca extend exclusivity beyond December 2029? Thank you.

I hate to do this to you on the last question, but I don't think we're going to provide additional information on either of those. Obviously, we've talked about the ability to go to a lower dose in patients than in healthy normals on 441. So that's one of the things we're exploring, even in a small number of patients. And then on Zepzelca, we don't have specific additional information on what that could mean in terms of longer exclusivity for that agent at this point.

That concludes our Q&A session. I will now turn the conference back over to Bruce Cozadd, Chairman and Chief Executive Officer, for closing remarks.

Yes. Thank you, operator, and I apologize to the couple of sell-siders we didn't get to. We were given on our best shot to get through everything. And hopefully, we'll talk to you later this evening. I'd like to just close today's call by recognizing our Jazz colleagues for their efforts and thank our partners and shareholders for their continued confidence and support, and thank you all for joining us today.

This concludes today's conference call. You may now disconnect.