Jazz Pharmaceuticals PLC
NASDAQ:JAZZ
Earnings Call Analysis
Q4-2023 Analysis
Jazz Pharmaceuticals PLC
The company demonstrated a modest but steady growth in net product sales with Zepzelca's sales climbing 3% year-over-year to $74 million in the fourth quarter, leading to a full year revenue of $289.5 million, a 7% increase from the previous year. This achievement has established Zepzelca as a leader in second-line small cell lung cancer treatments. Total revenues exceeded $1 billion in Q4 2023 and $3.8 billion for the full year, marking a 5% annual growth while overcoming competition challenges. Looking ahead, the company set an ambitious revenue guidance for 2024 ranging from $4 billion to $4.2 billion, indicating a 7% year-over-year growth at the midpoint, driven by double-digit growth expectations for Xywav, Epidiolex, and Rylaze combined.
Several near-term catalysts are on the horizon with a focus on oncology and neuroscience. The company has initiated a program for Zanidatamab in second-line biliary tract cancer and a Phase III trial for Zepzelca, anticipating progression-free survival data by the end of 2024 or early 2025. Additionally, top line data from a Phase III trial of Epidiolex in Japan is expected in the second half of 2024 and could form a part of a pivotal regulatory package.
The company's financial strategy remains grounded in disciplined and strategic capital allocation. The forecast for 2024 suggests that they expect to maintain an adjusted net income consistent with that of 2023, ranging between $1.275 billion to $1.35 billion. This stability is intended to be achieved while continuing investments in commercial growth drivers and the pharmaceutical pipeline.
Xywav, the only low sodium oxybate and leading treatment for narcolepsy, is projected to be a crucial growth driver in 2024. Despite the anticipated impact from competitors like LUMRYZ, the company expects Xywav to remain the preferred choice. With over 9,500 narcolepsy patients at the end of Q4 2023, the market presents a significant opportunity, with growth also expected to come from the treatment of idiopathic hypersomnia.
Oncology products such as Zepzelca and Rylaze experienced some variability in sales growth, which is partially attributed to the niche markets they serve and seasonality. Nevertheless, Zepzelca has solidified its position as the premier treatment for second-line small cell lung cancer and has growth opportunities in the first-line setting. Additionally, Rylaze, despite quarter-to-quarter variability, is identified as a growth driver for 2024.
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Good afternoon, ladies and gentlemen. My name is Abby, and I will be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals Fourth Quarter 2023 Earnings Conference Call. [Operator Instructions] Thank you. And I will 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 full 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 Robert 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 noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website. I'll now turn the call over to 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, generated 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 Phil Johnson is joining Jazz as our Chief Financial Officer, effective March 1. Phil comes to Jazz from Eli Lilly, where over the course of almost 3 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 way with 40% year-over-year growth.
Moving to our R&D and pipeline efforts. We have multiple near-term late-stage catalysts targeting significant market opportunities. Given the strength of clinical data to date across multiple indications, we've used Zanidatamab as our most derisked asset, with more than a $2 billion peak potential. On the operational front, our disciplined capital allocation provides the financial strength to invest in our continued growth and diversification while generating healthy operating cash flow and margins. We have a strong track record of successful corporate development and remain focused on evaluating additional transactions.
Turning to Slide 7. We made progress towards Vision 2025 based on our strong performance in 2023. On the commercial side, we've executed successful launches with leading therapies in narcolepsy and epilepsy and a growing oncology portfolio. Our investments in R&D have expanded our capabilities and the breadth and depth of our pipeline. And on operational excellence, disciplined capital allocation has put us in a strong financial position, and we continue to be mindful of making investments with the most impact to drive meaningful shareholder value.
I'll now turn the call over to Renee to review our commercial performance, after which Rob will share an update on our R&D progress. I will provide a financial overview, and then we'll open the call to Q&A. Renee?
Thanks, Bruce. We had a strong fourth quarter, generating quarterly revenue of more than $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 net sales plus royalties from high sodium oxybate authorized generics, or AG, 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 of choice, including the #1 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 health care 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 on Xywav. Given our confidence that the IH indication represents a durable growth opportunity for Xywav, we are continuing to invest in further building this market. We have expanded our sales force, adding field personnel who are focused on IH, with the primary directive to increase the depth and breadth of IH prescribers.
Turning to Slide 10. We drove another quarter of Epidiolex growth with net product sales of approximately $241 million in the fourth quarter, representing a 16% increase compared to the same quarter in 2022. For the full year 2023, Epidiolex revenue was $845.5 million, up 15% year-over-year, driven by underlying demand and geographic expansion. We remain confident in the long-term growth prospects and blockbuster potential of Epidiolex, which is now annualizing at more than $900 million in revenue. Key drivers of this demand growth in the U.S. include positive responses to data on the benefits of Epidiolex beyond seizure control, such as language and communication, cognition, executive function and emotional and social function, as well as increased penetration in the adult patient setting. Further opportunities for growth include continued education to support optimal dosing, focused data generation and geographic expansion beyond the more than 35 countries where Epidiolex is approved, with additional launches and market reimbursement expected in 2024.
Moving to oncology. Slide 11 highlights the strong performance of Rylaze in 2023, which contributed to our total oncology business exceeding $1 billion in annual revenue for the first time. Rylaze delivered net product sales of approximately $102 million for the fourth quarter of 2023 and approximately $394 million for the full year, representing 26% and 40% year-over-year increases in those periods, respectively. A number of factors are contributing to continued strong demand for Rylaze. Rylaze has been almost universally adopted in pediatric asparaginase-based oncology protocols in the U.S., and we continue to see strong adoption of the new Monday, Wednesday, Friday dosing regimen. We are also seeing increased usage of Rylaze in [ ALL ] patients due to some of the benefits of a short-acting profile relative to current first-line asparaginase therapies, including switches from these first-line therapies due to tolerability concerns and side effects.
In addition, we have an opportunity for continued growth with increasing use of Rylaze in the treatment of adolescents and young adults, or the AYA market. Turning to Slide 12 and Zepzelca. Net product sales for the fourth quarter increased 3% year-over-year to $74 million. For the full year 2023, net product sales were $289.5 million, up 7% year-over-year. We have established Zepzelca as the #1 treatment for second-line small cell lung cancer patients, and we continue to hear positive feedback from health care providers on its clinical benefit and ease of use and administration for patients and their health care practices. Since its launch, Zepzelca has generated almost $900 million in revenue, and is proving to be a highly accretive and well-executed corporate development transactions.
In addition to the second-line setting, there remains an unmet need for patients in earlier lines of therapy. The ongoing Phase III trial in first-line small cell lung cancer provides a further opportunity to improve patient lives and outcomes as well as drive future growth. With that, I'll turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?
Thanks, Renee. 2024 represents an exciting time for us on the R&D front. And we anticipate multiple 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 in 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 III trial of Epidiolex in Japan in the second half of 2024. We also have ongoing trials for suvecaltamide, or JZP-385, In 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 development plan for Zanidatamab. We have meaningfully progressed Zanidatamab development across indications since bringing it to Jazz last year. And based on the totality of the data, we are highly confident in this molecule as a differentiated therapy for HER2-expressing cancers. I'll note that we are hosting an R&D Day on March 19 that will focus exclusively on Zanidatamab, including perspectives from GEA and breast cancer KOLs.
Zanidatamab has shown compelling activity across a broad range of HER2-positive tumors, and our development plan represents a robust investigation of this molecule in multiple tumor types, as outlined on this slide. In addition to our BTC and GEA programs, we see meaningful opportunity for Zanidatamab to improve care for early and late-stage breast cancer patients. Slide 16 highlights 1 of the most critical factors contributing to our enthusiasm around Zanidatamab. Specifically, the data generated to date has demonstrated Zanidatamab activity as monotherapy in combination with other agents, in patients previously treated with other HER2 agents, and results in durable responses with encouraging progression-free survival and overall survival data.
Our development strategy for Zanidatamab starts with BTC, an area of high unmet patient need where there are currently no approved HER2 therapies. We believe coming to market in BTC will enable a fast-to-market strategy where we can leverage supplemental BLA findings and other indications. GEA is the next potential indication to follow BTC, and we believe a prior approval in BTC may accelerate adoption into GEA treatment guidelines and protocols. Following discussions with the FDA, we have elected to increase the enrollment target for the GEA trial to improve statistical power for the overall survival endpoint. This will not impact the time line to potential approval, which is still based on PFS from the original patient enrollment target.
We remain committed to rapidly advancing and expanding our development for a molecule that has the potential to transform the current standard of care in multiple HER2-positive cancers. Now I will turn the call over to Bruce for a financial update. Bruce?
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 3 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 in IH and Epidiolex, offset by the expected decline in Xyrem. I'll note this guidance is inclusive of AG royalties, which we expect to exceed $200 million in 2024. Our 2024 oncology revenue guidance range of $1.12 billion to $1.22 billion reflects expectations of continued double-digit growth for this therapeutic area.
I'd like to draw your attention to several items on Slide 21. With regard to operating expenses, our SG&A guidance range is $1.17 billion to $1.23 billion. The expected increase in SG&A in 2024 over 2023 will largely be a result of continued investments in our key growth drivers, including Xywav IH initiatives, commercial support for Epidiolex in the U.S., where we know the market is promotionally sensitive, geographic expansion of Epidiolex outside the U.S. and educational efforts for Rylaze in AYA. Our R&D guidance range of $800 million to $850 million represents an increase of 5% at the midpoint compared to 2023, driven by planned continued investment in our robust Zanidatamab development program. Both SG&A and R&D guidance at the midpoint represent the same percentages of total revenue compared to 2023.
On the bottom line, we expect adjusted net income in 2024 to be in line with 2023 with a guidance range of $1.275 billion to $1.35 billion. This reflects anticipated investments in our commercial growth drivers and pipeline enabled by top line growth and disciplined and strategic capital allocation.
I'll conclude our prepared remarks on Slide 23. In 2023, we delivered on our neuroscience, oncology and total revenue guidance. On the commercial side, our 2023 performance was driven by combined double-digit growth of key products Xywav, Epidiolex and Rylaze. On a combined basis, we expect these to grow by double digits again in 2024. This is a very exciting time for Jazz on the R&D front as we continue to advance our pipeline and invest in long-term growth, with multiple catalysts expected in the near term. As always, we remain focused on operational excellence and strategic capital allocation, with corporate development remaining an opportunity for additional growth and diversification.
In summary, we are poised to deliver top line growth and multiple pipeline catalysts in 2024. And longer term, with our expanding product portfolio, R&D progress and focus on operational excellence, we believe we are well positioned to achieve Vision 2025 and deliver further diversification, sustainable growth and enhanced value to patients and shareholders. That concludes our prepared remarks. I would now like to turn the call over to the operator to open the line for Q&A.
Thank you. [Operator Instructions] We'll take our first question from Jessica Fye with JPMorgan.
We're [ steering ] worries about Xywav's position in narcolepsy despite what looks like sleep neuro guidance clearly 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?
Yes. 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, 1 of 3 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 #1 treatment on 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 and 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 any discontinuations that we had. Also in the fourth quarter, we did see an increase in our nonrevenue [ 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 was 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 authorized generics, which, of course, we receive a significant royalty on, or to fixed dose 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 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 ], [ Vyxeo ] Zepzelca or [ Renees ], I'm sorry, Rylaze, I still say that, Bruce, I apologize. Any color you can give us just on the quarter? I mean, [ Defitelio ] and [ Vyxeo ] obviously much higher than expected. The other 2 products, flattish quarter-to-quarter. So anything you can provide would be helpful.
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, Vyxeo ] 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 Erwinaze, 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 #1 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.
My question, just how you foresee with Zani, the frontline GEA differentiating in the PD-L1 negative subpopulation, if you aren't stratifying patients on the basis of PD-L1 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 its [ KEYNOTE-811 ] regimen? Just kind of wondering how you can kind of paint that picture?
Thanks, Jason, for the question. Rob, you want to weigh in on that?
The PD-L1 biomarker wouldn't have any predictive value for Zanidatamab or any other HER2 therapies. So we think we can clearly define a benefit in the PD-L1 positive or negative subgroups. Of course, we have 2 experimental arms, one where Zani is combined with standard of care chemo. And we also have an arm where we add PD-1 antagonist to that atezolizumab from Beijing. And so we have an opportunity to address both the PD-L1 negative group where the standard of care continues to be [ Herceptin ] chemo, and the PD-L1 positive group where PD-1s have been shown to benefit patients. And we think in that segment, we have the superior anti-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.
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 sales force will focus on to drive additional prescribing debt?
Thanks, Ami, for those questions. Renee, I'll turn that one over to you.
Sure. Yes. And thank you, Amy. With respect to what we're seeing in narcolepsy, as I 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've 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're looking at a 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 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.
We will take our next question from Ash Verma with UBS.
So I wanted to just get your latest thoughts on what you're thinking about bridging to 2025 vision of $5 billion in sales. Do you think you need a digital 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 ], [ talletumab ], just -- if you can comment on how do you think the small cell lung cancer space might well?
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 move towards 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 nice growth both in the U.S. and outside the U.S. with Epidiolex. So we believe we're solidly on track for that. And we also said our oncology business will contribute north of $1 billion in 2025, with Epidiolex and oncology together contributing $2.5 billion. And we were very pleased, obviously, to see our oncology business grow to more than $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 like 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 the announced Vision 2025. Of course, that could include some revenue contribution from Zanidatamab, where we said we'll finish our rolling BLA submission in the first half of this year. And we're projecting that launch could come in 2025 or sooner. We're not suggesting that that would make up all of that $500 million in 2025. But we are in a 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 for 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, adds an additional growth driver and provides sustainability over not just 2025, but as we look through the period, 2025 to 2030. So long answer to a short question, but we're making excellent progress towards Vision 2025. And on the Zepzelca side, maybe Rob, I'll turn that one over to you.
Happy to, Bruce. As you know, [ tarolatimab ] is a very different mechanism of action than Zepzelca. The data that will support -- that have supported a BLA or in the third line versus Zepzelca in the second line. And the safety profile for [ tarolatimab ] is really quite different with a high risk of CRS and [ SeriousRS ], even 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 3 weeks. And that really makes it an ideal candidate for add-on therapy in the frontline setting. And as you know, 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.
We will take our next question from Joseph Thome with TD Cowen.
Maybe just 1 on Zanidatamab, how should we think about continued investment in the program overall? I know you outlined the breast cancer opportunity in 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?
Yes. I'll start, and then Renee and 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 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 with RBC Capital Markets.
Congrats on the progress. Maybe, Bruce, just adding on to some of the color that you 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 [ Jet Power ]?
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.
Now there can be pockets of areas where it seems like everyone's looking at the same time, valuations maybe 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 [indiscernible] to work to drive that growth and sustainable growth over a longer period of time.
We will take our next question from Annabel Samimy with Stifel.
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, what type of investment you need to make in the launch, the infrastructure to appropriately target GI 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 5 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.
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 43% margin back in 2021. I'll point out we essentially achieved 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 U.S. And we're also looking at Zani as a global brand, an important global brand for us. So after the U.S., 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 [ mean ] the U.S., Europe and Japanese markets. And then as we expand into breast, 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.
Can you just add a little more about Epidiolex and what drove the performance? Is -- are you seeing double-digit volume growth both U.S. and ex-U.S.? And was there any stocking benefit that we should be aware of?
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. So 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 U.S. as well as in Europe. We've said in the past, what continues to resonate with physicians, providers, patients 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 #1 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.
We will take our next question from Joon Lee with Truist Securities.
Thanks for the update and for taking our questions. When you do report top line data from suvecaltamide and [ ascentitremor ], will you have a go/no-go decision when you report the top line? Or is that something that you still have to consult with the FDA and the 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 the orexin program.
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 that time on that steps remains to be seen and remains to be -- remains dependent on the data. But in general, our view is we know what we need 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 of 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 will be quite informative, and 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.
We will take our next question from Gary Nachman with Raymond James.
So on Zani, just what's the time line 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?
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 -- the final overall survival end point. We plan to read out the progression-free survival based on the original sample size so -- to have no impact on the overall time line. 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.
And 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 with this change. And then on the mature OS data, we'd have more power.
And then...
Yes. I mean in terms of so -- I didn't get to the -- didn't address the question on revenue in 2025. There is 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 U.S. 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.
We will take our next question from Akash Tewari with Jefferies.
This is Amy on for Akash. Just a quick one on Zani and GEA. So given the mechanism similarity between [ Herceptin, Perjeta, Combo ] and Zani, why do you therapists' [ Phase III GEA trial Jacob ] failed? It doesn't seem to be like HER2 expression related given the treatment arm enrolled roughly similar HER2, 3 population compared to the comparator arm, which is perception plus chemo. So is there anything you are doing just only in your trial?
Rob, do 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 Perjeta ] 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 2 FAB fragments of the antibody on different receptors. And it causes receptor clustering, which enhances interference signaling, whether that be through HER2 or interference of dimerization with HER3 and therefore, interference is 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 biparatopic antibody and showing that it induces complement-dependent cytotoxicity, which is unique amongst any HER2 antibodies and also some experimental data comparing head-to-head to just combining those 2 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 Perjeta ] 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, Perjeta to BTC patients.
And we will take our next question from Charles Duncan with Cantor Fitzgerald.
This is [ Asiya ] 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 U.S. And also, you did mention additional market launches this year. So I was wondering if you can provide a bit more color on this?
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 3 different indications that we think provide quite an important opportunity. And 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 U.S. 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 5 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.
This is Michael Riad on for Jeff Hung. On the high sodium authorized generics, what evidence generation is needed to support the long-term health messaging and drive patients like 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?
Yes. I would say the evidence surrounding impact of sodium on cardiovascular health is pretty incontrovertible. Certainly, they underlie the original orphan drug exclusivity decision by FDA determining that Xywav was clinically superior to Xyrem on the basis of that lower sodium. The same thing could be said for LUMRYZ, which has the same sodium level as Xyrem. It 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 sodium oxybate therapy, we saw patients have a significantly increased either diagnosis of hypertension or beginning anti-hypertensive med. So even in a short period of time, you see that impact on people, even if they aren't already diagnosed as being hypertensive patients, which is, again, why that original determination was that Xywav will 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.
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 then Rob and 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 worked 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, has 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 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.
And ladies and gentlemen, this concludes today's call, and we thank you for your participation. You may now disconnect.