Jazz Pharmaceuticals plc (JAZZ) Q1 2025 Earnings Report, Transcript and Summary

Hello and thank you for standing by. My name is Tiffany, and I will be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals First Quarter 2025 Webcast Conference Call. 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] I would now like to turn the call over to Executive Director of Investor Relations, Jeff Macdonald. Please go ahead.

Thank you operator, and good afternoon everyone. Today, Jazz Pharmaceuticals reported its first quarter 2025 financial results. The slide presentation accompanying this webcast is available on the investor section of our website. Investors should also refer to the press release we issued earlier today that is available on our website. On the call today are Bruce Cozadd, Chairman and Chief Executive Officer; Renee Gala, President and Chief Operating Officer; Rob Iannone, Executive Vice President, Global Head of R&D and Chief Medical Officer; and Phil Johnson, Chief Financial Officer. On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential and anticipated development, regulatory and commercial milestones 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 uncertainty prescribed under the caption risk factors in our annual report on form 10-K for the fiscal year ended December 31, 2024 and our subsequent filings with the SEC, including our quarterly report on Form 10-Q for the financial quarter ended March 31, 2025, which identifies 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 reconciliation 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 Jeff. Good afternoon, everyone. Thank you for joining us today to discuss Jazz's first quarter 2025 results. I'll start on Slide 5. Jazz started the year with strong momentum following a productive 2024, and we're pleased with the meaningful progress we've made across the business in the first quarter of 2025. Our focus on execution and operational excellence resulted in solid commercial performance led by Epidiolex and Xywav and significant progress across our R&D pipeline. We submitted a supplemental new drug application or SNDA, to expand Zepzelca into first line maintenance in extensive stage small cell lung cancer, and received a positive CHMP opinion recommending the marketing authorization for zanidatamab and advanced HER2 positive biliary tract cancer or BTC in the European Union. In addition, the acquisition of Chimerix has further strengthened our presence in rare oncology. On the commercial front, we generated 898 million in total revenues across our portfolio. Our neuroscience portfolio had a strong start to the year with Xywav growing 9% year-over-year, remaining the number one branded treatment for narcolepsy as measured by revenue and the only therapy approved to treat idiopathic hypersomnia or IH. We saw strong Epidiolex demand as revenues increased 10% year-over-year, and we remain confident in its blockbuster potential. While we experience near-term headwinds with certain oncology products, our oncology portfolio is poised for growth with 3 potential regulatory approvals in the coming months, including Dordaviprone, Zepzelca expansion in the first line maintenance therapy in the U.S., and zanidatamab Advanced BTC in Europe. Moving to R&D, we're advancing promising opportunities in our pipeline. The HERIZON-GEA-01 Phase III trial evaluating zanidatamab in first line gastroesophageal adenocarcinoma or GEA remains on track to read out in the second half of this year. We continue to progress other key zanidatamab clinical trials, including the Phase III and Power BC 303 trial in breast cancer. We're looking forward to sharing important data on Zepzelca, zanidatamab, and Dordaviprone at ASCO in June. We added Dordaviprone to our pipeline through the Chimerix acquisition, which closed in April, enhancing our presence in rare oncology and bringing a near-term commercial opportunity to help patients with limited treatment options. Given its patent protection into 2037 with possible extensions and the potential for expanded use in the frontline setting, we view Dordaviprone as a meaningful and durable revenue opportunity for Jazz. We are well positioned with respect to the impact of potential tariffs and have maintained financial flexibility, supported by our strong balance sheet and cash flow. We remain confident in our top line revenue guidance and have updated our financial guidance to include the recent Chimerix acquisition and litigation settlement charges. I'll now turn the call over to Renee to discuss our commercial performance, after which Rob will cover our R&D pipeline. Bill will then provide a financial overview and discuss our updated guidance, and after that we will open the call to Q&A. Renee?

Thanks, Bruce. I'll begin on Slide 7 to discuss the continued progress of our commercial portfolio, starting with our sleep therapeutic area. I'm pleased to report total revenue for sleep, which includes Xywav and Xyrem net product sales plus royalties from high sodium oxybate authorized generics or AGs, was approximately 431 million in the first quarter of 2025. Xywav net product sales were approximately 345 million in the first quarter, an increase of 9% year-over-year. As a reminder, we typically see seasonality in our sleep revenue due to reauthorizations at the beginning of each year. Despite the expected seasonality, Xywav had a robust quarter of patient ads driven by strong execution from the field teams, and we continue to be excited about the direction of our sleep portfolio. There were approximately 14,600 active Xywav patients exiting the first quarter, representing an increase of approximately 450 net patient ads compared to the fourth quarter of 2024, comprised of 125 narcolepsy patients and 325 IH patients. Narcolepsy patient ads consisted predominantly of oxybate naive patients along with patients transitioning from high sodium oxybate. Our efforts to educate on the importance of reducing sodium intake and the increased risk of cardiovascular comorbidities among narcolepsy patients continue to resonate with HCPs and with patients. We see the most opportunity for patient growth from the IH market, where Xywav is the first and only FDA approved therapy. As we continue to build this market, disease education on the benefits of using a nighttime therapy to address sleep inertia and symptoms like brain fog and excessive daytime sleepiness for IH remains important to drive prescribing. We've launched consumer targeted digital and media campaigns to increase disease awareness coupled with promotion and medical education to HCPs. These campaigns are performing well, contributing to the growth of the IH market, and we continue to enhance our field effectiveness to optimize our impact for patients. Turning to Slide 8 in Epidiolex. Epidiolex had net product sales of approximately $218 million in the first quarter, a 10% increase year-over-year. Growth was primarily driven by underlying demand and to a lesser extent a favorable U.S. payer mix, partially offset by U.S. inventory burn. Exiting the first quarter, inventory was lower than we would typically see at this time of the year. Our Epidiolex commercial and medical teams have been executing well, with key drivers of demand growth in the U.S., including continued data generation on the benefits of Epidiolex beyond seizure control, expanded reach to adult patients and long-term care facilities, along with broad quality access and the nurse navigator program. We're pleased with the growth of Epidiolex and expect it to reach blockbuster status in 2025. Moving to oncology on Slide 9. Rylaze net product sales were approximately $94 million in the first quarter of 2025, a decrease of 8% year-over-year. As we've previously noted, Rylaze sales have been impacted by the update to Children's Oncology Group or COG pediatric treatment protocols for acute lymphoblastic leukemia made in mid 2024. Based on feedback from KOLs about their expected use of asparaginase, we continue to see the impact to Rylaze as temporary with revenue normalizing during the second quarter of 2025. We are making steady progress in the adolescent and young adult market and continue [indiscernible] place Zepzelca back on a growth trajectory. Moving to Slide 11 in our ongoing Ziihera launch. In December of last year, FDA approved Ziihera, the first and only dual HER2-targeted bispecific antibody approved for HER2 positive second line BTC in the U.S. We recognize that approximately $2 million of net product sales in the first quarter of 2025. [indiscernible] launch recession from ATP has been positive. We hear initial customer experiences are aligned with the clinical profile we observed in clinical trials. As a reminder, BTC is a rare disease with a limited number of patients, and we expect revenue contribution to be modest from this rare cancer. We expect this initial launch and second line HER2 positive BTC will help us [indiscernible] significant benefit for patients. In addition, the BTC approval helps healthcare professionals gain meaningful experience with Ziihera prior to its potential indication in GEA. I will now turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

Thanks, Renee. I'll begin on Slide 13. I'm excited about our pipeline and the significant progress we have made on key programs with additional milestones expected this year. Looking first at oncology, we completed the submission of an FNDA to FDA to expand the Zepzelca label to include maintenance therapy in first line extensive stage small cell lung cancer for patients who have not progressed during induction chemotherapy. The submission is based on statistically significant and clinically meaningful progression-free survival or PFS, and overall survival or OS data from the Phase III and IV day trial of Zepzelca in combination with the atezolizumab compared to atezolizumab alone. The results have the potential to be practice changing, and we look forward to showcasing the data in an oral presentation at ASCO on Monday, June 2. Presentation in a peer reviewed form also enables us to submit the data for potential inclusion in NCCN guidelines and compendia listing. We also remain on track for top line readout of PFS data from the HERIZON-GEA-01 trial in the second half of this year. The first interim analysis of OS will also occur at this time. We are encouraged by the positive results from 2 independent Phase II trials of zanidatamab in first line GEA that demonstrated increased median PFS, duration of response, and confirmed objective response rates. If the Phase III trial findings are positive, we expect the data will support registration based on potentially clinically meaningful PFS and supportive OS data. 3 zanidatamab ad presentations have been accepted at ASCO, including updated overall survival data from the Phase II first line GEA trial. In addition, there will be an oral presentation on the safety and efficacy of Dordaviprone. Turning to Neuroscience, we recently initiated our planned Phase IB trial to evaluate the efficacy, safety, tolerability, and pharmacokinetics of JZP441 in participants with type 1 narcolepsy. And with respect to our Epidiolex trial in Japan, we are continuing to collect long-term safety data, which was included in the trial design for 26-week and 52-week analysis. We observed numeric improvements in both the primary and several secondary endpoints, and we remain on track to meet with the Japanese health authorities in mid 2025. As outlined on Slide 14, zanidatamab has proven to be a unique, differentiated, and highly effective dual targeted HER2 therapy. Zanidatamab provides opportunities across multiple HER2 positive solid tumors and represents a global opportunity for Jazz in multiple markets. Following the FDA approval of zanidatamab in second line BTC last year, the CHMP recently adopted a positive opinion, recommending the marketing authorization of zanidatamab for the treatment of adults with previously treated, unresectable, locally advanced or metastatic HER2 positive BTC. We look forward to the European Commission's decision and for the opportunity to bring a new treatment option to patients in Europe if approved. We have also completed recruitment for our Phase III trial evaluating zanidatamab in first line GEA and expect topline PFS data later this year. The overall development program for zanidatamab includes multiple registration enabling trials, including pivotal trials in first line BTC, first line GEA, advanced breast cancer and in a pan-tumor basket trial focused on areas where we believe zani has the potential to emerge as the preferred HER2 targeted therapy. This comprehensive development program underscores our confidence in zanidatamab’s potential. Turning to Slide 15, we're also very excited that the Chimerix transaction has been completed and thrilled to welcome our new colleagues to Jazz. Our team is now engaged and working toward the shared goal of delivering Dordaviprone to patients. Dordaviprone is a groundbreaking first in class small molecule in development for H3K27M-mutant diffuse glioma, a rare high grade brain tumor that most commonly affects children and young adults. There are currently no approved drug therapies for these patients, and the median overall survival from diagnosis is approximately only one year. Multiple clinical studies have demonstrated Dordaviprone's benefit in patients with recurrent H3K27M-mutant diffuse glioma, both as monotherapy, pending combination with other treatment approaches, including radiation, with a consistently favorable safety profile. The FDA has accepted an NDA for Dordaviprone seeking accelerated approval for treatment of H3K27M-mutant diffuse glioma in adult and pediatric patients with progressive disease following prior therapy. The application has been granted priority review and assigned a PDUFA target action date of August 18 of this year. Based on communication with the FDA to date, we do not expect the agency to hold an oncology drug advisory committee meeting in connection with the review of the NDA. Beyond the recurrent disease setting, Dordaviprone is being studied in the ongoing Phase III action trial, evaluating its use in newly diagnosed H3K27M-mutant diffuse glioma patients following radiation treatment. This trial has the potential to confirm the clinical benefit of Dordaviprone in recurrent H3K27M-mutant diffuse glioma and potentially extend this treatment option into the frontline setting. We believe that Dordaviprone has the potential to transform the standard of care for this underserved patient population with very limited treatment options. 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 17. As a reminder, our full financial results are available in our press release, which is available today, and in our 10-Q, which will be filed tomorrow morning. In the first quarter of 2025, we recorded $898 million in total revenues. I'll note our first quarter revenues have historically been affected by several factors, including reauthorizations and inventory bill in the latter part of the prior year, which typically burns off in the first half of the following year. As Renee mentioned, for Epidiolex, we saw more of this burn in the first quarter of this year. Despite these factors, Xywav and Epidiolex revenues grew 9% and 10% year-over-year respectively. Our oncology products experienced a decline relative to the first quarter of 2024. In part, this was driven by having one fewer shipping week in the first quarter of 2025 compared to the first quarter of 2024. In addition, the decline was primarily driven by our 2 largest oncology products, Zepzelca and Rylaze. As Rene noted earlier, we believe we have a line of sight into our assumption of growth for these products in the coming quarters. As I'll highlight on the next slide, we are affirming our total revenue guidance for 2025 based on our conviction and the strength of our overall commercial portfolio. Adjusted net income and earnings per share in the first quarter of this year were impacted by charge related to certain Xyrem antitrust litigation settlements. This $172 million charge to SG&A in the first quarter reduced our adjusted net income by $146 million and our GAAP and non-GAAP EPS by $2.38 per share and $2.34 per share respectively. Before discussing our updated 2025 financial guidance, I'd like to comment on tariffs. Now, I'm sure we'll have several questions on this topic during the Q&A session, so I'll limit my commentary to the most essential items. I'll start with the tariffs already enacted on China, Mexico, and Canada, as well as the general 10% tariff levied more broadly. For 2025, we anticipate no direct financial impact from these tariffs, and currently expect any indirect impact resulting in inflation on goods we purchase can be managed within our existing internal budgets and external guidance. We won't speculate on the potential impact of future tariffs on pharmaceutical products imported into the U.S. at some hypothetical rate. As you'd expect, we've evaluated various scenarios and are positioned to comment in a timely manner if and when such tariffs are enacted. I can say we have sufficient inventory in the U.S. to serve all or nearly all of our 2025 needs for each of our products. Consequently, we expect that any impact for our 2025 financials would be de minimis, if any, and unlikely to affect our guidance. With that context, let's move to our updated 2025 financial guidance. Now, at first glance, the updates may seem complex. In reality, there are 3 drivers for the updates, and I think you'll find they're pretty straightforward. Those 3 drivers are the Chimerix acquisition, certain Xyrem antitrust litigation settlements, and slightly revised expectations for full year R&D expense. The Chimerix acquisition affects guidance in 3 ways. First, it will be accounted for as an asset acquisition. Consequently, we'll recognize a non-tax deductible acquired IPR&D charge that we estimate will be between $870 million and $900 million. Second, we'll recognize Chimerix's results from operations from the date of close to the end of the year. At a high level, this includes a non-material amount of revenue and cost of sales, as well as roughly $50 million in SG&A expenses and roughly $60 million in R&D expenses. Third, our interest expense and interest income expectations have been adjusted to reflect the timing of the net outlay for Chimerix, which was approximately $890 million as well as the continued investment in Chimerix's operations over the remainder of the year. Moving to the Xyrem antitrust litigation settlements, our 2025 guidance has been updated to reflect the tax deductible charge of $172 million we recognize in our SG&A expenses in the first quarter. Finally, excluding Chimerix, our guidance has been adjusted to reflect slightly lower R&D expense, roughly $20 million in aggregate in our existing Jazz portfolio, driven primarily by the successful early conclusion of 2 Phase IV Xywav studies. Moving on to the slides that illustrate the specific revisions to our guidance, you'll see on Slide 18 that we are affirming our full year 2025 revenue guidance. Our guidance range remains $4.15 million to $4.4 billion, which represents 5% year-over-year growth with the midpoint. This is driven by our confidence in both the neuroscience and oncology portfolios. Xywav continues to grow with impressive new patient ads and expansion of the IH market. We continue to expect that Epidiolex will reach blockbuster status in 2025 and anticipate Rylaze revenues will normalize during the second quarter of 2025. We also believe that Zepzelca’s potential expansion into first line maintenance therapy will provide more patients the ability to receive treatment for a longer duration. Turning to Slide 19, our non-GAAP adjusted SG&A guidance range for $1.25 billion to $1.31 billion has been updated to $1.47 billion to $1.53 billion. The revised range reflects the $172 million pre-tax charge both this quarter associated with certain Xyrem antitrust litigation settlements and the addition of Chimerix. Our non-GAAP adjusted R&D guidance range was $720 million to $770 million has also been updated to $760 million to $810 million. This change is driven primarily by additional investment in ongoing clinical programs for Dordaviprone, partially offset by the slight reduction in spend on the Jazz portfolio I mentioned earlier. On the bottom line, we expect adjusted net income to be $250 million to $350 million for the full year of 2025. The updated ANI guidance reflects the cumulative effect of all the items I described earlier. We're in a sound financial position with healthy cash flow generation over $400 million in the first quarter. And we have several near-term commercial opportunities and a particularly important upcoming data readout. We continue to believe that a disciplined approach to capital allocation, including prioritized spend on our ongoing R&D programs and lead commercial products, as well as corporate development, will drive long-term shareholder value. I'm now turn the call back to Bruce for closing remarks.

I'll conclude our prepared remarks on Slide 21. We had a strong start to 2025 with continued focus on commercial execution led by growth of Xywav and Epidiolex and the ongoing launch of Ziihera. In addition, we were pleased to close the Chimerix transaction and welcome our new colleagues as we work together to prepare for the potential launch of Dordaviprone. Corporate development remains key to our strategy, and the Chimerix transaction is representative of our ability to identify and execute transactions that are strong strategic fits. Dordaviprone is a potential near-term commercial opportunity with an efficient commercial call point and durable revenue stream. Our R&D pipeline continues to advance with the top line PFS readout from our Phase III GEA trial of zanidatamab expected in the second half of 2025, and near term PDUFA date of Dordaviprone in August, and the recent submission of the Zepzelca FNDA. Our financial position, balance sheet, and cash flow generation remains strong, supported by our focus on operational excellence and strategic capital allocation. We remain well positioned to continue delivering innovative therapies that transform the lives of patients and their families. That concludes our prepared remarks. I would now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Your first question comes from the line of Jason Gerberry of Bank of America. Please go ahead.

Hey guys, thanks for taking my question. And so I'm going to respect Phil's comment about not asking to speculate on tariffs, but what I'm going to ask is about your supply chain and specifically Xywav, so you have a U.S. CDMO and so I'm just curious, if you can speak to Xywav is not a very high volume product, so just curious to the extent that if need be in 2026, you could fully supply the product from your U.S. CDMO and if you can comment if your API can be sourced in the U.S. such that you've got a fully U.S. supplied product for the U.S. market.

Yeah, Jason, thanks for the question and I appreciate your being respectful of the prior comments as long as we can comment on what we can. So you're correct, we do have U.S. supplier for oxybate, including Xywav. That supplier does have enough capacity that we can access to fully meet our U.S. needs, and certainly if tariffs are coming into play would be very effective option for us to mitigate that exposure and there's no particular issues that I would note with regard to API and having that subject to tariff.

Your next question comes from Jessica Fye with JP Morgan. Please go ahead.

Hey guys, good afternoon. Thanks for taking my question. So following up on the first question, maybe thinking beyond oxybate, can you talk about Jazz's manufacturing footprint, including sources of API and any other possible mitigation strategies or contingency plans to neutralize any potential impact of biopharma tariffs if they're implemented?

Maybe I'll ask Renee to take the first part of that, which is just factually where we do our manufacturing, and then Phil, if you want to add anything more on tariffs, jump in.

Poor Bruce, and thanks for the question, Jess. So, with respect to where we manufacture Xywav and Xyrem, Phil mentioned we do have a CMO in the U.S. We also have a facility in Athlone, Ireland, and so we do have a level of flexibility there. With respect to Epidiolex, we have a facility in the UK where we produce that product and we have the capability to also develop other products at that plant and then some of our other smaller products on the oncology side are manufactured in different locations and Defitelio is in La Guardia, Italy. Vyxeos is manufactured by Symtra and then Rylaze is manufactured in Denmark. So, we do have quite a lot of manufacturing in Europe. In terms of our capabilities and what options we have going forward, obviously making changes to our manufacturing sources is something that we don't take lightly. It does take a period of time, but we do have a level of flexibility as we've mentioned today with our oxybate products, and we'll continue to evaluate both backup options and other sources of manufacturing. Phil?

Yeah, I know it's a great summary and as you'd expect, Jess, this has been, subject of quite a bit of work across functional team, since sort of late last year, early this year, and there certainly are opportunities for us to work with CMOs here in the U.S. to further reduce the exposure to Jazz beyond those that we're currently working with to date or the primary way that we've buffered impact would be through. Having sufficient inventory in market here in the U.S. to cover all or nearly all of our U.S. needs at this point for 2025 for each of our products, we'll continue with that strategy, then obviously depending upon if and when tariffs come into effect, what geographies they would impact and what rate we may have some protection from inventory for 2026 as well.

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

I actually wanted to ask a question about Zepzelca and competition from Imdelltra. I know it's having an impact, and the label expansion is certainly not lost on me, but I guess my question here is, how should we think about Zepzelca over time in terms of its trajectory? Do you anticipate that first line contribution will overwhelm the pressure in the second line setting and then also how are you thinking about the expansion of Imdelltra itself bearing in mind that Amgen has a pretty comprehensive development program in small cell lung, in terms of earlier lines of therapy. So, how are you thinking about Zepzelca overall as a growth product going forward?

Yeah, I'm happy to jump in and take that one. So, as we think about Zepzelca, we did have some dynamics impacting the first quarter as we look forward though to your point on Zepzelca returning to growth, even with competition and some delayed progression of first line limited stage patients coming into the second line, Zepzelca in the second line still remains the leading treatment as measured by market share. Importantly, we do look forward to both sharing our data at ASCO on the first line and forte trial where we showed stats [indiscernible] meaningful PFS and OS in our study of first line, extensive stage maintenance patients and so this is something we look forward to presenting at ASCO and then rapidly submitting that data for potential inclusion in NCC and treatment guidelines. We do expect this data to be practice changing and therefore going into the first line we look to a larger patient population to treat in the extensive stage patients, but also longer treatment duration. So, we do expect this to contribute to future growth of the brand and we would also expect patients that didn't receive Zepzelca in first line to have the opportunity to receive it in the second line. And then, Rob, do you want to take the question with respect to the views of tarlatamab going forward from a clinical perspective?

Yeah, again, Jess, I think you covered it very well, Renee, with our new data and ultimately adoption into NCCN and in the label as first line, that affords us a larger population for a longer duration of therapy, tarlatamab is not approved in that setting. And, it would be quite a while before a new trial would read out there. So, as a new standard of care, I think that's the key that extensive stage patients who don't progress after induction, as you said, should become the standard of care to get Zepzelca. And then for patients, who don't receive it in front line Zepzelca, has data to show that it's an effective second line therapy.

Your next question comes from Marc Goodman with Leerink Partners. Please go ahead.

Phil, your comments about tariffs not impacting 2025, I assume have to do with the fact that you have inventory that you've just built up in the U.S. and so you don't have to worry about it. But is it a fair question to ask what would be the impact for a full year just on an annual basis if you didn't have all that inventory built up? Like what would we be talking about here as far as the numbers?

Yeah, Marc, I appreciate the question, sort of in this theoretical realm of what might happen in the future, it depends obviously on what kind of rates being put in, what kind of geography are affected, so we're not commenting at this point in time on those hypotheticals. I would say again depending on when tariffs would go into effect if they are, we could get some coverage from inventory as we're getting effectively this year. And then we also have the ability for our oxybate products to use U.S. source to effectively mitigate that exposure. Beyond that, the main tools available to us would be things like looking to work with other third party manufacturers here in the U.S. to further reduce the impact, but feel very good about the position that we're in currently, obviously closely monitoring the situation, we'll take actions as needed.

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

Hi all, this is [indiscernible] on for Andrea. Thanks for taking our questions today. Would you – want to understand little bit better, why does the Chimerix acquisition make sense for Jazz and what do you find most compelling about the Dordaviprone commercial opportunity? And related to that, how are you thinking about additional BD activities going forward?

So, maybe I'll jump in at the total company acquisition level and then, Renee or Rob, if you want to add anything on Dordaviprone in particular, you can. We've been, I think, pretty clear about our corporate development strategy for some time now as a major pillar of how we invest capital to create value for shareholders in addition to what we do in our investments in our commercial portfolio and in our R&D efforts, and we've been clear that our priorities include finding products that would represent a real advance where there's unmet medical need, in a serious condition that aligns with our capabilities that has an efficient commercial call point, so that we don't need to do massive buildup of commercial expense that have long durability. And we really feel that Chimerix on all fronts was a perfect fit for us, matches well with what we do well, particularly in oncology, near term launch, again efficient and we're confident fills a serious unmet need. Rob, you want to jump in?

Yeah, I'd love to. The treatment for diffuse glioma hasn't changed since I trained as a pediatric oncologist 25 years ago. Patients get debulking surgery, which is never curative, and then radiation therapy, and that's essentially prior to the Dordaviprone and prior to the discovery that H3K27M mutations occurred and were driver for oncogenesis in this setting. It's been shown now with Dordaviprone that for patients with this mutation, the therapy is effective. We're really impressed with not only the efficacy, but also the safety profile in the disease setting, as I indicated, has an ongoing very high unmet need and without many other prospects unfortunately.

Your next question comes from Annabel Samimy of Stifle. Please go ahead.

Hi, thanks for taking my question. So for Rylaze, I understand obviously that the protocols have changed for the -- pediatric indication that delays treatment. But what can we expect for pickup in AYA? It's been, I guess quite a little bit of time that you've been trying to drive growth in that area, and when do you think we can get some critical mass there and some momentum to return Rylaze back to growth?

Renee?

Yeah, thanks for the question there. With respect to the AYA segment, it really does take time to drive education with adult treaters to use asparaginase and Rylaze. These are treaters that often have a different protocol that they're following. And so we were certainly pleased last year with the updated results from the protocol that created the gap in asparaginase treatment, because although it created a delay in when asparaginase is dosed and it has led to some of the challenges that we've had with revenues, we feel very confident that it is demonstrating the importance of asparaginase to treatment, and it's also resulted in much higher overall survival, which is good news for patients. But we are having some momentum and success with respect to the AYA segment. It does take a little bit more time than what we see in pediatrics, where we've had pretty much universal adoption, but there has been some delay in getting back to that continued use. Importantly, as we've said before, there is no change to the total doses of asparaginase with the new protocol that is in place, and so we expect we will be getting back to normalization in the second quarter and can continue to focus on the growth in AYA.

Maybe before we go to the next caller, I could just add something real quick. Annabel, if you think about our oncology performance particularly year-over-year here in the first quarter, I think it's important to keep in mind what I've mentioned about there being one fewer shipping week effectively in the first quarter of this year, probably it's hard to know when you have an additional week, you're getting that at average rate higher or lower, but just on pure math missing one out of 13 is 7.7% or roughly 8% of the opportunity. So, certainly there was an impact on the year-over-year growth just given the fact that we had one fewer shipping day. So, keep that in mind if you think about the trends and what you're seeing.

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

Hey, this is [Amy] [ph] on for Akash. Thanks so much for taking our question. Just one for HERIZON-GEA, would love to get your expectations on the control and performance and what gives you confidence that track chemo isn't outperforming what was shown with Keynote-811.

Rob?

Yeah, so as you know, there's been quite a bit of experience in this first line HER2 positive GEA setting, from the original ToGA trial that was the basis for the approval of Herceptin through the Jacob trial and then more recently Keynote-811, and across those studies, the control arm of trastuzumab chemotherapy has performed pretty consistently, with a median PFS between, I think, about 6.9 months up to a high of about 8.1 months in the more modern era. So, through these 3 -- Phase III trials, I think it gives us a pretty good idea of what to expect from the control arm, and we planned accordingly. We continue to have confidence in zanidatamab’s ability here. As you know, there have been 2 Phase II's published, showing very promising results Zani chemo with a medium PFS of 15.2 months. That's the last publication in Zani chemo [indiscernible] with a median PFS of 16.7 months. And at ASCO, this year we will update for the first time the overall survival data with Zani chemo, prior to this the medium wasn't estimatable based on the maturity level. We look forward to presenting those data as well.

Your next question comes from Joseph Thome with TD Cowen. Please go ahead.

Hi there, good afternoon. Thank you for taking my question. On Dordaviprone, I think Chimerix paused enrollment in the Phase III study ahead of the acquisition. So, kind of just curious if that has restarted and if you anticipate making any changes to the Phase III trial in the first line patients, maybe relatedly obviously a lot of shakeups at the FDA, I guess what kind of data points can you provide to make sure that everything is on track with the upcoming PDUFA date, especially given Chimerix did do a little bit of a 180 on the submission.

Rob?

Yeah, I'm happy to take those. So, with regard to the FDA, so far the review is going exactly as we expect, no surprises there and no indication that we would be off of our PDUFA date of August 18th. The first part of your question was related to pausing enrollment in the ongoing confirmatory frontline trial and just to clarify that was posed only in the U.S. and there we were anticipating an approval and availability of drugs and therefore, we want to avoid the problem of patients enrolling and then crossing over from the control arm to get through Dordaviprone by prescription, which could confound the overall survival results. As you mentioned, while the trial isn't rolling very well, we would have time potentially to make changes to the analysis plan, and we haven't announced any of those changes, but certainly we'll look at that carefully to be sure that that trial is well-powered to deliver the results not only in a timely fashion, but that would be most informative.

Your next question comes from Gregory Renza with RBC Capital Markets. Please go ahead.

Hey, good evening, guys. Thanks for taking my question. My question is just on the oxybate and as Renee, you were articulating just some effectiveness on the campaigns and how those are performing well. I just wanted to give you an opportunity to elaborate a little bit about what you're seeing and what the direct impacts are from the campaigns that have led to your reassurance about the contribution and the growth of the IH market.

Thanks for the question. So, we are seeing beneficial response to the campaigns. We're seeing as we are building in particular the idiopathic hypersomnia market, we are seeing our disease education and continued interactions with physicians helping them to better identify idiopathic hypersomnia. It also helps patients to better understand this condition, for which there has not been a lot of disease awareness in the past, because without an approved medication there's not a lot of incentive to actually diagnose someone with idiopathic hypersomnia. So, not only have we had good success with the digital and media campaigns that I mentioned, but we've continued to sharpen our execution in the field. We have continued to grow new prescribers. We've had great success with our field nurse educator program and we've had another -- sorry, a number of other initiatives that are proving effective and really give us confidence in the growth. If you look at where we ended this quarter, this first quarter of 2025, and compare that to where we were a year ago, stepping out of the first quarter of 2024, looking at the patient ads, we've seen an increase of 5%, and that is in a mature market with competition, which is really great progress. Then, with idiopathic hypersomnia, we've had an increase of 39% looking at the progress over the last 12 months. So, we're really excited about the continued momentum that we have. Certainly, we have seasonality each year in the first quarter, but still executing really well in this area.

Your next question comes from Joel Beatty with Baird. Please go ahead.

Hi, thanks for taking the question, and Dordaviprone, can you discuss a little bit more about where it could fit in the treatment algorithm initially upon approval, and then also when could the first results come from the action trial that might affect how it's used?

Rob?

Yes, we expect, based on the submission that we've made, we expect the initial accelerated approval to be in the recurrent setting. The action trials is treating in the frontline setting after patients received de-bulking surgery and radiation therapy, and that will give us an opportunity to expand to the front line. We haven't given specific dates on when that would read out, but we have said it's enrolling to plan.

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

Hi, thanks for taking my question. Can you provide us with an update on JZP441, where you are with the NT1 study and then we might get an update on that? And then just more broadly touching upon the comments previously around business development, have your priorities changed or evolved in the last couple of months as we've seen the market change and if you could sort of comment on what types of assets, whether it's by the therapeutic area or the stage of development you'd be focused on if you think about adding something inorganically.

I'm just going to remind people try to limit it to one question, but on this one maybe Rob you could talk about 441 and then Phil if you want to jump in on corporate development priorities?

Yeah, we have initiated the 441 trial, which I'll remind you is intended to be in a small number, approximately 10 patients with NT1, and we expect to look at those data as they come in, but we haven't given any specific guidance on when we would share information on those data just as yet.

Yeah, let me step in for the second part of the question. So, for corporate development priorities are unchanged. We continue to look at corporate development as a very important way for us to go ahead and reach more patients over time, create value for shareholders. We finished the first quarter in a really strong financial position with 2.6 billion in cash investments, $430 million in operating cash flow in the quarter. So, even after the payment of roughly 90 million net to acquire Chimerix, we're in a really strong position to continue to invest in our future. We do look across the various therapeutic areas that we're currently in, as well as selectively at other rare orphan diseases where we can deploy our capabilities to create value. We do look at both licensing like we did very successfully with the licensing deal with zymeworks and this brought us obviously Ziihera and then obviously for acquisitions like we've done, we've been very successfully looking forward to the upcoming PDUFA and then hopefully launch shortly thereafter of Dordaviprone. So, we continue to be active in looking at opportunities, see a number of them we think that would make sense for us across our various therapeutic areas, and I would expect to see us continue to be active in this area. I would say on the margin, the uncertainty that's created by some of the tariff and other policy discussions does not change fundamentally what we're looking to do, but probably the margin means that we want to take a slightly more conservative capital structure stance, maybe keeping a bit more cash than we might otherwise and maybe not fully using all of the potential debt capacity that we have, but still able to use a significant portion of that to advance our corporate development efforts, so that gives you some context.

Your next question comes from Ashwani Verma of UBS. Please go ahead.

Hi, thanks for taking my question. I just wanted to clarify, like, so when you, I think you mentioned that, one last week, of ordering, is that for a handful of products or which product is it for, or is it across the business?

Yes, that would have been across our U.S. oncology business and common for the various products there. Renee anything you want to add?

No, that's correct.

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

Great, thank you for taking my question. I have a question for you, Rob. In our conversation with some breast cancer doctors, the interesting takeaway was that it is not a hormone confusion that HER2 would become first line agent for all the HER2 positive patients, likely part of it is safety and comfort with the Cleopatra regimen. So, the question is, do you see a potential for Zani to be the first line as well, and what kind of trials you may have to do there, because Cleopatra is a really long regimen here.

Sure. I mean, I would just reinforce our primary strategy, which is to position after in HER2 because of the data we've generated showing activity of Zani, very promising activity after just about any prior and even multiple different HER2 agents, including standard frontline therapy, which is Herceptin, Perjeta and chemo, and HER2 TDM1 --, etc. So, positioning it after in HER2, which is currently second line and likely to move to front line for, I would say, a great majority of patients in this disease setting is really very meaningful, and there won't be any other HER2 therapies that will have been evaluated in that particular setting. Remember, these patients tend to go on to get multiple lines of therapy. You're right that there would be a few, there would be some patients who may not tolerate HER2 or would have some preexisting condition that would prevent them from, and I think in those cases, patient who's either progressed on or intolerant HER2 could move on to zanidatamab based on the 303 trial. If, HER2 is ultimately approved in the frontline setting, I do think it will be the great majority of patients who get it, based on the strong efficacy.

Your next question comes from [indiscernible] of Morgan Stanley. Please go ahead.

Hi, this is [indiscernible]. Thank you for taking our question. For Xywav, in narcolepsy, are you able to provide a more granular breakout for patients in oxybate versus high sodium switches? And then in IH, how are you thinking about Xywav’s value proposition with potential for a competitive threat there from [indiscernible]

Renee?

Yeah, so with respect to the narcolepsy ads, we have seen primarily ads in the quarter coming from new to oxybate patients, and I think that does speak to what we're now starting to see, which is a bit of an expansion to the market, given that this is a more mature product. We've been really pleased with what we're seeing in terms of both field execution, the appreciation of low sodium to physicians and also to patients, and that's really resonating. It's clear that HCPs and patients are prioritizing long-term health benefits of low sodium as well as the dosing flexibility that Xywav offers. So, we do see switching to or shifting over to IH. We do see IH as the area where there's the most opportunity to drive growth. With respect to any future potential competition in IH from --, I would say again Xywav is the only low sodium option, and we do know from the data that we have been able to generate. We know that narcolepsy in IH patients are at increased risk for cardiovascular comorbidities relative to the general population, and so we do continue to see all high sodium oxybate patients as potential Xywav patients and keep in mind that within our label for Xywav for idiopathic hypersomnia, there is flexible dosing. That indication is twice nightly or once nightly depending on what the physician and the patients choose to pursue in terms of their therapy. So, we feel we're quite well positioned with respect to narcolepsy and idiopathic hypersomnia.

I will also just jump in and point out that for those of you that saw the court decision today, given that our IP has been found to be valid that Avadel has admitted to infringing it. We still don't see even after today's ruling, a viable path for Avadel to commercialize, bloomerize an IH before the expiration of the relevant patent in 2036. So, I totally agree with everything Renee said in terms of potential competitive positioning and differences between the product, but it's -- there's some room to go before we actually do have competition in IH.

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

Thanks and good afternoon. So, first I hear on BTC, understanding it's a small indication, how is the ramp going, how rapid is the penetration, and what's the anecdotal feedback on how the drug is performing, have there been any challenges with access and how you're helping facilitate that? And then if GEA ends up being positive in first line as a bigger market, would you consider changes to pricing at all and also how your promotional efforts would change for that indication versus BTC?

Yeah, thanks for the question. So, we had our first patients treated in December shortly after launch for BTC, and the reception has been quite positive. HCPs are glad to have Ziihera available to treat patients. Just as a reminder, BTC is a very small patient population, 3000 patients in the U.S. in first line and second line. And therefore we do expect revenues from the first indication as we've stated to be quite modest. In terms of access, we haven't really had any issues. What we're in the process of doing is ensuring, we've spent quite a lot of time in these first few months ensuring that we have agreements and the necessary logistics in place for community and academic centers to be able to get access to the product rapidly and certainly the efficacy supporting this approval is something that they're excited to be able to bring to patients. When we look at GEA, we're excited to be able to read out that study in the second half with that data and with publication of that data, we would intend to go rapidly towards again trying to get NCCN guidelines in place similar to what we intend to do relative to Zepzelca. Of course, we would not promote without having an approval, but having the product on NCCN guidelines will enable use for that indication should physicians choose to do so. I think with respect to pricing we're in a good position. We typically will comment on pricing when we have a launch/approval, so stay tuned, but we think given the benefit that we are seeing in efficacy, we'll be in a good position where we are today.

Your next question comes from Charles Duncan with Cantor Fitzgerald. Please go ahead.

[indiscernible] on for Charles. Thank you for taking our question. So, you reiterated confidence and Epidiolex reaching blockbuster status in 2025. Can you speak about any catalyst or what market dynamics underpin that expectation? And also, can you talk about any [indiscernible] U.S. or an off label usage that could contribute to this trajectory.

Yes, Renee?

Yeah, I didn't hear the full question, but what I understood

I can jump in on the first part Renee and just say our confidence that it remains on track for blockbuster status is in part driven by -- it's already at that run rate and has been continuing to grow as you saw with the 10% of first quarter growth. Renee, you can comment on where growth can be coming from, but we're very solidly on track.

Yeah, thanks, Bruce. The call had cut out for me. So, we are quite confident in where we're going with respect to the future. Epidiolex is a highly differentiated product within the ASM landscape. e have a robust body of evidence supporting that both on the seizure side as well as the non-seizure benefits, and that data continues to resonate with physicians and caregivers, in particular on the non-seizure benefit side, cognition, behavior, emotional and social function, and also the broad spectrum efficacy and well characterized safety profile enables physicians to have Epidiolex combined well with other agents, which is particularly important in this area, given polypharmacy, while we do not promote off label, we do see the product used across a number of different epilepsy subtypes across the underlying seizures for which we've shown efficacy. And then in terms of additional growth, we're having great momentum in the adult and long term care setting. We have a new screening tool that we've put into that we've launched an additional initiative to help identify LGS for example, in previously undiagnosed patients in the adult setting, our access has been high quality and continues to improve. And then also with respect to our nurse navigator program, we're seeing strong persistency and seeing that even become stronger with respect to the nurse navigator program helping to guide patients through starting therapy. So, all of those elements give us confidence in the overall growth and of course the durability we've talked about having settled with our ANDA filers, we think we're in an excellent position there as well.

Your final question comes from Joon Lee with Truist Securities. Please go ahead.

Hey, thanks for squeezing me in. For the HERIZON-GEA, are you able to comment on the ratio of patients who are PD1 positive? I mean, is the ratio closer to what we saw in Keynote-811 or closer to your Phase I, II [indiscernible] study?

I don't have that information and I just would remind you that how you characterize positive depends a little bit on which assay you're using, etc. So, we are measuring it and we'll have the ability to look at that -- as needed to support regulatory approval.

That will conclude our question-and-answer session, and I will now turn the call back over to Chairman and Chief Executive Officer, Bruce Cozadd, for closing remarks.

Thank you, operator. Let me just say with Epidiolex and Xywav growth, some upcoming exciting approvals on the oncology side of our business, across 3 different products and GEA data upcoming. There's a lot to look forward to. I'd just like to close today's call by recognizing our jazz colleagues for their efforts and thanking our partners and shareholders for their continued confidence and support. Thank you all for joining us today.

Ladies and gentlemen that concludes today's call. Thank you all for joining. You may now disconnect.