Jazz Pharmaceuticals plc

Thank you for standing by. My name is Krista and I will be your conference operator today. At this time, I would like to welcome everyone to the Jazz Pharmaceuticals first quarter 2024 earnings 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. If you'd like to ask a question during that time, simply press star followed by the number one on your telephone keypad. And if you'd like to withdraw that question, again, press star one. Thank you. I would now like to turn the conference over to Andrea Flynn, Vice President, Head of Investor Relations. Andrea, you may begin your conference.

Thank you, Operator, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its first quarter 2024 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 Kozad, Chairman and Chief Executive Officer, Renee Galah, President and Chief Operating Officer, Rob Younone, Executive Vice President and Global Head of R&D, and Phil Johnson, Executive Vice President and Chief Financial Officer. On slide two, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential, and anticipated development and commercialization milestones and goals. which involve risks and uncertainties that could cause actual events, performance, and results to differ materially from those contained in these forward-looking statements. We encourage you to review the statements contained in today's press release in our slide deck and the risks and uncertainties described 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 three, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and 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, and thank you for joining us today. to review our first quarter results. I want to begin by welcoming Phil Johnson, who joined Jazz in March as our Chief Financial Officer. We're very excited to have Phil on our executive team and look forward to his contributions to delivering value for patients and shareholders. Beginning on slide five, we made important progress during the first quarter, including year-over-year combined double-digit revenue growth from our key growth drivers, ZyWave, Epidiolex, and Rylase. along with meaningful advances in our pipeline. I'm also pleased to report that we are affirming our 2024 financial guidance. On the commercial front, we generated more than $900 million in total revenues across our growing and diversified portfolio of medicines. ZyWave revenues increased 14% year over year, reinforcing our confidence in its trajectory and durability. Epidiolex demand remains strong, and we continue to be confident in its blockbuster potential. Our oncology therapeutic area delivered another strong quarter with 13% year-over-year revenue growth. This continues the momentum we established last year when we surpassed $1 billion in annual oncology revenue for the first time. Moving to our R&D and pipeline efforts, 2024 is an important year for Jazz with multiple late-stage catalysts for therapies targeting substantial market opportunities. We achieved a significant milestone for Xanidatamab in March with the completion of our rolling VLA submission for the treatment of HER2-positive biliary tract cancer, or BTC, and we expect commercial launch in 2025 or earlier. If approved, Xanidatamab would be the first HER2-targeted treatment specifically for BTC in the U.S. We also expect important clinical data readouts in the near future for suvacaltamide in essential tremor, zanidatumab in gastroesophageal cancer, Epidiolex in Japan, and Zebselka in first-line small cell lung cancer. On the operational front, we are maintaining our focus on disciplined capital allocation. Our financial strength, including healthy operating cash flow, enables us to invest in the continued growth of our commercial portfolio and pipeline while also positioning us to execute on corporate development opportunities. Turning to slide six, we remain focused on advancing the three core tenets of Vision 2025. This includes advancing leading therapies in sleep disorders and epilepsy, along with a growing oncology portfolio, investing in R&D to expand our capabilities and pipeline, and making disciplined capital allocation decisions to enhance value for shareholders as we realize our ambition to be a high-growth, global biopharma leader. 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. Phil will provide a financial overview, and then we'll open the call to Q&A. Renee?

Thanks, Bruce. I'm excited to report on the continued progress across our commercial portfolio. We delivered strong first quarter revenue, growing combined revenue from our key growth drivers, ZyWave, Epidiolex, and Rylase, by 12% compared to the same period in 2023. As is typical of the first quarter of the year, revenue was impacted by seasonal headwinds from payer reauthorizations and inventory drawdown. Let's get into the details, starting on slide 8 with our sleep franchise. Total revenue from sleep, which includes ZyWave and Xyrem net sales, plus royalties from high sodium oxovate authorized generics, or AGs, was $430 million in the first quarter of 2024, and we remain confident in the growth and durability of ZyWave. In the first quarter of 2024, ZyWave revenue grew 14% year-over-year to $315 million. I'll take a few minutes to discuss our view of the overall oxibate market, as well as several items of note from the quarter. In 2023, we saw the first competitive entrance to the oxibate market with the commercial availability of both high-sodium AG and branded fixed-dose high-sodium oxibate. We were pleased to deliver ZyWave revenue growth through this period and continue to expect ZyWave to remain the oxibate of choice including the number one treatment for narcolepsy. As expected, at the start of 2024, Xyrem was excluded from certain commercial formularies based on the availability of multiple newer OxyVe products, including ZyWave. Many of these patients and their physicians recognized the benefits of low sodium and chose to initiate treatment with ZyWave. I want to call out several downstream dynamics of this transition. First, we saw a significant increase in the number of active narcolepsy patients benefiting from ZYWAVE at the end of the first quarter of 2024 compared to the fourth quarter of 2023. Second, we saw an increase in utilization of our patient support programs in the first quarter as patients navigated the transition from ZYREN to ZYWAVE with their insurance providers. These programs provide free product for a limited duration, helping to ensure patients have uninterrupted access to therapy as they obtain ZyWave coverage. As a reminder, we have achieved benefit coverage in both narcolepsy and IH indications for approximately 90% of commercial lives. While we anticipate that other plans may exclude Zyrum from formulary going forward, We expect these changes will be less concentrated and spread out over time. We view the large number of patient transitions that occurred from the fourth quarter of 23 to the first quarter of 24 as a one-time event. Finally, this transition resulted in a significant decrease in Xyrem branded revenues. I'll note that all of these dynamics were accounted for in our 2024 neuroscience revenue guidance. Looking at our quarterly patient metrics, there were approximately 9,900 narcolepsy patients taking ZyWave exiting the first quarter, an increase of 375 patients from the prior quarter. Given the increased use of patient support programs, revenues for the quarter do not fully reflect these patient additions. We believe patient numbers are the best indicator of the long-term value and durability of this product, and expect that revenues will be more aligned with patient numbers going forward as newly transitioned patients revert to being fully covered by their insurance providers. Turning to IH, the transition dynamics associated with coverage for narcolepsy patients did not impact the IH market. We continue to view IH as the strongest growth opportunity for ZyWave, And exiting the quarter, there were approximately 3,050 active IH patients on ZyWave, an increase of 275 from the prior quarter. We are prioritizing investments to further build the market, and our expanded field force is now fully deployed. These additional field personnel are focused on increasing the depth and breadth of IH prescribers. Outside of the branded OxyBait business, we recognized approximately $50 million in AG royalty revenue, which was driven by both patient transitions and our increased royalty rate. Given our results for the quarter and increased visibility into OxyBait market dynamics since the entry of high-sodium OxyBaits, we remain confident in the durability of ZyWave and believe that we are well-positioned to achieve our Vision 2025 goal of $2 billion in sleep revenue. Moving to slide 9, we are pleased with the continued growth of Epidiolex with net product sales of approximately $200 million in the first quarter, representing a 5% increase compared to the same quarter in 2023. As a reminder, with Epidiolex, we typically see a build in inventory throughout the second half of the year, which then burns off in the first half of the following year, primarily in the first quarter. We expect future growth to be driven by underlying demand and geographic expansion and remain confident in the blockbuster potential of Epidiolex. Key drivers of increased demand in the U.S. included the positive response 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 synergies from treatment with Epidiolex plus Clobazam. We're also continuing to see increased penetration in the adult patient setting, which is supported in part by data showing that many patients may reach adulthood without a specific LGS diagnosis, and by providing HCPs with clear diagnostic tools for adult patients. 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 currently approved, with additional launches and market reimbursement expected in 2024. Shifting to our oncology business on slide 10, total oncology revenue for the quarter was approximately $258 million, led by Rylase and Zepselka. Rylase delivered another strong quarter with net product sales of $103 million, representing a 20% increase from the first quarter of 2023. Strong demand for Rylase continues to be driven by several factors, including its near universal adoption in pediatric asparaginase-based oncology protocols in the U.S. and adoption of the Monday-Wednesday-Friday dosing regimen. We are also seeing usage of Rylase in the first-line setting based on the benefits of its short-acting profile relative to current first-line asparaginase therapies. In addition, we remain focused on continued growth of Rylase in the treatment of adolescents and young adults, or the AYA market. Turning to slide 11 in ZAPCELCA, Net product sales for the 1st quarter increased 12% year over year to 75M dollars. We have established that as the number 1 treatment for 2nd line, small cell lung cancer patients. And we continue to hear positive feedback from health care providers. On its clinical benefit, as well as ease of use at administration for patients and their health care practices. In addition to the 2nd line setting. There remains an unmet need for small cell lung cancer patients in earlier lines of therapy. We believe positive data from the ongoing phase 3 trial in first-line small cell lung cancer is the biggest opportunity to drive significant growth and, most importantly, would provide a further opportunity to improve patient lives and outcomes. We expect data from that trial in late 2024 or early 2025. With that, I'll turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

Thank you, Renee. 2024 represents an exciting time for our pipeline, and we anticipate multiple meaningful catalysts across oncology and neuroscience. On slide 13, we 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 Xanadatamab, we have completed our BLA submission for second-line biliary tract cancer, or BTC, in the U.S. with potential for accelerated approval. Additionally, we are targeting late this year to report top-line data from the ongoing Phase III first-line gastroesophageal adenocarcinoma, or GEA, trial as positive We expect this trial would support registration. I'll speak more to our Xanadatamab development plan in just a moment. We're also pleased with the progress of the Zabzalka first-line trial, which completed enrollment in January. Top-line progression-free survival data for Zabzalka in combination with Dicentric in first-line extensive stage small cell lung cancer is expected at the end of 2024 or early 2025. If approved, this new indication would enable more patients with small cell lung cancer to potentially benefit from longer duration of therapy with Zypselka. Turning to neuroscience, we expect top line data from our phase three trial of Epidiolex in Japan in the second half of 2024. We also have ongoing trials for suvacaltimide, or JZP385, in both essential tremor, or ET, and Parkinson's disease tremor, with top-line data from the EP 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. I'd also like to provide an update on JZP441, our clinical stage orexin-2 receptor agonist. We paused the JZP441 phase one trial last November after observing a signal for QTC interval prolongation on automated ECG recordings. Since that time, we engaged external experts to perform manual reads of ECGs. That work was recently completed with the initial report indicating there may be a therapeutic index to exposures predicted to be efficacious in narcolepsy type 1 patients. We are reviewing this information with our alliance partner, Sumitomo Pharma, And JAWS will then make a decision on next steps, if any. I expect to be in a position to provide an update on our 2Q earnings call. Returning to XANA DataMap, slide 14 provides more detail on our development plan. We have meaningfully progressed XANA DataMap development across multiple indications since bringing it to JAWS. And based on emerging strong data across indications, We remain excited about the potential of Xanadatamab to transform the current standard of care in multiple HER2-expressing cancers. As was noted earlier, we completed our BLA submission for second-line BTC at the end of March and anticipate a response from FDA within the usual 60-day window. Upon acceptance, FDA would also establish the priority overview and PDUFA timeline. I'll also note we are planning to present more mature data from the ongoing BTC trial at ASCO this year, including overall survival. Our development plan represents a robust investigation of this molecule in multiple tumor types, including an ongoing trial in GEA that we believe would support registration in that indication, and several trials in breast cancer. We recently announced plans to initiate the phase three power trial in the second half of this year, which will evaluate Xanadatamab in combination with chemotherapy after progression on HER2, where we have the opportunity to be the first HER2 targeted therapy to demonstrate efficacy and safety in breast cancer patients post-HER2. In summary, we're executing a regulatory strategy that we believe will enable us to bring XanaDataMap to the market in the near term with an initial indication in second-line BTC and the opportunity to rapidly advance other indications. In total, we believe our development program can deliver for patients in need and generate a significant commercial opportunity of more than $2 billion. I would encourage listeners to go to our IR website and access the R&D Day webcast we hosted on Xanadatamab in March, which included a detailed overview of data demonstrating Xanadatamab's differentiation from other HER2-targeted agents, how it would fit in the HER2 treatment landscape, and perspectives from external thought leaders on the potential of Xanadatamab to improve the quality of care for patients with HER2-expressing tumors. Turning to slide 15, with a top-line data readout, from the essential tremor trial anticipated in the second quarter of this year, I'd like to highlight suvacaltimide, which is a highly selective and state-dependent modulator of T-type calcium channels in clinical development for the treatment of ET and Parkinson's disease tremor. There is a high unmet need for ET treatment with no new medicines approved in more than 50 years. ET can be highly debilitating with significant negative effects on a patient's quality of life and activities of daily living, such as eating, drinking, dressing, shaving, and writing, and can lead to substantial impairment in physical functioning. Some patients also experience cognitive deficits, anxiety, social phobia, depression, and sleep disturbance. In the US and key European markets, there are approximately 2 million diagnosed patients with a prevalence estimated at approximately 11 million patients. Moving to slide 16, I want to touch on suvacaltamide's differentiated mechanism of action. While the exact underlying pathophysiology of ET is not clear, there is strong evidence to support the role of T-type calcium channels. T-type calcium channels regulate the balance of calcium ions, acting as a gatekeeper to help ions both enter and leave the cell membrane. In some pathological states, such as ET, increased activation of these channels leads to excessive rhythmic signals that prompt tremor. The high selectivity of suvacaltimide for T-type calcium channels makes it a promising candidate for the treatment of ET, which was demonstrated in the Phase II TCOM trial. Importantly, suvacalcamide is differentiated from other T-type calcium channel blockers in development as it is state-dependent, meaning that it targets channels under conditions of hyperexcitability while sparing the form of the channel important for normal neuronal signaling. Now I will turn the call over to Phil for a financial update.

Phil? Thanks, Rob. First, I'd like to express how excited I am to join JAWS. I came to the company because of its history of success innovating to transform the lives of patients and their families, and because of the quality, integrity, and enthusiasm of its people. What Jazz has accomplished since its founding is impressive, and we have great opportunities ahead of us to enhance our impact on the lives of the patients we serve and to create significant shareholder value. Turning now to our first quarter 2024 financial performance, slide 18 summarizes the highlights. As a reminder, more information on our financial results is available in our press release and 10Q. We saw continued top line growth in the first quarter of 2024 with $902 million in total revenues, representing a 1% increase over the same period in 2023. As Renee noted, our first quarter revenues have historically been affected by several factors, including reauthorizations, which drive the use of patient support programs and inventory build in the latter part of the prior year, which leads to inventory burn in Q1. Our Q1 results are in line with our expectations, and we are affirming our full-year revenue guidance of $4.0 to $4.2 billion, including our expectation for combined double-digit growth from our key growth drivers, ZyWave, Epidiolex, and Rylase, and double-digit growth in our oncology therapeutic area. Moving to slide 19, Non-GAAP-adjusted SG&A reflected investments dedicated to our key growth drivers, including the ZyWave IH commercial initiatives, commercial support for Epidiolex in the U.S., where the market is promotionally sensitive, geographic expansion of Epidiolex outside the U.S., and educational efforts for RILAs and AYA. Non-GAAP-adjusted R&D expense for the quarter was driven by investment in multiple late-stage programs. which we view as critical to enhancing the future value of our pipeline. We are executing on a robust development plan for Xanadatamab with trials across multiple tumor types, as well as phase two trials for suvacalpamide in two different disease areas, and programs for Epidiolex and Zefzelka that have the potential to expand those products into new geographies and patient populations, respectively. I'll note that our operating margin and expenses are not linear. and we incur spend at the time that best supports strategic initiatives for our commercial business and pipeline. Investments in our commercial business to support our key growth drivers ramped up in the fourth quarter of 2023 and extended into the first quarter of 2024. We expect these investments to positively impact revenue as the year progresses. SG&A expenses in 1Q24 also included a bad debt expense and higher litigation costs. primarily related to the Avidel patent infringement trial. Our R&D expenses, along with clinical trial activity, ramped up in 2023, and we expect these expenses to remain at relatively consistent levels throughout 2024. Therefore, we are affirming our full-year 2024 SG&A and R&D guidance. I'd also point out that we recorded a discrete tax expense related to expired stock options. While this significantly increased our non-GAAP effective tax rate for the quarter, we expect our full year 2024 non-GAAP effective tax rate to remain in the range of 10 to 13%. We continue to generate significant cash from our business, driven by the strength and diversity of our portfolio. We recorded approximately $267.2 million of cash from operations in the first quarter and ended the quarter with $1.8 million in cash on hand. Our strong financial position and operating cash flow provide flexibility to invest in priority commercial and R&D programs, as well as corporate development opportunities. Non-GAAP-adjusted net income of $182 million and non-GAAP-adjusted EPF of $2.68 were driven by our top-line growth, along with significant investment in our key growth drivers and pipeline, including multiple late-stage clinical programs, presenting DataMabs, Epidiolect, suvacaltamide, and zebzelka, all of which have the potential to generate significant long-term value. Based on our results from the quarter and continued focus on discipline and strategic capital allocation, we are affirming our non-GAAP-adjusted net income guidance of $1.275 to $1.35 billion. Since joining Jazz, I've spent considerable time speaking with investors and analysts and greatly appreciate the perspective and input they shared. In these conversations, I heard a concern that Jazz would overpay for an acquisition to meet our goal of corporate development contributing $500 million to 2025 revenue. Here's how we're thinking about this. First, acquiring or licensing innovation from outside our walls is central to how we'll achieve our purpose of transforming the lives of patients and their families. Second, as we allocate capital to internal projects and to corporate development, We are focused on making investments that can deliver sustainable revenues and create value for shareholders. We will remain disciplined on price and will not make an acquisition just to meet our Vision 2025 goal. I'll close by noting that while I'm still getting up to speed, I'm incredibly excited about the future of this company and the opportunities we have to deliver value to both patients and investors. With that, I'm going to call back to Bruce for closing remarks.

We'll conclude our prepared remarks on slide 21. We've made important progress towards delivering on our 2024 guidance and objectives and are pleased to be affirming our guidance today. On the commercial side, we expect continued growth of our key products in 2024. And on the R&D front, we continue to advance our pipeline and to invest in long-term growth. We see multiple catalysts in the near term, including data readouts for suvacaltamide, danidatamab, Epidiolex, and Zepselka. 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. We will now begin the question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw that question, simply press star 1 again. If you are called upon to ask your question and are listening via loudspeaker on your device, please pick up your handset to ensure that your phone is not on mute when asking your question. And please ask one question. Your first question comes from the line of Jessica Fye with J.P. Morgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my two-part question on the oxibate narcolepsy dynamics in the quarter. First, can you quantify the headwind to 1Q from the increase in use of patient support programs as those Xyrem patients transition to ZyWave? And second, Do you have an understanding of how many Xyrem patients losing coverage transition to generic Xyrem or once nightly and not to ZyWave? Thank you.

Thanks, Jess, for the question. And Renee, maybe I'll let you take both parts of that.

Sure. So, Jess, in terms of the, I'll take the second question first. We're not disclosing a breakdown of those patients in part because That AG data is not our data to share. But with respect to being able to quantify how many patients came over, I would say there was a good portion of patients that made the decision along with their HCPs to adopt low-sodium ZyWave And we did see and establish those patient support programs to ensure that we have uninterrupted access for those patients to be able to go from Xyrem directly to ZyWave. So what we'll see in future quarters is you should see a better representation of those patients in the revenue and the net sales that come from ZyWave.

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

Oh, hey, guys. Thanks for taking my question. My question is about your Phase IIB essential tremor study. So, you know, if this trial is successful, I'm wondering how you're thinking about the subsequent second confirmatory trial. Would it look something like this trial, which took roughly two and a half years from start to data, or could there be some sort of more abbreviated randomized withdrawal study that you could run to get yourself to goal line in a more expeditious manner? Thanks.

Rob, you want to jump in on that?

Yeah, happy to. So, first of all, Jason, remember this is a Phase IIb trial. we believe or contribute to the pivotal regulatory package. But we call it a Phase IIb because we included three dose levels of suvacaltamide. And when we would move to what's called a confirmatory Phase III trial, we wouldn't necessarily have to bring all those dose levels forward. And ideally, we expect we would choose one dose level. So that creates a more streamlined design. And to your point, when we have data in hand and we engage regulatory authorities, we certainly, with compelling data, would be looking for the fastest path to approval and look at all possible trial designs to support that.

Your next question comes from the line of Mark Goodman with Lyric.

Please go ahead.

Bruce had a lot of discussions with investors over the past six months about what jazz wants to be and what it's transitioning from and to and just the whole big picture discussion. And a lot of investors believe, you know, you want to become an oncology company. At least that's the perception out there. I was curious, can you talk about just what is it that you expect jazz to become, what you're looking for jazz to be? you know, in five years, six years, seven years, just, you know, because all the investments you're making today are obviously going to be reflected in five or six years and just talk about that and how maybe it's evolved since what, you know, Jazz was five, ten years ago. Thanks.

Yeah, thanks, Mark. So we're in the nice position of having growing assets on the neuroscience side of our business in Zywave and Epidiolex with, we believe, promise in front of us. including pipeline programs like the 385 program we were just talking about. We're also excited about what's going on on the oncology side of the business with double-digit growth coming from our current portfolio led by Riley's, but also opportunities in front of us with, say, any data map where we've already got the submission complete and looking forward to a launch in 25 or earlier. ZEPS-ELCA data upcoming, but also an earlier stage pipeline, including particular expansion opportunities with ZanyDatamab and beyond. So we're excited about both those franchises. While there has been a lot of focus on oncology and certainly the single largest program in our R&D pipeline right now is ZanyDatamab, I would not say we're trying to turn the company into an oncology company. We'd like to have strength in both of our franchises. The investments we're making, and I think Phil described it nicely in his comments, are designed to both help the short term, particularly some of our commercial investments that we think can continue to generate great growth from our commercial portfolio, and R&D investments that will continue to broaden that pipeline and provide growth over both the near term and the medium and long term, but then also those corporate development opportunities fueled by our strong cash flow and balance sheet and a history of doing transactions that continue to add to our portfolio, allow us to impact more patients in more diseases in more territories around the world. So I think about it as having to make smart investment decisions, which we're in a position to do given the financial strength of the company to fuel both the short and the long term to create value for our shareholders. So Execution in the short term, important. Investment decisions, always important. But I think that should give you a better sense for where we're headed.

Your next question comes from the line of Annabelle Asamimai with Stiefel. Please go ahead.

Hi. Thanks for taking my question. I had a two-part on Zannie. I guess the first is, how should we think about the opportunity for Zannie and GEA in light of the better keynote data OS that they announced today on Keytruda. And I guess secondly, where would Zany fit into this paradigm? Separately, for a launch of Zany, and as we think about all these indications, how should we Think about how rapidly new cancer drugs with superior efficacy profiles can disrupt mainstay standard of care. I guess, in other words, are these ramps going to be more rapid or just as challenging as, say, in other non-fatal conditions? So just wanted to get some characterization there. Thanks.

Yeah, Annabelle, thanks for the question. And on the Xanny data map, first question in GEA, you know, we had been expecting positive OS results at some point out of that trial. I think most people had, so I don't think that changes the landscape. But I'll let Rob comment on where Zany could fit into the GEA landscape. And then on your second question, it's all about results and uniqueness of mechanism of action and benefit relative to other therapies that determine how fast you can make progress from launch. And when we have the opportunity to bring something really new to patients in terms of benefit, particularly in the oncology space where I think things can move sometimes even ahead of a regulatory approval, if there's strong data that's been presented that's picked up in the NCCN guidelines and allows for reimbursement, you can get fairly rapid traction with a better option. Rob, you want to talk about the landscape in GEA?

Yeah, so in the context of HER2 positive overexpressed gastroesophageal adenocarcinoma, we think Xanadatumab has the potential to be the HER2 antagonist of choice because of its differentiated mechanism of action and because of the differentiated efficacy and safety profile. Certainly in the PD-L1 negative population, which we think is sizable, there is no approved PD-1 agents, and so the comparator there is for SEPTA and chemotherapy. But even in the PD-L1 positive population where we think PD-1 agents are essentially interchangeable, we have the opportunity in combination with tizolizumab to show the benefit of sanodatamab, again, as a differentiated HER2 antagonist in combination with backbone chemotherapy and a PD-1 antagonist.

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

Hey, thanks so much. You know, just going on the Horizon GEA study, how should we really interpret the Jacob trial? Here we saw the addition of Progetta didn't provide any OS benefit in GEA on top of Trask Chemo, and this is a large-scale phase three. What gives your team confidence that ZW25's early data will hold up in this setting? And then maybe just on essential tremor, JCP358 effectively showed no benefit on an accelerometer measurement in its phase two trial. Do you feel like there was something about how the hits were administered in that study that may have skewed those results? And how confident do you feel in your ability to show a signal on the accelerometer endpoint with your upcoming data? Thank you.

Yeah, Kosh, thanks for the two questions. And maybe I'll start on the essential tremor and then let Rob add anything he'd like on the ongoing trial and then comment on your Xanny question. You know, just to remember that the prior TCOM study for essential tremor did demonstrate a nice benefit on Tetris 80 activities of daily living. which we believe is a measure that's actually more important to patients than the measurement of the quantity of tremor. What patients want is to be able to live their life, to do the things they need to do, to be able to drink out of a cup, to be able to button and unbutton clothes, to be able to apply makeup, to do the things they care about. And we were very pleased that that became more of a focus for the pivotal endpoints in later stage trials. I think, you know, FDA too understands you want to do what's really going to provide a benefit to patients. Rob, you want to talk a little bit about our ongoing trial and then pivot to Zannie?

Yeah, happy to. And so, I would agree, Bruce, that the endpoints that we prioritize is primary, not only the most meaningful to patients, but endorsed by FDA. And on those endpoints, we have confidence from the TCOM trial. And I would just add to that in the current phase 2b trial with a new once daily formulation, we've been able to push that dose to exposures that would be higher than in the TCOM trial itself because we have 10, 20, and 30 milligram doses in that trial. So we think based on that, we're positioned for success. And then coming back to the question on Jacob and GEA, the key point I'd like to make is we really believe that Xanadatamab is differentiated from even the combination of Herceptin and Progetta. As we presented at our R&D day, we stepped through some important data that were published in Nature Communication showing how Xanadatamab is differentiated. The two epitopes necessarily bind to distinct receptors, causing more effective receptor clustering and internalization, and have demonstrated better immune function, for example, complement fixation. And so in that paper, head-to-head and preclinical experiments better than Perceptin and Progetta, and the clinical data bear that out without going into great detail. If you look at the BTC data where the response rates are over 40% and duration of response greater than 12 months, That compares very favorably to prior data with the combination of Herceptin and Progetta. And of course, we have data in breast cancer showing activity as a data map, even after patients have failed a frontline therapy with Herceptin and Progetta as part of a Cleopatra regimen. So that in combination with the data that you referred to, Xani and chemo, and then separately a cohort of Xani chemotizolizumab showing very promising not only response rates, but very, very durable responses, that's what gives us confidence that our phase three trial will be successful.

Your next question comes from the line of Amy Fabia with Needham & Company. Please go ahead.

Hi, good evening. Thanks for taking my question. Perhaps I had a question for Phil, just with regards to his comments around business development. And, you know, that's a question that we get often from investors as well. Um, can you talk about some of the metrics that, uh, you would use to really evaluate, uh, potential deals, uh, in terms of kind of what really would meet the bar in terms of what, uh, judge would, uh, be interested in executing on. And also, can you talk about capital, uh, use of capital, uh, across, um, R&D, business development, but also perhaps buyback of shares. Thank you.

Thanks, Ami. Phil, go ahead and jump right in.

Great, Ami. Thank you for the question, my first one on a jazz earnings call. And even though I've been around for a while, my mom still listens to these. So thanks for giving her early Mother's Day presence. In terms of our corporate development evaluation, first and foremost, there are a number of non-financial criteria that we would look at. Primarily, these are things like, is there an area with significant unmet need? Would the medicine that we're looking at acquiring or medicines really meaningfully impact patients? Is there an efficient commercial call point? We do have a relatively focused business and want to make sure that we're set up for success to commercialize the assets that we're bringing in. Will it allow us to leverage the expertise we've got in-house, the commercial footprint we've built out and continue to build out, for example, with Japan coming soon? And we'll stay largely focused, as we talked in the past, in neuroscience as well as oncology, but we have looked at things in the rare orphan space as well, given the kinds of capabilities that we've built up selling products with these types of limited patient populations. From a financial perspective, it really is, I think, some of the traditional things that you would expect. We do want to have line of sight to getting a good return on the investment. We'll look at things that would vary some of the key assumptions, not only draft launch label and competitive landscape, but also timeline to continue to make a return on investment in the marketplace, different options for exclusivity, be that through orphan drug exclusivity, through Patent Live or other extensions. So I think by nothing unusual in terms of the financial evaluation that we'd have there. But first and foremost, we need to figure out is this a jazz asset and one where there can be a significant value proposition for patients. In terms of capital priorities, you know, I'd say first and foremost, very consistent what you've heard in the past from Bruce, Renee, and the team. We're focused on driving the commercial opportunities for the in-market products that we have and are dedicating significant monies to get those to as many patients as possible that can benefit from those medicines. We then are looking to rapidly progress the existing pipeline that we have. Obviously, we're making significant investments behind ZanyDataMap, given the data that we've generated post the licensing deal. And then looking at business development to further augment our growth prospects for the future. Once we've exhausted those possibilities, then we'd look to return excess cash to shareholders. So, hopefully that gives you a sense for how we're looking at prioritizing capital going forward.

Your next question comes from the line of Joseph Thaum with TD Cowen. Please go ahead.

Hi there. Good afternoon and thank you for taking my question. Maybe one on the upcoming essential tremor readout. What is sort of the bar for clinical meaningfulness on the Tetras endpoint? Or I guess what is your internal bar, you think, for kind of taking the program forward? And then one just point of clarification, because I think in response to one of the earlier questions, the phase three for essential tremor was referred to as a confirmatory trial. So I just want to make sure that was actually confirming the dose and not that this phase 2B could potentially be used for approval and then you would do a phase three confirmatory study. Thanks.

Yeah, thanks for giving me the opportunity to clarify. I didn't mean to imply that we would get approval based on the Phase 2B, just that it would be part of a package. And typically in this space, FDA would be looking for independent studies to confirm efficacy. I did want to point out that when we go to that second efficacy study, we're likely to only use one dose, which would be a streamlined design, because I think the earlier question had to do with, you know, could you move more quickly than you did with the phase 2B study. You know, we haven't said in particular or specifically, you know, what level of difference on the ADS or the performance scale, you know, that would be meaningful enough for approval or for patients. But I would just highlight that there really hasn't been any therapies for this disease, you know, almost ever, even though things like propranolol and primidone you know, are used, they really have minimal efficacy. So there's a substantial on that need. And I would just say, based on what we saw from the TCOM study, we think that subacaltamide really has an opportunity to make a meaningful difference on the endpoints that matter to patients. And overall, in terms of its provability, it'll be based on that, you know, the effect size of those primary and secondary endpoints, as well as the overall tolerability, which we think, you know, will be good given, given the once daily extended release and the titration that we did in the trial.

Your next question comes from the line of Ash Verma with UBS. Please go ahead.

Hi there. Yeah, thanks for taking my question. I just wanted to get a sense, like in the long term for narcolepsy, I understand from your perspective that you believe that Zyvi will remain an oxidative choice, but in your view, like what percentage of patients do you think may ultimately switch to a once-nightly or generic item? And then as you're trying to extend your leadership in the sleep arena, are you committed to potentially pursuing another or extend or try to internally develop a once-nightly candidate?

Thanks.

Yeah, Ash, maybe I'll take the second part of your question first, and then Renee, maybe you can hop in on the narcolepsy side. You know, Rob gave you a little bit of an update on the 441 program. We're doing a little more work there and conferring with our partner before we announce next steps. We have previously said we have other backup programs behind that as well. We find this an interesting area, certainly. with a lot of promise, though development remains early in the erection space. But in terms of a new mechanism of action, it already has proof of concept, and we're definitely interested in the benefit that can bring to patients. Renee?

Yeah, thanks, Bruce.

So I would say with respect to ZyWave, Clearly, we saw both strong patient growth and net sales growth. Year over year, that was 14% in terms of net sales growth. And we believe that reflects CyWave as being a differentiated therapy, the only low-sodium oxidate on the market and the number one treatment for narcolepsy. I would say with respect to people trying a fixed-dose high-sodium oxidate, We've said we do expect some patients to try that branded therapy. We do expect that certain patients and HCPs will want to get experience with a fixed dose regimen. What we are hearing anecdotally and also seeing with respect to patients is that we are seeing some patients not get a full night's coverage. We believe that there is benefit to being able to have a full night's coverage in terms of sleep and the flexibility that comes with the twice nightly dosing. But more importantly, as the only low sodium OxyBate on the market, we are seeing that educating on the benefits of low sodium publishing and investing in evidence generation on this front. That message is resonating with HCPs. We have seen data showing the faster than expected negative impact from a cardiovascular perspective that patients have when they start a high-sodium-oxidate therapy, and we believe that Patients and HCPs will ultimately continue to prioritize long-term health when it comes to their oxibate therapy with respect to narcolepsy. These are both chronic conditions, and that gives us continued confidence in the long-term growth and durability of Zyways.

Your next question comes from June Lee with Truist Securities. Please go ahead.

Hey, thanks for the updates and for taking our questions. We had a lot of presentations at AAN, and one in particular was on the efficacy of Epidiolex and focal onset seizures in the context of an expanded access program. And the study showed, you know, the median seizure reduction in the mid-70% range. How prevalent is the off-label use of Epidiolex, and what sort of growth opportunities do you think you have there? There's a lot of investor interest in focal onset seizures these days.

Thank you. Renee, you want to take that?

Sure. Well, clearly with respect to our promotional activities, we focus our promotional activities on those indications where we are approved, that being LGS, DRIVE, and TSC. However, we do see continued use based on seizure type. And we do see continued use in other refractory epilepsies. And that is an area that we assume will continue to provide growth for Epidiolex. The reality when you think about the overall benefits of Epidiolex in terms of being a highly differentiated treatment, it has broad spectrum efficacy working through a novel MOA. And in an area which is characterized by polypharmacy, having a favorable and well-characterized safety profile means that the product lends itself well to being combined with multiple other therapies, in particular for physicians that see patients that are refractory with respect to seizures. And on top of that, they're really starting to appreciate even more based on the data that we continue to generate and present around the benefits beyond seizures and also underpins our further investment in generating additional data such as the EPICOM study that we're getting underway. So we do believe we'll continue to see growth with Epidiolex both in our approved indications and also in other refractory epilepsies which, again, we do not promote for. This is a long-lived, durable asset for us that we will continue to look at as a global growth product with additional growth opportunities outside the U.S.

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

Hey, good afternoon, Bruce and team. Thanks for taking my question. Bruce, we certainly appreciate all the color you and Phil have provided on the strategic thinking as well as capital allocation, especially when it comes to internal investments. And just aside from the diversification of top line when it comes to neuroscience and sleep as well as the oncology portfolios, can you just speak to the synergies, the benefits, and even the crosstalk that you think is important for us to know when it comes to keeping both portfolios under the jazz umbrella? Thanks so much.

Yeah, well, Greg, we're fortunate to have growth opportunities on both sides, places that are worth investing, whether that's commercial or R&D. And I also believe there's benefit in being able to look across these two therapeutic areas on the corporate development side. As we've all seen over the past few decades, there are times when an area heats up and valuations get high. And if you can look more broadly across therapeutic categories and across stages of development, I think you're often more likely to find an opportunity that's both a strategic fit but also offers a nice return profile. You know, there are a number of services we provide across the company that are centralized and, you know, may provide some marginal benefit by not having to reproduce things across services. multiple therapeutic areas, I would say that's the strategic driver. But again, we're in a position where we've got nice opportunities in front of us short and long term on both sides of the business.

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

Hey, just have a quick question on the balance sheet and the cap structure. Can you talk to any potential long-term leverage targets that you have? You've done a lot of deleveraging in the years since the GW transaction. Obviously, you're active on Biz Dev, but are you thinking about perhaps accelerating debt pay down? as a means of potentially supporting the equity? Is that something you're contemplating? And just help us better understand how you're thinking about leverage ratios over time.

Thank you. Phil, you want to jump in on that? Yeah, happy to.

So, David, as you mentioned, you know, when we had the GW acquisition, there was a really strong interest and communication that we would rapidly deliver down to about three and a half turns by the end of 2022. You saw us actually beat that by about six months. We currently sit with about two and a half times net leverage, I think still a very strong position at this point in time. We feel very good about the overall debt complex that we've got with about 60% of that being fixed, only about 40% of that being variable exposed to interest rate movements. And with the weighted average cost of debt of south of five and a half percent at this point in time, you're probably where we do have an upcoming maturity of our 2024 convert. We're in active planning, as you'd expect, looking at some alternatives for how we might approach that particular financing opportunity or repayment opportunity. I would say if we were to engage in additional business development that had the debt increase in the near term. I think like we did with GW, we'd have a strong plan to reduce that quickly to get back into the kind of levels that we've currently got or below where we've got significant flexibility to continue to look at ways to build a business through business development or corp dev opportunities. To date, we have not specified any kind of a specific targets below where we're currently sitting and where we'd like to get to. But this will be actively discussed and worked through as we move forward, looking at the investment opportunities in front of us, both internal as well as external. I'm sure, Bruce, if you want to comment additionally.

No, Phil, I think you covered it well. I think we've seen some recent positive commentary from the rating agencies in general about the financial profile of the company. You know, we've used leverage to do transactions when we thought that was the best thing for shareholders, but as Phil said, we've always tried to deliver rapidly after that.

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

Thanks. Good afternoon. So, on ZyWave, you know, understanding the patient support program was a key factor for the lower revenue in 1Q. Is ZyWave also still getting a lot of the occibate-naive patients in narcolepsy? And, you know, is that a factor that can impact revenue in coming quarters to consider? And then NIH, are physicians staying strictly on label? Or are you hearing there could be some off-label use with lumerize if it's with younger patients, I guess, in particular? And maybe talk about the competitive dynamics in NIH going forward. since that space is going to get a lot more crowded, I guess, in the coming years. Thank you.

Yeah, thanks for the question. I'll hop right in there. So, with respect to OxyBait-naive patients starting on ZyWave for narcolepsy, while we don't have full visibility into the new to OxyBait patient numbers, Based on our estimates, we do believe we continue to capture more of those new to-oxibate narcolepsy patients than any other currently available therapy. And I would say that speaks to the differentiation of the product. It speaks to our host of patient support services more broadly. And being a continued leader in sleep, you know, the high overlap when we're looking at narcolepsy and IH of being in front of physicians and continuing to be able to educate them on the benefits of low sodium. With respect to IH, we don't, we're not really seeing much, if any, off-label use with Lumerize given the payer restrictions on these products and the need for a validated sleep test for either narcolepsy or for IH, we tend to see that being required in order to receive a prescription. And so it would be pretty unusual to be able to see a prescription for the AG or for Lumerize for idiopathic hypersomnia. And then with respect to competitive dynamics, I think we'll continue to probably see wake-promoting agents studied for idiopathic hypersomnia. Keep in mind, we had a rather large percentage of patients that came into our idiopathic hypersomnia study on wake-promoting agents. and continued to see meaningful benefit while on therapy with ZyWave in addition to being on that wake promoting agent as part of their baseline. Very much like we've seen the wake promoting agents end up being complementary to ZyWave in narcolepsy, we would expect a very similar dynamic in idiopathic hypersomnia. For example, with WACICs coming onto the market for narcolepsy, we saw little to no impact to our OXIV8 franchise and would expect largely the same dynamic with respect to IH.

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

Thank you. Good afternoon, Bruce and team. Thanks for taking our question. And congrats on the BLA submission being completed with Annie. That said, the next day to read is actually neuro with subacaltamide and essential tremor. And so I'm going to ask for a little bit more granularity. I know others have tried, but I'm really wondering what would you like to see out of the phase 2B to move forward? Is it If it's supportive of a registration strategy, it definitely seems like STAT-SIG is important, but will you be looking at certain effect sizes and responder analysis? And of the two composites, which of the two are important to you? Thanks.

Yeah, Charles, I'll start with the dangerously general comments and then let Rob jump in if he wants to provide more specifics. You know, what we want, aside from a package that would generate a regulatory approval, is something that really adds value, something that is of value to patients, that patients and prescribers and payers will all see as providing a really meaningful benefit. And, you know, certainly our trials are designed with prospective key endpoints that we need to hit, but We measure lots of things in these trials that really go to establishing that benefit profile for patients against a backdrop, as Rob said, of really nothing that's currently available that's providing that kind of benefit. Rob, do you want to talk about anything specific?

Well, again, I don't want to necessarily specify an effect size that we think is meaningful because it really is the holistic picture that matters. But what I would say is, you know, when you look at the TCOM data, we thought there was an important effect there. We've optimized our trial in many respects, you know, honing the primary endpoint in agreement with FDA, optimized the dose, made some changes to how we measure to be sure we get more accurate measurements. And I think all of that would, you know, would bode well for the trial. I think the other reference point you would have is you know, other T-type calcium channel inhibitors in development. We certainly think supracalcamide is differentiated in a couple of respects. It's a state-dependent inhibitor, which means it really targets the hyperactive ion channels that are pathologic in the essential tremor condition. And with that, we think it potentially gives us a better therapeutic index, which is why we've been able to push the dose even to doses and exposures that are higher than we would have achieved in TCOM. So again, it's the totality of the data around the primary and secondary endpoints that we've included that will be meaningful to patients and we know accessible to FDA.

Your next question comes from Balaji Prasad with Barclays. Please go ahead.

Good evening, everyone. Just a couple from me. On Epidiolex, can you comment on the adult opportunity, either quantified or quantified? Primarily asking because I'm curious. At most, I thought the primary indications approved were childhood diseases that patients tend to outgrow. And also, when do you expect to see these additional data and what is the data that you're expecting? Secondly, on the 2024 guide, can you help us understand the double-digit percentage growth that you provided for Zyvae, Epidiolex, and Rylase combined, since all three are in different categories? It would be helpful if you could dissect this further. Thanks.

Yeah, Balaji, on the first part of your question, you know, we often refer to these childhood onset seizure disorders to point out they're not only childhood disorders. They do persist into adulthood, and we think there's substantial opportunity there that I'm going to let Renee jump in on if she wants to. But let me also hit the second part of your question and say we're emphasizing the double-digit combined growth of our key growth drivers, ZyWave, Epidiolex, and Rylase, just because we don't provide single product guidance for the year, as you know, and that's not different this year from any other year. That's why we do it on that basis. Obviously, each quarter we're reporting actual results for each of those products. Renee, anything you want to add on adult opportunity for Epidiolex?

Yeah, I'm not sure if we'll quantify it here, Balaji, but I would just say that as we look at the broader growth drivers, we do see the adult population, the long-term care environment, one that is currently underserved. With respect to Epidiolex, Epidiolex is weight-based dosing, so you do end up with higher dosing when it comes to that population. But at times when you move from an environment of pediatric care into long-term care, there is, I would say, perhaps less attention placed on the actual indication of what the adult has. You would have heard in my prepared remarks a focus on ensuring that we have the right diagnostic tools with respect to long-term care centers and continuing to ensure whether it's getting the right diagnosis or getting to the right level of dosing where you can optimize results or better educating on the combined impact of Clobazam and Epidiolex. Those are all opportunities that we see going forward.

Ladies and gentlemen, that concludes our question and answer session, and I will now turn the call over to Bruce Crozet for closing remarks.

Thanks, Operator. As always, I'd like to close today's call by recognizing our JAWS colleagues for their efforts on behalf of patients and their families, and thank our partners and shareholders for their continued confidence and support. Thank you all for joining us today.

This concludes today's conference call. Thank you for your participation, and you may now