Good afternoon, ladies and gentlemen, and welcome to the Third Quarter 2021 Jazz Pharmaceuticals Earnings Conference Call. [Operator Instructions]. I would now like to turn the conference over to your host, Ms. Andrea Flynn, Head of Investor Relations. Ma'am, please go ahead.

Thank you, and good afternoon, everyone. Today, Jazz Pharmaceuticals reported its third quarter 2021 financial results. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also refer to the press release we issued earlier today, which is also posted to our website. On the call today are Bruce Cozadd, Chairman and Chief Executive Officer; Renee Gala, Executive Vice President and Chief Financial Officer; Dan Swisher, President; and Rob Iannone, Executive Vice President, R&D and Chief Medical Officer. Kim Sablich, Executive Vice President and General Manager of North America; and Phil Jochelson, Neuroscience Therapeutic Head, will join for Q&A. On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential and anticipated development and commercialization milestones and goals, which involve risks and uncertainties that could cause actual events, performance and results to differ materially from those contained in these forward-looking statements. We encourage you to review the statements contained in today's press release, in our slide deck and in our latest SEC disclosure documents, 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 3. 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 the slide deck 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. I'll start on Slide 5. We remain laser-focused on executing our strategy across commercial, R&D and corporate development, positioning Jazz to deliver sustained growth as we continue to build our high-value portfolio of commercial and clinical stage therapies. In the third quarter, we continued to make progress in our transition to a diversified innovative biopharma company by focusing on our 3 primary pillars. First, growing sales of existing products in our commercial portfolio, including through indication and geographic expansion. The market-leading adoption of Xywav for narcolepsy and top-tier launch of Zepzelca in small cell lung cancer highlight our commercial execution across both our neuroscience and oncology therapeutic areas. The recent approval and launch of Xywav for idiopathic hypersomnia, or IH, showcases our ability to expand to new indications, in this case, where there are no other FDA-approved therapies. Further, our progress in securing access and reimbursement for Epidiolex across major European markets demonstrates our team's capabilities beyond the U.S. Our acquisition of GW Pharmaceuticals epitomizes our second strategic pillar, acquiring differentiated commercial products and late-stage programs. This acquisition brought in a high-growth, durable commercial product in Epidiolex and expanded our R&D portfolio. Our third pillar is pursuing pipeline development of differentiated therapies. Excluding the acquisition of GW, since 2015, our team has increased our pipeline assets fourfold, resulting in 11 product approvals. Now with the addition of the GW pipeline and cannabinoid platform, we are excited about a more robust pipeline that will further enhance that R&D productivity. Turning to several key highlights this quarter. In 2020, we established an aggressive target of completing 5 commercial launches in 2020 and 2021. I'm pleased to announce that earlier this month, we launched Xywav for IH in adults, which completes…

Thanks, Bruce. Well, I'm excited to share the progress across our commercial portfolio. So starting with neuroscience, we saw strong momentum during the third quarter for our oxybate franchise. Average active oxybate patients increased to approximately 16,000 in the quarter, a 6% increase over the same period last year. And we exited the quarter with approximately 6,000 active Xywav patients, up from approximately 5,100 at the end of the second quarter. We see significant opportunity for Xywav to continue to grow in narcolepsy and remain focused on educating physicians and patients about the lifelong burden of high sodium intake, particularly in a patient population like this one with an increased risk of cardiovascular comorbidities. In addition to the strong adoption of Xywav from existing Xyrem patients, we continue to see the large majority of oxybate naive patients being prescribed Xywav as opposed to Xyrem. As Slide 7 illustrates, we've achieved market-leading adoption for Xywav in narcolepsy relative to launches of other next-generation neuroscience products. This speaks to the strong product profile, which includes FDA's published findings of the clinical superiority of Xywav to Xyrem based on greater safety because of reduced sodium as well as our deep understanding of the sleep space and our ability to successfully drive adoption of new therapies. And we believe the IH indication will drive further growth of Xywav. Our commercial launch began on November 1, and I'll remind listeners that a replay of our October webcast discussing the commercial launch strategy of Xywav for IH is available on our corporate website for those who missed it. As we roll out this launch, our initial focus is on driving awareness and adoption among existing oxybate prescribers and the approximately 37,000 people who have been diagnosed with IH and are actively seeking health care. Expanding the…

Thank you, Dan. On Slide 15, we've detailed key clinical programs in our pipeline. Starting with our neuroscience development programs, the integration between our Jazz and GW R&D teams is progressing really well. We are advancing multiple therapies across our neuroscience portfolio, including a number of programs emerging from the GW cannabinoid platform. Epidiolex is currently approved to treat seizures associated with 3 refractory epilepsy disorders. And we remain on track to initiate a registrational Phase III trial for a fourth indication, epilepsy with myoclonic-atonic seizures, or EMAS, in the first half of 2022. EMAS is characterized by generalized myoclonic-atonic seizures. And this trial will provide the first randomized, controlled clinical data with Epidiolex in this seizure type, which we believe will provide further data on the potential effectiveness of Epidiolex in treating a broad range of seizure disorders. Now turning to nabiximols. The program has 3 active clinical trials focused on multiple sclerosis-related spasticity. We expect data from the first trial, which is a smaller, shorter trial relative to the other 2, in the first half of 2022. If results from this first trial are positive, there is the potential for a regulatory submission in the U.S. in the next 18 to 24 months. And we expect data from the 2 additional trials, which have larger sample sizes, to read out in late 2022 and early 2023. Now to discuss JZP-385. We recently initiated our Phase II clinical trial for JZP-385 in essential tremor and expect data to read out in the first half of 2024. In the U.S. and top 5 European markets, it's estimated that there are approximately 2 million people diagnosed with essential tremor, with about 0.5 million being drug treated. We are also on track to initiate our Phase II trial for JZP-150, a fatty…

Thanks, Rob. Full financial results are available in our press release and 10-Q and several key metrics are highlighted on Slides 17 and 18. On today's call, I'll discuss our overall financial performance and provide additional color around our updated guidance. We have made significant strides in transforming our business through the first 3 quarters of 2021. And we're well positioned to finish the year with positive momentum entering 2022. We remain on track for substantial annual revenue growth this year and for the first time, expect to exceed $3 billion in annual revenue. This growth was demonstrated in our third quarter revenue results of $838 million, which represented a 39% growth over the same period last year. Our strong performance is underpinned by commercial execution, financial discipline and strategic allocation of capital as well as prioritization of commercial and R&D opportunities that have the most impact on our future growth. Launching multiple products over the past 2 years, coupled with the acquisition of GW Pharmaceuticals, has enabled us to significantly advance our objective of diversifying revenue. 52% of net product sales in the third quarter were generated from products which we have launched or acquired since 2019. Given our expectations regarding the durability and growth potential of these products, we remain confident in reaching our goal of at least 65% of net product sales coming from these newer products in 2022. Focusing specifically on the GW acquisition, we are demonstrating our ability to execute on the corporate development front. We successfully closed this transformative transaction in approximately 90 days post signing, issuing over $5 billion of new debt with attractive and flexible terms to support the deal. The broad commercial and R&D portfolio we gained in the GW acquisition has accelerated our transformation, not only in terms of revenue…

Thanks, Renee. I'll conclude our prepared remarks on Slide 19. Building on our current momentum, we expect to finish 2021 on strong footing, which will position us well going into 2022. With FDA approval of Xywav for IH, we achieved our goal of 5 product launches in 2 years. Our commercial teams have demonstrated strong performance on the launches of Xywav for narcolepsy and Zepzelca. And we expect that successful execution will carry forward to the launches of Rylaze and Xywav for IH. The GW team orchestrated an excellent launch for Epidiolex. And its addition to our commercial portfolio provides us with the opportunity to deliver an important therapy to patients with refractory epilepsies. Our R&D organization continues to evolve and expand its capabilities. Trials for nabiximols, JZP-385, Rylaze and Zepzelca are now underway, and we are planning to initiate multiple mid- and late-stage clinical trials in the next 12 months. Our disciplined capital allocation has enabled us to expand our pipeline and diversify our revenues, and we are in a position to invest in those assets and opportunities that hold the highest potential to drive sustainable long-term growth and shareholder value. We have the ability to generate strong cash flow that allows us to make appropriate investments in our business while also achieving our deleveraging targets. That concludes our prepared remarks. And I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions]. Your first question comes from the line of Marc Goodman from SVB Leerink.

Rob, I heard that there's been some R&D activities that have kind of gone away. That's what Renee said. Can you talk about some of the programs that have stopped? I'm just kind of curious. There was -- GW had an autism program. They had a product for schizophrenia. They had a next-generation Epidiolex that they showed some early data on before the merger. Just curious, have those all been stopped? Or -- just give us a sense of that. And then if you guys could just give us a little more color on Rylaze and how to think about what's backlog versus what's real demand and whether we should expect a massive step up this quarter.

Renee, I'm not sure if you want to comment on what you were specifically referring to. But the way I would answer that question is in coming together with GW, we've really had the opportunity to continue to invest in the highest value opportunities. And of course, we've prioritized certain things, as we've described in this call tonight. There were many, many smaller studies that may have been investigated or initiated or that we've supported along the way, either on the GW or Jazz side that may not ultimately progress in the pipeline. But I think by and large, we've continue to invest heavily in all the key areas that we were investing in prior legacy companies.

And can we -- go ahead, Renee.

Yes. I was just going to add that this is also about as we bring our organizations together, the how as much as the what, certainly, we've seen a lot of complementary skill sets coming from both areas. So in some cases, as we put together hiring plans and looked at the skill sets that we've needed, we've seen these 2 groups come together and offer more versus what was originally anticipated. And that's not something that you'd have a really good idea of, Marc, until you get the groups together and really start integrating. We've also seen examples certainly of certain programs that would be duplicative across both pipelines. That's a great problem to have as you look at where to invest your capital, to ensure that you're putting your capital behind your highest value activities.

Kim, maybe I can ask you to jump in on the Rylaze question?

Sure. Yes. So I'll start by saying that we've laid a really strong foundation and Rylaze growth is continuing to accelerate. We've gotten initial feedback from our accounts that's very encouraging. We've received positive reports on the ease of both ordering and dose preparation as well as the Jazz care support services. What I can say about ordering is that when Rylaze was made commercially available in mid-July, there was still Erwinaze on the market on hand in hospital pharmacies that they were looking to utilize before placing orders. The temporary importation of U.K. Erwinaze from June, we saw run out of stock in September. And that's where we really saw a notable uptick in Rylaze orders beginning in September from customers. So overall, we're very encouraged by feedback from accounts. And we think we're in a strong place from an order standpoint.

Your next question comes from the line of Jason Gerberry from Bank of America.

So mine's on Xywav and thinking about the progression of the launch here. Do you think there are accelerants to the rate of quarterly additions that are moving on to Xywav? In your latest thoughts on Hikma, I think last quarter, you framed it as a possible risk of market entry in 2022. Just curious if that's still the case. And ultimately curious, Bruce, your comment about 4Q and providing an update there. I guess what materially changes in the contracts that could allow you to talk about Hikma timing in February versus not being able to talk about it today in November?

And maybe I'll take the back half of your question for Jason and I can ask Kim to comment on Xywav progression. What will change in the fourth quarter earnings announcement is we'll be doing that in the context of giving full guidance for 2022 across our business, including neuroscience and including oxybate. And I think I can give you a better sense of how we expect the year to play out. So it's not a comment specifically on contractual terms. It's just providing a full explanation of our expectations for oxybate. On the question of timing, nothing has changed since our disclosure over the last couple of quarters, honestly, in terms of recognizing that although the contract says entry no later than January 1, 2023, there is a market decline provision that we believe could be tripped in 2022, but that's not different from what we've said before. On Xywav progression, I'll ask Kim to jump in, but we're really excited to have launched a product last week in a new indication. And so for the first time in our fourth quarter 2021 results, we'll, of course, have both narcolepsy and the beginnings of the IH launch. So that will be a little bit of a change of just the trajectory we've seen thus far. Kim?

Sure. Great. So as Dan shared, we're excited that Xywav has achieved a market-leading adoption in narcolepsy and that we continue to see some nice solid growth through the third quarter. We've seen to date very strong adoption among high-volume oxybate prescribers and are now really increasing our focus on HCPs who have either not yet adopted Xywav or have not transitioned yet the majority of their narcolepsy patients. Among those that have transitioned, most of their patients were focusing on oxybate naive patients. While we anticipate that the adoption rates among these HCPs, and actually, we've observed will be slower than we saw in the first 3 quarters, we do remain focused on educating these HCPs and patients about the lifelong burden of high sodium intake. So we remain optimistic that HCPs will see the value in lower sodium oxybate as we see the majority of oxybate naive patients today being prescribed Xywav as opposed to Xyrem. And we're very pleased that the FDA recognized the importance of lower sodium options by granting Xywav the orphan drug exclusivity back in June and went on to state that the clinical superiority findings were that Xywav is clinically superior to Xyrem by means of greater safety because Xywav provides a greatly reduced chronic sodium burden compared to Xyrem. And then the other driving factor as Bruce just mentioned, of course, is that we launched Xywav for the treatment of IH last week, which is the first and only FDA-approved treatment for adults with idiopathic hypersomnia. And we really see this launch as a significant value driver, with approximately 37,000 adult patients out there who have been diagnosed with IH and are actually out there actively seeking treatment for it in the health care system. So our commercial teams are working to educate right now about Xywav for IH while also, very importantly, continuing to educate about the importance of transitioning narcolepsy patients to Xywav due to the benefits of the lower sodium. So specifically in IH, we're focused on executing a very targeted launch strategy that includes both robust disease education and branded efforts. And to support this strategy, we have a variety of digital and in-person efforts that are helping to demonstrate both the IH is a unique medical condition and the clinical benefits and safety profile of Xywav. So moving forward, we're going to be providing a number of metrics. First, we'll continue to provide the average number of oxybate patients. We'll continue to provide the total number of patients on Xywav. And we will start to provide the breakdown of the number of Xywav patients based on diagnosis of either narcolepsy or IH.

Your next question comes from the line of Jessica Fye from JPMorgan.

Renee, you talked about how, as the newly launched commercial portfolio matures and scales, that you expect to realize further operating leverage. Can you talk about if we should expect operating margin improvement in 2022 over 2021?

Yes. Thanks for the question, Jess. So I would say, stay tuned for 2022 guidance. As Bruce mentioned, we'll plan on giving that specific guidance in early 2022 when we're reporting our year-end results. And that would be more appropriate after we've gone through our full budget and goals process with our Board of Directors. But beyond that, I would think more broadly about, yes, as our newer products then start to mature into products that have gotten through that initial launch phase that are off to a strong start, that you should expect over time that operating margin, whether it be specific to SG&A or as we're thinking about our broader cost structure to improve.

Okay. Got it. Yes. I'm just trying to figure out if next year counts as one of the years of those launch products beginning to mature or still kind of more of an investment year?

Jess, what I would say is -- go ahead, Renee.

Yes. I'd say without giving specific guidance on what that would look like, we'll be focused on ensuring that in 2022, we're positioned to achieve our goal of having 65% of our revenues associated with those newer products, that being Xywav, Epidiolex, Zepzelca, Rylaze. And as you think about where our focus is, it's making sure the long-term growth is positioning us to be able to achieve those operating margins. Of course, with the transaction, we did say that we expected accretion in the first full year. And we've also talked a lot about investing in our pipeline. So while we're going to be focused on improving our bottom line margins, we're also going to be focused on ensuring that we're putting sufficient investment behind our R&D portfolio and pipeline, to ensure that we're creating greater strength and greater durability.

Your next question comes from the line of Jeff Hung from Morgan Stanley.

You mentioned high persistency for the Epidiolex indications. I guess from here on out, which of the indications do you see as the bigger potential drivers for Epidiolex sales? And what kind of impact do you expect going forward potentially from off-label indications?

Dan or Kim, you want to jump in on Epidiolex?

Yes. I'm happy to start and then, Kim, you can add in. But as I mentioned in the earnings call, we anticipate, especially as the COVID-19 pressures ease and based on the real-world experiences that we've had with physicians who have adopted the therapy, that there's plenty of room for patient growth across all 3 of our indications. And kind of more broadly, there's this pool of treatment-resistant epilepsy patients, 160,000 pediatric and 1 million overall, many of them are with syndromes that are not -- that have no FDA-approved therapies. And so often, the physicians are looking at the seizure types for those disorders. And given that Epidiolex has a broad range of activity across multiple seizure types and good market access to support physicians and patients in those settings, like most antiepilepsy drugs, we do think that Epidiolex will become a cornerstone of therapy across multiple seizure types beyond the indicated label. Kim, I don't know if you want to add anything?

No, I think you covered all the points well, Dan.

Your next question comes from the line of Ami Fadia from Needham.

Just more on Epidiolex. Can you give us some more color on where you are with the patent application? You indicated that you expect it to be initiated -- sorry, to be issued by the end of the year. So maybe any more color there? And then just with regards to the myoclonic-atonic seizures, why did you pick that? What was the basis on which you thought that there was applicability in that seizure type? And if you could give us some preliminary sense of what is the target market potential if it works in that seizure type?

Yes. Ami, nothing more to add on the timing of the new patent issuance and Orange Book listing. And I'm not sure the timing of that is particularly important other than, obviously, what the long-dated expiration of that patent would be. Rob, maybe you could talk a little bit about why we've elected to go into the EMAS trial next? And then Kim or Dan, you can talk about potential in that marketplace as well. Rob?

Yes. Happy to, Bruce. So first of all, it's an important unmet medical need in EMAS amongst pediatric epilepsies. And based on prior data and other seizure disorders, we think there's a high probability of working in that setting. So there will be a direct benefit to those patients. We also think it adds just evidence and broad antiepileptic activity of Epidiolex by studying a syndrome that is known to have a seizure type that is different than we currently have an indication for. And so it will complement the seizure types that we've already addressed in our indications. And as you know, doctors treat seizure types. They don't necessarily treat the underlying -- this sort of is part of the epileptic therapy. And so it provides that additional data on broad activity across seizure types. And while we wouldn't promote off-label, these are the kinds of data that physicians often look for to provide evidence of efficacy in the patients that they're intending to treat.

Yes. And just jumping in there, EMAS represents approximately 2% of childhood epilepsies, so not an insignificant disorder. But even more importantly, it rounds out our data set, which includes strong activity and combinability and safety in tonic, atonic and now myoclonic and clonic seizure types. So it's this painting the broad evidence generation across multiple seizure types that are typically seen in this treatment-resistant epilepsy population. So that, along with other studies we're considering and investigator-sponsored studies, both looking at disorders, safety efficacy endpoints and other endpoints, where we see benefit beyond seizure type or seizure reduction is part of our overall evidence plan.

Your next question comes from the line of Gary Nachman from BMO Capital.

Could you talk about the overall reimbursement and access for Xywav? How the net pricing has been trending for the narcolepsy indication? What the initial status has been for IH? How you've been managing that? And then what might change when an AG of Xyrem is available next year? How much visibility you have on that at this point? And just one other one, if I could sneak it in. Just on Sunosi, there was a big acceleration, it seems in the third quarter. So you didn't comment on that in the prepared remarks. How much of that is net pricing versus actual demand volumes?

Kim, maybe you could address both those Xywav payer dynamics now and going forward as well as Sunosi progress in the third quarter?

Sure. Yes. So with Xywav, we're very pleased that we continue to have greater than 80% commercial coverage for patients in narcolepsy. And this really sets us up well for IH. I think we've said we continue to see with the launch of IH, what we are looking to do is to see payers add basically utilization management criteria to the existing contract and coverage for Xywav, and that criteria being specific to patients with IH. In the meantime -- and we're anticipating that, that will happen as fast, if not faster than it did with the launch of narcolepsy, where our goal was. And we saw us achieve broad coverage within 6 to 9 months or so of launch. In the meantime, many patients can pursue the medical exception process and get coverage there. And then lastly, where that didn't work, we do have patient access and support programs available for those patients starting with day 1 of launch. I think your next question perhaps was about what might change in terms of the AG and our coverage situation. We feel quite confident that we will continue to enjoy strong coverage based on our conversations with payers in this space. We don't anticipate for them to really change the coverage and ultimately to put down the AG side by side with Xyrem specifically on their formulary not advantaging or disadvantaging in any way.

And then, Kim, maybe just a comment on what we saw on Sunosi in the third quarter.

Yes, sure. So in the third quarter, we saw that Sunosi sales more than doubled compared to the same period last year. And we saw prescriptions specifically increase by 8% in third quarter over the second quarter. So since launch, we've seen very encouraging reactions to the profile of Sunosi from both our physicians and our patients. And we continue to receive positive feedback from those who have actually utilized the product. Patients had a really good experience on Sunosi in terms of what they're seeing is the impact on their excessive daytime sleepiness. And these are patients who have often been quite frustrated as they rotated through other wake-promoting agents and stimulants over time. I don't have the breakdown of that growth as to what was demand and what was price. I don't know, Renee, if you have that or not.

Yes. I don't have that in front of me. But certainly, we saw gross to net stabilize a few quarters after launch as we finalized our broad access. So what you're seeing now almost exclusively represents volume growth.

Your next question comes from the line of Akash Tewari from Jefferies.

And I apologize for this question being a bit on the nose, but what is the current market penetration for Epidiolex in Dravet, LGS, TSC and other refractory epilepsies? And then maybe on guidance, it looks like full year guidance was lowered, $70 million for SG&A; R&D, about $45 million. And you talked about kind of 3 different reasons for that. How much of the OpEx decrease was spend that was supposed to occur in 2021 going to 2022 given COVID-19? And how much of that was GW integration and R&D prioritization? Can we expect a more 4Q like cost basis going forward into next year or not?

So Dan or Kim, maybe I'll ask you to talk a little bit about using our existing indications and where we are there in terms of room for growth? And then, Renee, perhaps I can ask you to weigh in on the cost side?

Yes. I mean sure. What I'll basically say is that we're pleased with the penetration rates we're seeing. I don't think we shared the specific data on that. But what we see is that there is substantial room for growth, particularly in LGS and our newest indication, around TSC. So we remain very encouraged in terms of the growth opportunity for this product across the indications.

Yes. And maybe I'll just add. And while there's some use outside of those disorders, there's clearly a lot of -- it's a very small penetration into that treatment-resistant patient population, whether it's the pediatric population of 160,000 or the 1 million overall. So again, I think the real-world experience plus data set will continue to support strong growth going forward.

Do we know what percent of sales is in the other refractory epilepsies as a percent of total sales for Epidiolex right now?

Yes. We're not providing that level of detail at this point.

And I'm happy to jump in, Dan, on OpEx. So really, the categories, of course, that I provided are where we're seeing the biggest part of the shift in OpEx. We're trying to be very thoughtful about how we integrate Jazz and GW, much of which has already been completed. And as we've prioritized some of these activities, be it on the commercial side or R&D activities, it's really focused on where we're going to get the maximum value. When we initially provided our guidance and rolled that forward in the prior call, we were continuing to learn how the operations were coming together, continuing to figure out what we needed to invest appropriately behind our combined pipeline and our commercialization activities. And we're also looking at how we should operate moving forward as a larger combined company and how to be more effective and efficient as we prepare ourselves to scale with our increased revenue growth over time. So that's largely how I would encourage you to think about the way that we've brought down the expenses. And then I would also say with respect to the implied Q4 numbers, I wouldn't immediately apply those to our future rates. As I've mentioned earlier, we'll provide specific guidance for 2022 as we report out our year-end earnings in early 2021. And then I would also just remind you, we stated in our prepared remarks that in Q4, we're launching IH. We're also initiating multiple clinical studies -- sorry, clinical studies in the quarter. And so there is some expense that's associated with taking on initiation and getting those underway.

Your next question comes from the line of Balaji Prasad from Barclays.

I just want to discuss Epidiolex a bit further. While I understand that you had limitations on access in pediatricians, the data point and interactions going down you gave is quite insightful. But what I'm struggling to understand is the lack of vaccine and how that's impacting on the ground. I'm surprised that parents with kids suffering from epileptic conditions are not accessing or getting the treatment needed. Maybe some qualitative or quantitative comments on it? And secondly, maybe just on the individual markets. Do you have a better understanding of the current market size of Lennox Gastaut or Dravet syndrome currently? What's the number of patients that are out there and penetration to tell?

Yes. On the first part of the question, maybe I'll just jump in and talk a little bit about what I've heard from parents and treaters during this period, which is parents of kids with these refractory seizure disorders are very interested in getting to better seizure control and better overall health status of their child, but they can be worried that in the process of changing meds, you can disrupt in a way that can actually bring on additional seizures during that change. And those additional seizures can, in some cases, result in needing to visit a hospital. And so we think based on conversations, again, with both parents as well as treaters, that there has been a tendency to avoid making those changes for fear of having to go into a medical environment and risk COVID with unvaccinated kids during this period. We don't think that's unique to Epidiolex as a product. We think that's more general for these treaters and these conditions generally.

Your next question comes from the line of Esther Rajavelu from UBS.

I'm going to add to the list of Epidiolex questions here. I guess for the OUS market, can you just share any early feedback from prescribers and families? I'm basically trying to get a sense for pent-up demand in the developed EU markets. And then in the U.S. among Dravet patients, can you share whether any of the newer drugs like Fintepla are used in combination with Epidiolex? And then lastly, can you give us some color on the proportion of the GW sales force that continues to be employed by Jazz and whether you've had to expand hiring efforts in the U.S. for this product?

Yes. Maybe I'll take -- go ahead, Dan.

Yes. I was just going to jump in on the ex U.S. and then the other question. But on the ex U.S. side, we've got a strong team, much like we had in the U.S. that GW had built up in the major market countries. And importantly, the gating factor, of course, is getting favorable reimbursement. And we've now achieved that in 4 of the 5 major countries. And that really opens the gate to full promotion and rollout. And in the fall, we've got the additional sort of growth going on with the 2 markets that most recently got that reimbursement, which were Italy and Spain. We're very targeted now on the fifth remaining country, which is France, which could be a very significant growth market for us. In that one, we anticipate to be launching in 2022. I think relative to other sort of orphan price branded products to have overall pricing in these major countries at greater than 70% of the wholesale acquisition cost in the U.S. is very successful and really speaks to both the market need, the product profile and the data that's been generated. So we look forward to further updates, but that definitely was a big part of our valuation of Epidiolex, was the worldwide potential for this important new therapy.

And then I'll jump in on the last part of the question -- operator, I think we're not quite done. So on the sales force, the North American business unit within GW, the Greenwich team was brought over in its entirety to Jazz. So no, there's been no reduction in that effort. Again, we're trying to build on the success that GW is having and move forward together. On the question about combination use with Fintepla, I would say, in general, we see combination use of products for these conditions. We hear good feedback about combination of Epidiolex with other agents. In terms of its side effect profile, in terms of ease of initiation of adding Epidiolex in, we hear that when patients are rotating off therapies, they often preferentially continue on Epidiolex. So I'm not sure I have lots of quantitative data on Fintepla specifically at this point. But I'd say what we hear about use of Epidiolex in general seems to be what we're hearing here as well.

Yes. Bruce, I'll just throw in a couple of proof points. I mean, as Dan shared earlier that what we're seeing in market research is that about 40% of respondents indicate they are moving Epidiolex up in their treatment algorithm. So we see that as a very good signal and believe it's underpinned by more prescribers having positive experience with Epidiolex over time and gaining experience with the product. And then the other point is just we see very strong persistence with the product. Once patients go on this product, they stay on it for a really long time. So I think both of those are data points that point to levels of satisfaction out there in the market on the part of both prescribers and patients.

Your next question comes from the line of Ronnie Gal from Bernstein.

Just about Rylaze, the pick for the Erwinaze market was around $200 million. It came down to around $170 million during the year when there was not enough supply. And I was kind of wondering, as you now have more information with the Rylaze launch, where do you see the end of the kind of initial ramp-up where you simply replace Erwinaze versus where you'll have to start building the demand further with some marketing? Just kind of help us look at the shape of that product for the next couple of years.

Kim, Dan, maybe I could ask you to jump in on just the overall market opportunity with Rylaze moving forward, both U.S. and ex U.S. as well?

Yes. No, it's a good question, Ronnie. And I think we don't quite know how big the market could become because as you know, as we ran into those supply constraints more than 5 years ago, we pulled back all promotional efforts, all medical education initiatives. And we had to put in fairly strict ordering policies, where it was on a patient-by-patient basis and institutions really had to triage which patients got the therapy. So I think in addition to growing back the market fully, there's also the retraining of physicians and caregivers having the opportunity, that at the slightest hypersensitivity reaction, you don't continue to read challenges they may have during shortages and so risk anaphylactic shock. But you give the opportunity to switch more quickly to a non-E. coli-based asparaginase. And importantly, with Rylaze, given that we had a year's supply at the time of launch and a very robust supply chain, the institutions and COG who worked with us on the study have great confidence that they can look for silent inactivation, look for that hypersensitivity reaction and really grow the market. We said, in addition to that, there's an opportunity to go more fully into adolescent young adult, which is -- could be sizable. And there's more drug use there because it's on a per weight basis. And then there's geographies like Japan that have an unmet need, where the product never got introduced because of supply and quality issues and Rylaze is in a very different situation. So I look forward to giving sort of further color to exactly what that potential could be, but we do see it as a growth driver for our immediate future.

Your next question comes from the line of Brandon Folkes from Cantor Fitzgerald.

I just want to circle back to Xywav, the goal of having 50% of -- or more than 50% of patients on Xywav by 2023. You seem to be well on your way there. But maybe can you just talk about how dependent achieving that goal is on IH from here?

Yes. Maybe I'll jump in on that one and just say we picked a date a little further out in this metric of 2023 because we specifically wanted to address what we think would happen to Xywav, even in the face of competition from a generic or branded higher sodium oxybate. So it wasn't so much just a continuation of the existing trend and where we'd get to but where we'd still be after potential other entrants to the marketplace. So hopefully, that makes that metric a little bit clearer to you. We do see a very significant opportunity in idiopathic hypersomnia with no indicated treatments prior to our launch last week of Xywav, patients who really need effective therapy to treat excessive daytime sleepiness but symptoms even beyond that in IH. This is a new launch. No product has been promoted in this space before, so we do have some education to do. It's also a little unlike Xywav in narcolepsy, where many of our Xywav patients were coming over already titrated up and on an effective dose of Xyrem and then moved over dose for dose, Obviously, naive IH patients coming on will be titrated up on dose over time. So a little bit different dynamic in terms of uptake. But we certainly see that as a significant opportunity, potentially over time, rivaling the size of narcolepsy in terms of potential overall patients with better diagnosis and treatment. And we're not predicting that in the near term, but certainly, that opportunity is there for a really substantial improvement for a number of patients with IH.

Your next question comes from the line of David Amsellem from Piper Sandler.

On Epidiolex, with the clear evidence of some off-label use beyond the 3 indications in the U.S. label, I was wondering if I could get your thoughts on payer contracting and just trying to get more aggressive with payers such that you could facilitate less in the way of utilization management. How do you think about that? And then I'm sorry if I missed this, but are you disclosing or did you disclose the ex U.S. contribution from Epidiolex during the quarter? If you can disclose that, that would be helpful, too.

Yes. David, I'll take the second half of your question. So I don't think we've provided a specific U.S. versus ex U.S. breakdown product by product. But we're really excited about how the Epidiolex launch continues to roll out in Europe across markets, both in terms of pricing and access we're receiving, but also how our teams are performing in the early periods of these launches and see this as a really significant opportunity relative to the U.S. over time. On payer coverage and what that means in terms of utilization of the product, Kim, could I ask you to weigh in on that?

Yes, sure. So right now, we're very pleased that Epidiolex enjoys a 98% commercial coverage across commercial lives. And yes, as you suggest, we are -- we do see it as a strategic priority and we are focused on trying to broaden that coverage. And so that coverage is in the indicated lives that we have. We are working with payers to try to broaden that coverage. And we've been very successful on that front in the Medicaid space and are continuing to try to get there in the commercial space.

Your next question comes from the line of Ken Cacciatore from Cowen & Company.

Bruce and team, sorry, I'm really late getting on the call. But I wanted to go back and ask about your reference to the Epidiolex composition of matter-like patents. Can you get into a little bit of nuance on these patents, more in the specificity of them? Was this being worked on for a while at GW part of your original diligence and you are aware of them, something that maybe you help them with? Can you give a little more specificity around them?

Yes. Ken, this is something we were aware GW was working on. I think GW did make reference to it publicly on a couple of occasions. We're getting more specific now just about timing. I think we'll wait to say more until that patent is visible to everyone and we can talk about it more specifically. I don't think it makes sense to do so right now. But obviously, what we're trying to communicate is that the IP continues to broaden, that it has different pieces to it and can have different expiration dates, in this case, out to 2039. So more to come when we have more in the public domain. But just wanted to make sure people are focused both on the near-term opportunity for Epidiolex in the U.S., in the ex U.S. launch that's underway, in potential new indications in broader use but also recognize that we view this as a very durable asset.

Your next question comes from the line of Greg Fraser from Truist Securities.

What percentage of new to oxybate patients are being prescribed Xywav versus Xyrem? You mentioned a large majority, but can you be more specific? And what are the reasons that you hear as to why oxybate naive patients are still prescribed Xyrem? Is it access-related? Physicians just aren't aware of Xywav yet? Any color on that would be helpful.

Yes. Greg, I particularly like the end of that question. That's always a good question when you've got a better therapy, a superior therapy available. Kim, do you want to talk a little bit about oxybate naive patients and what we're seeing and what might be driving that?

Yes. So a couple of reasons. So one is that while we have very strong commercial coverage, over 80% in commercial patients, there is still a portion of patients that don't have immediate access to Xyrem. So that's one of the reasons. But really, the biggest reason out there right now is that health care -- Xyrem is a -- patients love their Xyrem and HCPs love Xyrem. And so the #1 reason we're hearing is that -- I'm sorry, that's on the transitions that patients are satisfied with Xyrem. But we still have some work to do, as I said before, with some segments of physicians and really motivating them to adopt Xywav based on the low sodium. But we feel very confident that we're making strong progress there and that these smaller segments of HCPs will eventually move along that continuum and adjoin the rest of the high-volume oxybate prescribers, who really do see the benefits of going with a product that lowers that sodium burden.

Your next question comes from the line of Navann Ty from Citi.

First, a follow-up on the lower-than-expected SG&A and R&D. Are you able to tell us which products will be impacted by the lower selling and R&D expenses or which will be prioritized? And then my second question is on your latest thoughts on the litigation versus Avadel FT218 after the action date was delayed?

Yes. I'll take the second part of your question first and just say nothing additional to say on litigation ongoing with -- around FT218. Obviously, we have existing IP, which is -- you've seen more of over time and we'll defend that IP as we see fit. On the expense side, what we were lowering here was guidance for the full year in terms of overall spending across 2 organizations that just came together a few months ago, as well as our expectations, in particular, as we have more visibility late in the year. Renee, I'll let you weigh in on what else you want to disclose there.

Yes. Actually, I think you've covered it. And I think just to address the specific question in terms of how does this look by product, if you think about the commercial side, obviously, we have multiple product launches we've been moving forward. And the impacts of COVID and that lack of in-person interaction that many companies had expected to grow in Q3 and Q4 hasn't been impacted by COVID. So it's not specific to one product necessarily, other than in thinking about where we're really putting our commercialization dollars right now. And that is to support the new product launches that we've talked about, representing the 65% of revenues that we expect in 2022 from those products that have been launched or acquired since 2019, so Xywav, Epidiolex, Zepzelca, Rylaze and Sunosi.

This concludes our question-and-answer session. I would now like to turn the conference back to Mr. Bruce Cozadd for the closing remarks.

Yes. Thanks, operator, and thanks to all of you for the good questions. I'll just say we're really happy with where we are this year in terms of kicking off our fifth launch, continuing progress early in the launches of Rylaze and continuing to progress Zepzelca. A flurry of activity at the end of the year, initiating some mid- and late-stage trials we're really excited about. You saw our delevering, in the first 5 months a half turn, which I think is really excellent progress. And then the ability to bring more of this to the bottom line as we operate as a combined, more agile company. So really excited about where we're headed and what's in front of us for 2022. We look forward to speaking with many of you at the upcoming Jefferies London and Evercore investor conferences. And I'd just like to recognize all our Jazz colleagues for their efforts, which have led to delivering these new therapeutic options to patients and to thank our partners and shareholders for their continued confidence and support and thank everyone for joining us today. Stay well, everyone.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and have a wonderful day. You may all disconnect.