Good day, and thank you for standing by. Welcome to the Q3 2022 Jazz Pharmaceuticals Earnings Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. I would now like to hand the conference over to your speaker today, Andrea Flynn, Vice President of Investor Relations. Please go ahead.

Thank you, operator and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its third quarter 2022 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also refer to the press release we issued earlier today, which is also posted to our website. On the call today are Bruce Cozadd, Chairman, and Chief Executive Officer; Renée Galá, Executive Vice President and Chief Financial Officer; Dan Swisher, President and Chief Operating Officer; and Rob Iannone, Executive Vice President, Global Head of R&D. Kim Sablich, Executive Vice President and General Manager, US, will join the team for Q&A. On slide two, I’ll remind you that today’s webcast includes forward-looking statements such as those related to our future financial and operating results, including expectations related to Vision 2025 and our guidance for 2022, growth potential and anticipated development programs and pipeline, regulatory activities and commercialization milestones, goals and expected timing, and statements with respect to our licensing agreement for Zanidatamab that is subject to closing condition, 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 in our latest SEC disclosure document, 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. Turning to slide three, on this webcast, we’ll discuss non-GAAP financial measures. Reconciliations of GAAP to non-GAAP financial measures are included in today’s press release and in the slide presentation available on the Investors section of our website. I’ll now turn the call over to Bruce.

Thank you, Andrea. Good afternoon, everyone, and thanks for joining us today. I'll start on slide five. In the third quarter, strong operational performance across all areas of our business enables us to deliver significant year-over-year top and bottom-line growth for the quarter, building on a productive first half of the year. I'm pleased to report that based on our performance through the first three quarters of 2022, we are raising the midpoint of our full year revenue guidance, reflecting increases in the guidance midpoints of both our neurology and oncology net sales projections. Renée will discuss these and other updates to our guidance later in the call. Our commercial business continues to execute well. In our neuroscience franchise, we are seeing compelling adoption of Xywav in both narcolepsy and idiopathic hypersomnia, or IH, and we're pleased to have achieved another important milestone. Exiting October 2022, there are now more narcolepsy patients taking Xywav than Xyrem. Looking ahead, we remain confident in the durability of Xywav as a core component of our commercial portfolio. For Epidiolex, we are seeing growth driven by underlying demand. And recently, we completed the pricing and reimbursement process in France, paving the way for commercial launch in this key European market. We believe Epidiolex can become a cornerstone of treatment for refractory seizures and remain confident in Epidiolex's potential to achieve blockbuster status. Moving to oncology. Zepzelca is established as the treatment of choice in second-line small cell lung cancer. Our ongoing clinical development efforts are focused on expanding within that indication as well as looking to address additional patient populations who may benefit from therapy. Rylaze had another strong quarter, as momentum with prescribers has continued. Rylaze remains the only therapy available to patients in the US who experience a hypersensitivity reaction to E. coli-derived asparaginase. Dan will provide a detailed overview of our performance across the commercial portfolio later in the call. Our pipeline efforts were productive again this quarter, with multiple clinical trial starts. We enrolled the first patient in our Phase 1 trial evaluating JZP815, our pan-RAF inhibitor for the treatment of solid tumors that contain mutations in the MAPK pathway. We initiated a Phase 2 trial for suvecaltamide in Parkinson's disease tremor, which complements our ongoing Phase 2b trial in essential tremor. And for Epidiolex, we initiated our Phase 3 trial evaluating Epidiolex in patients with epilepsy with myoclonic atonic seizures, or EMAS, as well as enrolled the first patient in our pivotal trial in Japan. And just last month, we announced a licensing agreement to further expand our late-stage pipeline as part of our agreement with Zymeworks to acquire development and commercialization rights to zanidatamab, a novel HER2-targeted bispecific antibody in the US, Europe, Japan and other markets. Rob will provide additional comments on our pipeline programs in progress, including zanidatamab later in the call. Turning to slide six. Vision 2025 includes three components central to driving sustainable growth and enhanced value as we transform our company; commercial, pipeline and operational excellence. Starting with commercial, we're positioned to grow revenue to $5 billion in 2025 through a combination of existing products, potential new therapies emerging from our pipeline and corporate development. Our R&D organization is advancing key programs, addressing significant patient needs in neuroscience and oncology and we anticipate delivering at least five novel product approvals by the end of the decade through a combination of existing pipeline programs and corporate development. The zanidatamab transaction is an example of a corporate development initiative that could contribute to both our commercial and pipeline objectives. And on operational excellence, our 2021 adjusted operating margin was 43% and we plan to improve that by 5 percentage points from 2021 to 2025, delivering more of our top line through to the bottom line. With Vision 2025 as our roadmap, we continue to transform our business and operating model to ensure we have the appropriate structure in place to scale, while continuing to invest in our business in order to meet our goals. We believe our accomplishments in the third quarter position us for a strong ending to the year, entering 2023 with considerable momentum across the business and well positioned to achieve Vision 2025. I'll now turn the call over to Dan to review our third quarter commercial performance, after which Rob will share an update on the progress of our R&D programs. Renée will provide a financial overview, including corporate development updates, and then we'll open the call up for Q&A.

Thanks, Bruce. I'm excited about the progress we've made on the commercial portfolio and pleased to report on our strong third quarter performance. Starting with neuroscience on slide eight. We are maintaining positive momentum for our oxybate franchise. With Xywav, we have meaningfully advanced patient care with a lower sodium oxybate product. In the third quarter, average active oxybate patients increased to approximately 17,600, representing growth of approximately 10% compared to the same period last year. There were approximately 9,500 active Xywav patients exiting the quarter resulting from strong adoption in both narcolepsy and IH. We continue to see strong uptake of Xywav for narcolepsy in the third quarter and we exited the quarter with approximately 8,050 narcolepsy patients taking Xywav. As Bruce mentioned, we've reached an important milestone with more narcolepsy patients taking Xywav than Xyrem. In addition to continued adoption of Xywav among current Xyrem patients, the large majority of new to oxybate narcolepsy patients are being prescribed Xywav. We expect that trend to continue as our educational efforts around the benefits of lower sodium oxybate are resonating with prescribers and patients. With continued strong adoption in IH, we have a substantial growth opportunity. There is a high level of engagement and receptivity in the market for a new IH therapy. We have secured reimbursement on par with narcolepsy – and importantly, we continue to grow the IH prescriber base. As physicians gain experience prescribing Xywav for IH and they have the opportunity to observe its clinical benefits within their own practices, we are seeing increased enthusiasm for identifying appropriate patients and initiating therapy. Exiting in the third quarter, there were approximately 1,450 IH patients taking Xywav, and we're focused on educating prescribers about IH diagnosis and patient identification. Xywav is the first and only FDA-approved therapy for IH and we are confident in our ability to maximize its potential in this underserved market. We expect that Xywav will be the oxybate of choice in 2023, even as authorized generics enter the market and as branded competition potentially becomes available. Xywav is the only lower sodium oxybate and is the only oxybate approved for both narcolepsy and IH. We have confidence that Xywav is a durable product that will continue to contribute meaningfully to Jazz's commercial portfolio. Turning to slide nine. In Epidiolex, net product sales increased by 22% in the third quarter of 2022, compared to the same period last year, driven primarily by demand. Our overall volume of engagement with health care providers continues to grow, which is a positive development for the brand given the promotionally sensitive nature of Epidiolex, and the anti-epilepsy market as a whole. We're also pleased that our market research indicates nearly 60% of prescribers are moving Epidiolex up in the treatment algorithm. Polypharmacy is the dominant treatment strategy in treatment refractory epilepsy and one approach we have taken that is resonating with US healthcare professionals is to highlight data on the synergistic effects of using Epidiolex in combination with Clobazam. Clobazam is one of the most widely used anti-seizure therapies, and healthcare providers have been very impressed with the combination data. Both Epidiolex and Clobazam have demonstrated effectiveness in reducing seizure frequency in LGS, Dravet and TSC. In combination, Epidiolex plus Clobazam have been shown to reduce seizure frequency by around 60% in LGS and Dravet and nearly 50% in TSC compared to an approximately 30% reduction in seizures for patients giving Clobazam plus placebo. These data are particularly relevant for healthcare professionals who have limited experience with Epidiolex, offering a strong rationale to begin incorporating Epidiolex into their patient's treatment regimens. There has also been continued adoption and growth of Epidiolex in markets outside the US and we recently completed the pricing and reimbursement process in France. We expect to launch later this year, at which point Epidiolex will be reimbursed and commercially available in all five major European markets, including France, Germany, the United Kingdom, Spain, and Italy. We also have the opportunity for additional growth coming from multiple new market and indication launches throughout this year and next. Given Epidiolex's differentiation in the anti-epilepsy drug market and its ability to be combined with a wide range of other therapies, we remain confident it will emerge as a global standard of care in treatment-resistant epilepsies. Now moving to oncology. I'll begin with Zepzelca on Slide 10. We have established Zepzelca as the treatment of choice in second-line small cell lung cancer. In the third quarter, net product sales were in line with our expectations. As we noted in our third quarter 2021 earnings announcement, Zepzelca's 3Q 2021 net product sales were favorably impacted by approximately $10 million, relating to a reduction in the returns accrual rate, which was due to lower-than-estimated actual returns. Excluding that impact, net product sales increased by approximately 14% in 3Q 2022 compared to the same period in 2021. We're also exploring ways to further expand market share in our current indication by investing in real-world evidence and observational studies that we believe will generate additional data around Zepzelca's utility in a broad range of second-line small cell lung cancer patients. Rob will cover our development plans for Zepzelca in more depth, which also includes trials in first-line small cell lung cancer and other tumor types, providing the opportunity for meaningful future growth in new patient populations. Turning to Slide 11. We have continued to see strong demand for Rylaze since our US launch in the third quarter of 2021. This reflects robust brand awareness among customers and prescribers, confidence in a high-quality reliable supply of product and Rylaze's position as the only therapy available to patients in the US, who have a hypersensitivity reaction to E. coli-derived asparaginase. We continue to hear from healthcare professionals that based on the availability of Rylaze, they are returning to best clinical practice and switching to non-E. coli-derived asparaginase earlier when there has been an initial hypersensitivity reaction observed. Rylaze has been adopted almost universally in US pediatric oncology protocols and we are encouraged to see that there is increasing use of Rylaze in the treatment of adolescents and young adults. Now I will turn the call over to Rob to provide an R&D update. Rob?

Thanks Dan. I'll kick things off on slide 13. In mid-October, we announced our agreement to license development and commercialization rights to Zanidatamab. This is an extremely promising program. Zanidatamab is a novel HER2-targeted bispecific antibody with biparatopic binding that has the potential to transform the current standard of care in multiple HER2-expressing cancers. The ongoing clinical program for Zanidatamab is well designed and includes anticipated near-term data readouts that could support registration. Topline data from a pivotal trial in biliary tract cancer performance BTC, are expected by year-end, and topline data from the ongoing pivotal Phase 3 trial in gastroesophageal adenocarcinoma, or GEA are expected in 2024. Potential approval in BTC would enable us to deliver this therapy to patients as quickly as possible, allowing healthcare professionals to gain real-world experience with this drug in BTC prior to potential approval in other larger cancer populations such as GEA. As an oncologist, I'm impressed to see monotherapy activity with Zanidatamab across multiple HER2-expressing tumor types, including cases resistant to prior HER2 therapies. And the ongoing trials are expected to provide data that will inform development beyond BTC, GEA. We're looking forward to working with the experienced team at Zymeworks to achieve our shared objective of realizing the full potential of Zanidatamab for patients. Slide 14 provides an overview of our near-term R&D opportunities. We are advancing a number of programs across the pipeline. Within neuroscience, I'm pleased to report that we have initiated our pivotal Phase 3 trial for Epidiolex in Japan that includes Dravet, LGS and TSC with the first patient enrolled in October. We have also initiated our Phase 3 trial for Epidiolex in epilepsy with myoclonic atonic seizures, or EMAS. This would add a potential fourth indication to our label and provide the first clinical data on a floor seizure type. Our Phase 2 trial for JZP150 in post-traumatic stress disorder is progressing, as is our Phase 2b trial for Suvecaltamide, or JZP385, for the treatment of essential tremor. And based on preclinical evidence and significant patient need, we have initiated a separate Phase 2 trial for Suvecaltamide in Parkinson's disease, too, and expect to enroll the first patient by the end of the year. We've completed our analysis of the nabiximols MSS1 trial. We have assessed the nabiximols program's potential to support regulatory approval for multiple sclerosis related to spasticity in the US as well as in the context of our broader pipeline opportunities. We have made the decision to discontinue the program. There is no impact to patients currently enrolled in the trial, and they will complete the study per the clinical trial profile. On behalf of my colleagues at Jazz, I want to extend our gratitude to the investigators, clinical sites, patients, and their families who participated in the recent nabiximols trials. Sativex, the brand name for nabiximols, was approved outside the US for the treatment of MS-related spasticity based on a comprehensive clinical trial program, including three positive Phase 3 randomized controlled clinical trials completed in Europe. We continue to believe that Sativex confers benefit to patients with MS-related spasticity and are continuing to support the availability of Sativex in the 29 markets outside of the US where it is approved, so that it remains available to patients who benefit from therapy. We also remain excited about the GW cannabinoid platform and are committed to advancing cannabinoid programs, including those beyond Epidiolex, with the potential to address critical unmet patient needs. Moving to oncology. We continue to execute our robust development effort for Zepzelca. This includes an ongoing Phase 3 trial supported by Jazz and Roche to evaluate Zepzelca in combination with Tecentriq in first-line extensive-stage small cell lung cancer. A confirmatory Phase 3 trial in second-line small cell lung cancer being run by our partner, PharmaMar, and our own post-marketing observational trial in second-line small cell lung cancer. We are also exploring Zepzelca in other solid tumors in a Phase 2 basket trial. Turning to Rylaze, the FDA is continuing to review our sBLA for Rylaze to update our label to a Monday, Wednesday, Friday intramuscular dosing schedule, with patients receiving 25 milligrams per meter squared on Monday and Wednesday and 50 milligrams per meter squared on Friday. This schedule, which is more in line with current clinical practice to avoid weekend dosing, would allow patients to maintain a clinically meaningful level of serum asparaginase activity through the entire duration of treatment. Currently, the labeled dosing schedule is every 48 hours at 25 milligrams per meter squared. We also completed a separate sBLA to support intravenous administration. Similar to the review of our original BLA, both the Monday, Wednesday, Friday, dosing schedule and the IV formulation supplemental BLAs are being reviewed under the real-time oncology review program. While we do not believe these label updates would have a significant impact on usage, they do have the potential to improve the Rylaze experience for clinicians and patients. We have also completed an MAA submission to the European Medicines Agency for Rylaze, which included Monday, Wednesday, Friday, and every 48-hour dosing schedules, as well as IV and IM administration with potential approval in 2023. Looking at our earlier stage programs, we recently reached the milestone for JZP815, our pan-RAF inhibitor for the treatment of solid tumors that contain mutations in the MAP kinase pathway, enrolling the first patient in our Phase 1 clinical trial in October. We are also advancing a number of programs towards IND submission. In summary, our R&D portfolio has evolved dramatically over the last 24 months. We have a robust pipeline of mid and late-stage programs, with data readouts expected through 2024, further complemented by promising early-stage programs. I've never been more excited about the compounds in our pipeline. With our R&D organization integrated following the GW transaction, we have an exceptionally talented, experienced, and diverse team, with the expertise and capabilities to rapidly drive development toward the goal of delivering additional innovative therapies to patients. Now, I will pass the call off to Renée for a financial update. Renée?

Thanks, Rob. I'll begin on slide 16. Our third quarter financial results reflect strong execution across the business. We achieved impressive top and bottom-line growth with third quarter total revenues of $941 million, representing growth of 12% compared to the same quarter in 2021. Our continued focus on both the top and bottom line drove third quarter adjusted net income of $370 million, a 42% increase compared to the same period in 2021. Adjusted EPS was $5.17 in the third quarter, a 23% increase compared to the same period last year. Adjusting our 3Q 2021 results for the accounting change for convertible debt, our adjusted EPS growth for 3Q 2022 would have been 38% compared to the same period in 2021. Our updated guidance is outlined on slide 17. Based on results from the third quarter, we are raising the midpoint for all of our revenue and net sales guidance metrics and updating the ranges for full-year total revenue guidance to $3.6 billion to $3.7 billion, neuroscience net product sales to $2.7 billion to $2.8 billion, and oncology net product sales to $860 million to $920 million. In all three instances, we have cut the upper end of our guidance the same while increasing the lower end. With regard to OpEx, we continue to focus on strategic, disciplined use of capital. We noted last quarter that we expected to come in towards the lower end of our guidance range, and we are now narrowing our SG&A expense guidance to $1.09 billion to $1.12 billion, and reducing R&D expense guidance to $490 million to $520 million. We are excited about our pipeline and investing in multiple ongoing clinical and preclinical programs, and the reduction in R&D guidance was driven primarily by the discontinuation of the nabiximols program and continued focus on financial discipline. We are raising our 2022 non-GAAP ANI guidance range to $1.225 billion to $1.275 billion. This is a $35 million improvement at the midpoint despite the inclusion of a $50 million upfront payment related to the Zanidatamab transaction that we expect to pay by year-end upon expiration of the HSR waiting period. Should we decide to continue with the transaction following review of data from Zymeworks, we anticipate the second upfront payment of $325 million would be recognized in the fourth quarter, with both payments included in our IP R&D line. Turning to slide 18. Our non-GAAP net leverage ratio was approximately 2.9 times at the end of the third quarter. We have now delevered two full turns since the close of the GW transaction in May 2021, which we've accomplished through both paying down debt and increasing adjusted EBITDA. Our focus remains on managing the balance sheet through disciplined capital allocation to ensure we are investing at our highest priority initiatives across the business and leveraging our strong cash flow, all of which provides us with meaningful flexibility for further corporate development initiatives. Corporate development is a foundational pillar of our strategy to deliver long-term growth and value for both patients and shareholders and is important to our efforts to achieve Vision 2025. We believe our recent transaction with Zymeworks is an ideal strategic fit for Jazz and exemplifies our approach to corporate development. This transaction has the potential to further diversify our commercial portfolio in the near term with an innovative therapy that we can evaluate in multiple tumor types following potential initial approval in BTC. A few aspects of this transaction that I'll call particular attention to. First, it is aligned with our strategic focus on opportunities where we not only have unique insights and there is critical unmet patient need, but where we can also leverage Jazz's existing integrated capabilities and global infrastructure to commercialize efficiently. Notably, in the US, there's a significant overlap with our existing Zepzelca call universe where we have built strong relationships and quickly established Zepzelca as the standard of care in second-line small cell lung cancer. Should we continue in the licensing agreement and secure approval for Zanidatamab in BTC and GEA, which are the first two potential indications, there is a concentrated physician audience for efficient commercialization. Second, this is a durable asset with the opportunity for significant regulatory exclusivity, following potential approval and a robust patent portfolio expiring several years later. And third, as Rob noted, Zanidatamab has potential in a broad range of cancers. As we look to continue to diversify our commercial portfolio, we believe this type of asset and transaction offers significant upside with a relatively modest upfront investment, including a deal structure that is weighted towards achievement of regulatory and commercial milestones rather than higher upfront payments. I'll also point out that the scope and structure of the transaction, coupled with our strong cash flow, leaves us with plenty of bandwidth to continue to be active on the corporate development front. As I noted on the previous slide, with respect to the GW transaction, we've shown the ability to lever up and then quickly delever in order to opportunistically transact and we ended the quarter with nearly $900 million in cash, cash equivalents and investments. As in prior years, we plan to provide 2023 guidance in our full year earnings disclosure. However, I'd like to comment on two items that are shaping our perspective on 2023 and Vision 2025. First, upcoming oxybate competition. As we've previously noted, we expect that Xywav will remain the oxybate of choice in 2023 and even as the first Xyrem authorized generic enters the market, either late this year or early next year with others to follow and branded competition potentially becomes available. We have orphan drug exclusivity that extends to 2027 for narcolepsy and 2028 for IH, as well as Orange Book listed patents that extend out to 2033. We also expect to receive meaningful royalties for all Xyrem authorized generics, and we expect the oxybate franchise, led by Xywav, will continue to be an important component of our revenue stream in the coming years. Second, operating margin improvement. Our updated 2022 guidance implies an operating margin of 49% at the midpoint, positioning us to both further invest in our business in 2023 and 2024 and achieve the operating margin target outlined in Vision 2025. With our strategic investments, expanding product portfolio, R&D progress and focus on operational excellence, we believe we are well positioned to achieve Vision 2025 and deliver further diversification, sustainable growth and enhanced value to patients and shareholders. I'll now turn the call back to Bruce for some final remarks.

Thanks, Renée. I'll conclude our prepared remarks on slide 20. We finished the third quarter with strong momentum across our business and are in an excellent overall financial position despite a challenging period in the biotech sector, and global markets in general. Our commercial efforts have driven strong uptake for Xywav in both narcolepsy and IH, growth in Epidiolex resulted in an outstanding launch for Rylaze and established Zepzelca as the treatment of choice in second-line small cell lung cancer. Our R&D team continues to advance multiple mid and late-stage programs and we expect to submit several INDs through 2023. The pending addition of zanidatamab strengthens our oncology pipeline to add a program with anticipated near-term clinical milestones and the potential to contribute to our Vision 2025 commercial and R&D objectives. Operational excellence also remains a key area of focus, including our goal of improving our adjusted operating margin, while maintaining diligent and disciplined capital allocation to drive shareholder value. In summary, we remain on track to achieve Vision 2025, and our updated guidance reflects our team's execution across the business in the first three quarters of 2022. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

Our first question comes from Ken Cacciatore with Cowen. Your line is now open.

Hi, everyone. We've made great progress and performance. Bruce, can you share insights on the retention you're observing with the early patients using Xywav? I understand it's still early, but what are your thoughts on the retention rate? Additionally, you mentioned an increasing number of prescribers. Can you clarify who is already prescribing it repeatedly? Lastly, some people are still concerned that the patient count might just be a temporary spike. Given your experience in the field, what are your thoughts on the patient size? You've previously mentioned it being similar to narcolepsy. Do you still believe that Xywav could eventually reach the same level of success in idiopathic hypersomnia as Xyrem did in narcolepsy? Thank you.

Yes. Ken, I'll start with a comment on the overall market opportunity and then maybe let Kim take the questions on what we're seeing in initial patient experience with Xywav. On the overall market size, while we do believe that the market opportunity as we move forward in time is very large and may, in fact, be the size of the narcolepsy opportunity, if you look at diagnosed and undiagnosed patients. Our initial focus, as we've talked about, is going after that segment of the market where we know patients already have a diagnosis of IH and are actively seeking medical care. So it's a subset of that, but yes, the opportunity long-term is larger. Kim?

Sure. Yes, what I'll emphasize is we're still seeing a really high level of engagement and receptivity in the market overall for this new IH therapy. And as you mentioned, Ken, we're continuing quarter-over-quarter to bring new prescribers on and grow that prescriber base among those prescribers who have utilized the product so far in their patients. We're hearing very positive experience. And ultimately, that they're seeing the products perform, both efficacy and safety wise, in line with what we saw in the Phase 3 clinical studies. So, very positive experiences as well as positive experience with the availability of the product on formularies. Again, we've got 90% coverage for both narcolepsy and IH in the commercial patient population at this point in time. So overall, what we're seeing and hearing is that, as a healthcare provider gets their own first-hand clinical experience with prescribing Xywav in this idiopathic population and has the ability to observe its clinical benefits within their own practices, we really see increased enthusiasm about it, and an effort on their part to start to identify additional appropriate patients in which they can initiate therapy. So all of this, positive signals from those who have utilized as well as those who have not allows us to continue to be really confident in our ability to maximize the potential of Xywav in this really underserved market, and it makes us very pleased that we're continuing to grow Xywav across both narcolepsy and IH, putting us well on track to be the oxybate of choice in 2023.

And Ken, maybe I'll just wrap by saying if you contrast what physicians are seeing with Xywav in IH, with the options they had available to them before our launch, they were using unapproved drugs off-label, primarily just to address EDS. And as a reminder, Xywav is broadly indicated to treat the disease idiopathic hypersomnia across a number of important symptoms. So we're seeing that effectiveness come through to both patients and clinicians.

Thanks so much.

Please standby for our next question. Our next question comes from Jessica Fye with JPMorgan. Your line is open.

Great. Good evening, guys. Thanks for taking my questions. Does the IRA influence your business development priorities or how you evaluate potential targets? And what about within your own pipeline? Does it impact your thinking on which indications or efforts to prioritize?

So, I guess, I would say, like other companies in our industry, we're continuing to evaluate the impact of the IRA legislation, particularly as we learn more over time about how it's going to be implemented to see how that will impact our investment decisions, and it may impact our investment decisions across our R&D portfolio, but also importantly, across corporate development opportunities. There are parts of IRA we liked, including really trying to address out-of-pocket cost for patients. I think that was a step in the right direction. There are other provisions that we think are actually challenging to innovators in terms of some of the probably unintended consequences or not fully recognized consequences in terms of providing a return on capital for those investments. So we, like everyone, will be looking at potential impacts. I don't think we believe for our existing commercial portfolio of products. We see much certainly in any near-term period that would concern us, but we will take it into account when we're making longer-term investment decisions.

Thank you.

Our next question comes from Jason Gerberry with Bank of America. Your line is now open.

Hey, guys. Thanks for taking my question. First question, not asking for guidance, but just curious if directionally you see 2023 as a revenue growth year? And the reason I ask is because you have this 2025 target out there. And I think from an investor standpoint, it's easier to believe that if you think 2023 is a growth year. And given the generic competitor entry, I think it would just be something that would be helpful to you guys could address at some threshold. And then the Epidiolex quarter was impressive. I'm just curious if you can speak a little bit to like the one or two biggest growth drivers on a year-over-year basis. You guys were pushing into adults, into rural and suburban kind of areas. So just kind of curious if you could give us a little bit more color on what specifically were some of the bigger growth drivers for Epidiolex? Thanks.

Maybe I'll ask Renée to take the broader revenue trends question, and I hear that you're not asking for guidance, so thank you. and then maybe I can turn it over to Dan and Kim to talk a little bit about our Epidiolex growth.

Yes. Thanks, Bruce. And Jason, thanks for the question. So with respect to 2023, as you would expect, we typically provide that full year guidance for a new year alongside our full year results in the first quarter. So you can expect that from us in early 2023. However, with respect to how we're thinking about 2023 relative to AGs or potential competition, I would say we continue to expect Xywav to be the oxybate therapy of choice. We're confident in the path that we have ahead of us for 2025 and the ability of the oxybate franchise, more broadly, to deliver $2 billion of revenue across Xywav, branded Xyrem and then the royalties of AGs, which, of course, carry meaningful economics to us. But going back to 2023 and Xywav, as you would have listened to our comments and looked at our third quarter results, we believe we are very well-positioned for Xywav to be the therapy of choice within the oxybate for the year. We've established excellent payer coverage for both narcolepsy and IH. You've heard today, we now have more narcolepsy patients on Xywav than Xyrem, another important milestone for the brand. And we've also, in the third quarter, now generated over $50 million of net sales in a single quarter with Xywav. So all of this points to meaningful progress and success for the brand and positions us really well as we prepare to enter 2023.

Kim?

Yes. So I'll start off by talking about the US, and we have really seen a number of things giving us momentum here in the US and leading us to be optimistic about the future. And I think there are some of the themes that we've been talking about for the past year are looking for. The first is that, as Dan mentioned, our overall volume of engagement with HCPs has really been continuing to grow nicely quarter-over-quarter, which is really important to a product this early in the life cycle such as Epidiolex and given that we have a number of customers have yet to use it or utilize it broadly. So promotion and education efforts are absolutely important in this highly-sensitive, promotionally-sensitive market that we're operating in. So that's one. I think the second driver is as we've kind of talked about and predicted is that we're really seeing this reality of HCPs getting more experience with Epidiolex, seeing what it can do for their patients, feeling more comfortable with the product and impressed and utilizing it more broadly. Dan mentioned that quantitatively, we're also seeing this in terms of market research showing that HCPs are reporting that 60% of them versus a year ago have moved Epidiolex up in their treatment algorithm. So that's working exactly as we had predicted and had been seeing early on. So lots of great momentum. And then the last one I'll point to is we've been talking all year, again, about our promotional focus and effort in terms of trying to get HCPs to utilize the product for the first time or more broadly by sharing that combination data that we have with Clobazam. It has been very impressive. It really does when they see that there's a synergistic effect of using these two products together and that most of their patients are already on Clobazam. And its ability to reduce this combination seizures by 60% in LGS and Dravet, 50% in TSC, it really does give them pause. And until they tell us it's highly motivating for them to either try it for the first time or to utilize it in their patients who are already on Clobazam who really could benefit from further seizure reduction. So I look at those three things really as the major things putting wind in our sales and leading to both the 22% year-over-year growth we saw in the third quarter, but also leading to the optimism that we have that this product is going to continue to grow nicely and achieve blockbuster status. And that's just the US. So I'll turn it over to Dan to talk about our efforts outside the US.

I will keep my remarks brief as they align with the trends and growth drivers Kim highlighted. We are currently launched in 15 markets and have 34 countries approved. There are ongoing launches both geographically and as we introduce TSC to the label in some of these markets. We are observing strong healthcare provider engagement which is advantageous since it is a promotionally-sensitive brand. France will be the final major market for us in Europe, where we have obtained pricing and reimbursement approval. Our pre-launch activities have been successful, generating awareness among patients who are already benefiting from the drug. We aim to transition into full commercial launch mode by the end of this year, with a view towards realizing full commercial benefits next year. Globally, we remain optimistic that Epidiolex could become a key treatment option for therapy-resistant epilepsy and turn into a blockbuster product for us.

Great. Thanks, guys.

Please stand by for our next question. Our next question comes from David Amsellem with Piper Sandler. Your line is open.

Thank you. I have two questions. First, regarding the long-term targets for 2025, you mentioned margin expansion approaching 48% or close to 50%. I'm curious about how much of that expansion is driven by expense control, particularly in R&D, excluding in-process R&D and focusing on organic R&D. How should we view that, especially considering your guidance of approximately $490 million to $520 million this year? My second question is about Epidiolex. You mentioned growth in new prescribers, and I would like to know how well you are penetrating your target audience. What is your outlook on the pace of new prescriber growth as we progress through 2023? Thank you.

David, it's Renée. I'll take your first question in terms of margin expansion. So, certainly, we've been highly focused on operational excellence. And, yes, we have set out a 2025 adjusted operating margin ambition of being at 48%, in terms of the midpoint of our guidance today and my comments for the full year being in a position where we're already at 49% for 2022. We've accomplished that through a number of areas. Of course, we said R&D was favorable, largely due to the nabiximols program decision as well as continued discipline. But as we look forward at what we're trying to accomplish, ultimately, we're looking to better leverage SG&A overall to be able to accommodate additional business development, to be able to accommodate additional investments in R&D in our pipeline. And so, by being in the position that we are already gives us the opportunity to, between now and 2025, invest in our business, invest in the brands that we're launching, the pipeline, our capabilities, continue to leverage that G&A footprint as our top line grows so that we can scale effectively and efficiently, and then still have the capacity to be active in future corporate development, which, of course, could result in additional commercial or R&D expenses. But we certainly have a commitment to continuing to expand our R&D pipeline. We now have enhanced capabilities across the pipeline coming out of our transaction with GW, and that's an area we would expect over time will continue to generate more value for patients and for shareholders. And then I'll turn it over to Dan to answer your second question.

Yes. On the Epidiolex, yes, we're not giving specific penetration rates, but we had said in the past that Dravet is a little more penetrated because of the smaller indication. LGS and TSC, we see more opportunity. We also just see broadly that the drug works in a number of different seizure types and there's many that make up these refractory populations that don't have FDA-approved therapy. So then it's a question of physician use and experience and market access. And that's all going beneficially for us as well. There's a lot of focus in terms of retention, and we've seen very strong retention. So when patients start the drug, they find this to be very beneficial within a polypharmacy setting. We also see that as physicians gain experience and they push up the doses that, that also generally leads to better efficacy. And so continuing to titrate up, and I think in some of the markets, we feel we're under-dosed. So that's going to be an area of growth. And then we've got a broad indication for starting at a young age going all the way up and I think we've done a good job with the pediatric settings in most markets. But there's still an opportunity to transition those pediatrics as they become young adults and even adults with these lifelong conditions and also addressing the adult patient population. And then, there's still additional geographic opportunities in some of the countries we haven't been in. And longer term, we're investing in data generation for new seizure types such as EMAS but we're also looking to address new significant markets like Japan and Asia.

Good. Thank you.

Please standby for our next question. Our next question comes from Marc Goodman with SVB. Your line is now open.

I'm sorry to focus on Epidiolex again, but could you clarify a few points for us? Last year, the third quarter was relatively weak, while the fourth quarter saw a significant increase. Is it possible that one quarter affected the other, perhaps due to inventory changes? This quarter has been substantial, and we're trying to understand the details. Can you explain whether the growth was mainly from new regions in Europe or if there was also genuine growth in the United States? Can you confirm if there was double-digit growth in the U.S. year-over-year and whether there were any changes in inventory? Lastly, regarding the study in Japan, prior to Epidiolex's approval in the U.S. and Europe, there was widespread CBD use readily available in shops. Is the situation similar in Japan? Do you anticipate a comparable ramp-up and excitement there? Thank you.

Yes. Mark, this is Bruce. I'll take the first part of your question and then maybe have Dan make a couple of comments on Japan. It's going to be a short answer. The growth you saw in Epidiolex is real. Yes, it's in the US as we continue to roll out in new countries and new indications as Dan described in Europe, we are seeing solid growth in the US and no, it's not due to changes in inventory. Dan, you want to take Japan?

Yes. On the Japan side, we're super excited for that market and to now have launched our official study and so worked very closely with the regulatory agency and developing thought leaders who needed we're very interested in the data that was coming out of Epidiolex. But unlike other markets, there is really no cannabis allowed vector, the Cannabis Control Act, which prevents use of whether it's regulated or non-regulated. And so we're also working in parallel as GW had done successfully in other geographies with government officials to allow for exceptions to the Cannabis Control Act for regulated medicines that have gone through a safety and efficacy evaluation. And we're feeling confident we'll be able to do that change of law and sort of change of practice. And then meanwhile, so enroll and get the experience within Japan from the clinical study. So that's where we are with Japan.

Thanks.

Our next question comes from Ami Fadia with Needham. Your line is now open.

Thank you for the question. I would like to ask about Vision 2025. There seems to be a significant difference between the consensus and your outlook. Can you discuss where you feel more confident in the business's performance? Additionally, how much do you need to depend on future business development or new pipeline successes to reach that $5 billion target? Thank you.

Yes. Hi, Ami, and thanks for the question. I would say that even when we first communicated Vision 2025, we talked about having revenues from our existing commercial portfolio, but also including a placeholder for productivity out of our pipeline and/or corp dev with a strong commitment to doing corp dev. And maybe Renee can make a few more comments about how we're thinking about that.

Sure. Yes, I'd be happy to. Well, Ami, as we look forward, we certainly expect corporate development to continue to be an important strategic pillar for us. Clearly, it had a huge impact on our ability to grow and diversify our revenues to date and also expand our pipeline. So as you look at the deal we just transacted on with Zanidatamab, it has the potential, as Bruce had mentioned, to contribute to Vision 2025 both as part of the $500 million placeholder we've identified from future growth in corporate development, but also as part of the five novel therapies to deliver by the end of the decade. As we look at that strategic framework for corporate development, we're looking at early assets that have the opportunity to continue to grow that pipeline, but also late molecules and then things that can also be very close to commercial. I'd put zanidatamab in that category in terms of being able to contribute to two different pillars. And we're excited in the case of zanidatamab to be a potential best-in-class therapy. This is the sort of transaction for us that we think has the potential to have a meaningful impact for patients, where we can apply our unique insights, where we have the ability to commercialize efficiently given the overlap with Zepzelca. And we'll continue to look at transactions of this nature. And then, I'll just note, just given our financial position right now and the speed at which we've delevered the health of our operating cash flow, we feel confident in our ability to continue to leverage corporate developments. We, of course, as we look forward, see a lot of opportunities, still given valuations where they are today, and have a corporate development group that's quite busy. So we're excited about the opportunity to continue to lean into that part of our business to augment what we have already as a business. We're really excited about the opportunities we have to grow the top line and continue to drive the pipeline forward with what we have in-house today.

Thank you.

Please stand by for our next question. Our next question comes from Ash Verma with UBS. Your line is open.

Hi. Thanks for taking my question. Just one. So on Epidiolex, I think the NCE plus forward timeline passed on September 28. Can you confirm if you have visibility whether there were any Paragraph IV patent certification? Thanks.

Nothing to add other than we've made clear in our filings that that's the earliest filings could occur. We fully expect there may be filings over time. Of course, those go into the FDA first and come to us later, but nothing to report at this point.

Okay.

Please stand by for our next question. Our next question comes from Madhu Kumar with Goldman Sachs. Your line is now open.

Thank you for taking our question. We are interested in understanding the growth of Xywav in idiopathic hypersomnia and how you view its current trajectory. Do you anticipate that there could be further growth as physicians gain more experience and comfort with Xywav? How should we approach this potential increase in usage?

Yes. Kim, do you want to talk a little bit about future opportunity for growth with IH?

Sure. So lots of opportunity for growth. We've talked in the past about there being already out there in the marketplace, 37,000 patients who are diagnosed with IH and they're actually out actively seeking healthcare. So it's not a sales diagnosis. So we've got a nice, healthy patient population to go after. What we're focused on right now is really ensuring that we're educating around IH diagnosis. Despite this, given we really want to try to help HCPs ensure that they're taking into consideration the full range of symptoms that patients are experiencing, they're really used to mostly focusing on that excessive daytime sleepiness the off-label usage of weight-promoting agents and stimulants have been enabling them to address, and we want to make sure that they're thinking much more broadly about the breadth of symptoms that patients are experiencing and that Xywav can treat. And then secondarily, we're helping HCPs to identify patients who may be ready for Xywav. And again, a big part of that is around making sure they're thinking about that full breadth of symptoms. So overall, strong excitement and feedback in the market, but as we've said, I think for a long time now, idiopathic hypersomnia is a new market. And we're excited to build it just like we did with narcolepsy, but we expect that it will take some time and grow gradually. So overall, lots of reasons to be optimistic, but also to appreciate, Jazz has been working in the narcolepsy market for a decade or more now. And we plan to be successful there ultimately with Xywav in idiopathic hypersomnia, but it will take some time.

I would like to add that our sales force is focusing on two key areas: increasing adoption in the new market of idiopathic hypersomnia and continuing our outreach to the narcolepsy community. This includes emphasizing the importance of the reduced sodium content in Xywav, which led the FDA to grant orphan exclusivity due to its safety benefits, particularly concerning cardiovascular events. Therefore, it's essential to maintain our narcolepsy messaging as we expand in idiopathic hypersomnia.

Okay. And then in terms of corporate development, you guys have a really impressive rate of deleveraging. I guess as we think about future corporate development, will it be kind of like Zymeworks where it's kind of the partnering kind of pulling out individual assets or how you may like outright acquisitions like GW? How should we think about that on the forward?

Yes, I'm happy to talk about...

Yes, Renée, why don't you talk about the breadth of approaches? Yes. Great.

Corporate development will remain a key focus for us. Reflecting on our strong cash flow, we generated over $930 million in operating cash during the first nine months. We've successfully reduced our debt by two full turns, paying down more than $1 billion since the deal was closed, while increasing our adjusted EBITDA by over $400 million, which is more than 30%. This positions us well, giving us the capability to pursue transactions at various levels. With this improved EBITDA, we have greater potential for larger scale initiatives if we choose to go that route. Currently, we believe we can continue making transactions similar to those we executed in Q2 with Werewolf and Sumitomo, both exciting early-stage assets. The Zani deal is also nearing pivotal data, representing a significant opportunity to generate long-term value. The strength of our cash flow, combined with our broader capabilities throughout all stages of our pipeline—especially in research—offers us many opportunities moving forward. Our primary focus is on neuro and oncology, though we do explore other areas when the opportunity arises. We remain technology agnostic, evaluating both small and large molecules, concentrating on where we can create the most impact for patients and shareholders.

Operator?

Our next question comes from Balaji Prasad with Barclays.

Good afternoon. This is Joe for Balaji. Thanks for taking our question. I have a quick inquiry regarding the Zani deal. We understand that the option for continuation will depend on the pivotal data from BTC, considering that BTC represents a relatively small market and that a significant portion of revenue is expected to come from other indications like GEA and breast cancer. I'm curious if there's anything noteworthy regarding the risks associated with the BTC pivotal data that might impact the other indications, such as GEA and breast cancer, which Jazz finds promising. Is timing a consideration in this context? Thank you.

Yes. Maybe Rob, I'll ask you to talk about what we think we'll learn in the near term and how we're thinking about the broader opportunity set.

Sure, Bruce. Happy to. What I would say before I answered the question directly is I've been impressed with the broad activity of this drug across really any tumor types that express HER2 and even in cases where patients have progressed after HER2 therapy. And so I think that speaks to the promise, both in gastric and BTC and then I would say beyond. And we're doing additional studies in breast cancer and colorectal cancer, et cetera. What we'll see at the BTC readout is going to give us a sense of whether we'll have that near-term opportunity to file with BTC. And that's potentially important just even beyond the specific indication. Remember, if we get approval in a relatively small indication, such as BTC, the next submission would be a supplemental. It would mean a more rapid review by FDA, it could mean that we would get NCCN guidelines around gastric based on the published data even before its approval, and it gives us a chance to do some preparation in the marketplace as well. So I think that becomes a factor in that regard. But I don't expect that it's going to have kind of a direct read through to the ongoing gastric trial.

Got it. This is very helpful. Thank you so much.

Our next question comes from Gary Nachman with BMO Capital Markets. Your line is now open.

Thanks. Good afternoon. Just back to Xywav, can you confirm that the strong reimbursement that you have already locked is going to be locked in for next year? Or is there still some uncertainty there for certain payers, depending on how the generic market forms for Xyrem? So how did those negotiations take place? And then generally, how much is the launch of IH helped overall awareness with narcolepsy as well as – you definitely continue to increase the number of patients treated in narcolepsy, not just in IH? Thanks.

Yes. In terms of 2023 coverage, I mean, what I can just say at this point in time is that we've got 90% commercial coverage for Xywav in both narcolepsy and idiopathic hypersomnia. And we think that bodes very well for us heading into next year. I believe you asked about the authorized generic really based on our conversations with payers as well as the strong contract that we have in place. We think the most likely scenario is going to be that payers will put the AG on the – put on their formularies in a comparable position to that of Xywav. In terms of IH helping the awareness of narcolepsy, look, what I'll just say is it's not so much just around the disease, but we are out there now wherever we can with the same sales force of the same customers largely due to that overlap that Bruce mentioned, a 90% overlap with the IH targets with those that we're calling on already for narcolepsy, that we're many times getting into discussions. So we've essentially, in many cases, doubled the amount of promotion around the brand itself. So I do believe that, that just overall leads to momentum in both directions for both indications.

Please standby for our next question. Our next question comes from Annabel Samimy with Stifel. Your line is now open.

Just wanted to ask about Rylaze. When you think about the trajectory here, obviously, you had a really nice uptake. I'm a little bit curious to see if this is a new peak level, obviously, higher than Erwinaze. Is it going to be plateauing here given that you seem to have tapped the pediatric market? How should we think about growth from this point forward? Is it harder to get into LDL patients, AYA patients? X geographies? How should we think about the dynamic of growth? Is it a plateau? Or is it just a gradual growth from here?

Yes, I'd be happy to take that one because we are incredibly pleased that Rylaze sales have exceeded prior U.S. peak sales of Erwinaze and that we believe this is a strong signal that the unmet needs of the market had never really been fully met before Erwinaze started to have supply issues. So I'll point to a number of things. We now have robust brand awareness among customers and prescribers. We've created high confidence in the high-quality and reliable supply of the product. And right now, we enjoy the position as the only available therapy to patients in the U.S., who have a hypersensitivity reaction to E. coli-derived asparaginase. We're continuing to hear from customers that based on the availability of Rylaze, they are returning to that clinical practice and switching to non-E. coli-derived asparaginase earlier than they previously were during the supply shortage when they see initial hypersensitivity reaction observed. At this point, Rylaze has been adopted, as you kind of said, almost universally in the pediatric oncology protocols. But we're also encouraged to see that there is increasing use of Rylaze in the treatment of adolescents and young adults. Now, the majority of the patients out there are pediatric. And it's important to note that many adolescent and young adult patients are actually treated in pediatric centers under the really strong pediatric protocol. So that's a good driver of the growth. Our launch was focused in the last year on establishing Rylaze with our existing asparaginase prescribers who, again, were predominantly in the pediatric setting. And next year in 2023, we aim to increase our efforts to driving prescribing in the adolescent young adult population and seeing if we can further expand the market. So again, that's just inside the U.S. And certainly, there's lots of growth opportunity ex-U.S. for Dan to talk about.

Yes. Internationally, we have submitted our application to the EMA and are optimistic about a potential approval in 2023, depending on the duration of the review process and the response to inquiries. The market dynamics differ from those in the U.S. with lower pricing and Erwinaze already available in Europe. However, we have gained valuable experience in the U.S., particularly by optimizing the dosing schedule with a larger dose on Fridays to ensure comprehensive patient coverage. Additionally, our product offers benefits such as its concentration, being fully recombinant, and containing no particulates in the solution. We look forward to providing another treatment option for physicians. In regions outside of Europe, such as Japan, where Erwinaze is not yet available, we are actively exploring opportunities and will collaborate with regulators to determine if there is a fast track to provide this important medication to patients in need.

Please stand by for our next question. Our next question comes from Gregory Renza with RBC Capital. Your line is open.

Hey, good evening, Bruce and team. Congrats on the quarter and thanks for taking my question. Bruce, I just wanted to ask a specific one on Vyxeos. Perhaps you can just give us some updated color on the Vyxeos performance and view and trajectories from here? And maybe related to that, it's super helpful to hear Renée and the team's color elaborating on BD and zani as a potential blueprint. I'm just curious, as you reflect on Celator from a few years ago and with Vyxeos now under Jazz, how that potentially juxtaposes as far as the strategy back then to how you're looking at deals like zani going forward? Thank you very much.

Yes, Greg, thanks for the question. And always interesting to learn from your past corp dev deals as you consider your important strategy going forward. In the Celator deal, we brought in a near-term launch with Vyxeos now on the market in the US and abroad as well as the CombiPlex platform, which we continue to see as a source of other interesting products for our future development and commercialization. And I'll just remind you that Vyxeos remains under study in other areas inside and outside AML that we think may allow us to broaden use in the future. So Rob, maybe talk a little bit about how Vyxeos is being studied right now? And then maybe, Renee, you can jump in with the prompt of how we think about different approaches to corp dev moving forward.

Sure, Bruce. It's being studied in a number of different ways through ISD's collaborations with major cancer centers and cooperative groups as well as in some ongoing studies that we're conducting. And I would just highlight a couple of things. One would be in combinations that could be highly relevant, like combinations with venetoclax. Those trials are ongoing. And also trials that would seek to extend the indication to a broader group of patients, such as the cooperative group with AMLSG, which is not just the high-risk patients but more broadly, front line.

Yes. I want to conclude by discussing our approach to business development moving forward. When we examine the Zanidatamab deal, we are focused on ensuring that our transactions align with our strategic goals while balancing the financial upfront investments with associated risks and other value-enhancing opportunities. We are thrilled to utilize the expertise of the Zymeworks team to advance our studies in the short term and explore innovative ways to leverage our partners' unique strengths and skills as we continue to execute our strategy. In this particular deal, we are satisfied with the financial terms and value milestones, particularly regarding the regulatory aspects and future commercial opportunities. As we look ahead, we intend to seek inventive approaches to structuring our transactions that will benefit both Jazz and our patients and shareholders, as well as our partners.

At this time, I am showing no further questions. I would now like to turn the conference back to Bruce Cozadd for closing remarks.

Thanks, Michelle. So thanks for joining us, everyone. We look forward to a strong finish to 2022 and remain focused on achieving Vision 2025. And I'd just like to close today's call by recognizing our Jazz colleagues for their commitment to delivering new therapeutic options to patients and want to thank our partners and shareholders for their continued collaboration and support. Have a good evening, everyone.

This concludes today's conference call. Thank you for participating. You may now disconnect.