Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to Xywav in IH launch. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your host, Andrea Flynn, Vice President of Investor Relations. Please go ahead.

Thank you. Good afternoon, everyone, and thank you for joining us today for a discussion on Xywav for idiopathic hypersomnia as we approach our commercial launch. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also reference the press release we issued on August 12 regarding FDA approval of Xywav for the treatment of adults with IH. On the webcast today are Bruce Cozadd, Chairman and Chief Executive Officer; Dr. Rob Iannone, Executive Vice President, R&D and Chief Medical Officer; and Kim Sablich, Executive Vice President and General Manager, North America. We're pleased to have external sleep expert, Dr. Richard Bogan, joining us today. Dr. Phil Jochelson, Neuroscience Therapeutic Head; and Dan Swisher, President, will participate in the Q&A portion of the webcast. Moving to Slide 2. I'd like to remind you that today's webcast includes forward-looking statements, which involve risks and uncertainties that could cause actual events, performance and results to differ materially. We encourage you to review the statements contained in our latest SEC disclosure document, which identify certain factors that may cause the company's actual results to differ materially from those projected. We undertake no duty or obligation to update our forward-looking statements. I'll now turn the call over to Bruce.

Thanks, Andrea. Starting on Slide 4, I'll remind everyone that FDA approved Xywav for the treatment of idiopathic hypersomnia in adults on August 12 of this year. Xywav is the first and only approved therapy to treat idiopathic hypersomnia, or IH, and we're excited to be able to deliver a much-needed therapeutic option to patients living with this very serious and disruptive sleep disorder. I'm also very pleased to announce that we are in the final days of preparing for the commercial launch of Xywav for IH, which we expect to initiate in early November, just a few weeks from now. Jazz has been a leader in sleep medicine for the past 2 decades, and bringing Xywav to people with idiopathic hypersomnia allows us to deliver on our purpose to innovate to transform the lives of patients and their families. In the case of IH, we are serving patients who have not had an FDA-approved treatment option until now. As you'll hear later in the presentation, robust efficacy data from our Phase III clinical trial demonstrated statistically significant and clinically meaningful benefits of Xywav for the treatment of IH. The approval and launch of Xywav for IH means Xywav will now be available to a significant number of patients who previously did not have access, with approximately 37,000 patients in the U.S. already diagnosed with IH and actively seeking care. Importantly, Xywav has been shown to help with other aspects of IH patients' daily activities beyond addressing certain symptomatology and is indicated broadly for the treatment of idiopathic hypersomnia. This is also a significant milestone for our company. Our oxybate franchise has been and will continue to be a pillar of Jazz's value. Our team successfully executed on our strategy to first bring lower-sodium Xywav to people with narcolepsy who experience excessive daytime sleepiness and/or cataplexy. This represents a meaningful advance for patients. And FDA has recognized Xywav as clinically superior to higher-sodium Xyrem in the treatment of narcolepsy. And now we have the opportunity to bring Xywav to a new disease area, idiopathic hypersomnia, where there is a high unmet need and a significant market opportunity, and where oxybate therapy has not previously been utilized. A combination of regulatory exclusivity and patents out to 2033 make this a durable, long-lived franchise. Our agenda is outlined on Slide 5. The main objectives of today's discussion is to provide a clinical overview of idiopathic hypersomnia and how this condition impacts patients, review the data that supported our FDA approval and discuss our commercial strategy for Xywav in IH. I'll open today's call with a brief discussion on how Xywav for IH will contribute to our oxybate business. We have the privilege of being joined by Dr. Richard Bogan, who will provide background on the clinical presentation and treatment paradigm for idiopathic hypersomnia as well as review key findings from the Phase III trial that supported our sNDA submission to FDA for approval. Dr. Bogan is a pulmonologist and sleep disorder specialist, serving as President of Bogan Sleep Consultants, and previously as the Chairman of the National Sleep Foundation and Chief Medical Officer of SleepMed, the largest sleep diagnostic company in the U.S. He is also an associate clinical professor at the University of South Carolina School of Medicine, an associate clinical professor at the Medical University of South Carolina in Charleston, South Carolina. He was a clinical investigator for the Xywav of IH Phase III trial and has been an author on presentations detailing the trial findings. Our Chief Medical Officer, Rob Iannone, will share additional analyses we have completed on the Phase III data as well as review key aspects of the product label. Executive Vice President and General Manager of North America, Kim Sablich, will follow with an overview of our commercial strategy, and then we'll open the webcast for Q&A. Turning now to Slide 6. Over the past several years, our execution on multiple fronts, including clinical development, commercialization and business development, has positioned us to deliver long-term value for shareholders. We're excited about the future growth opportunities across our commercial portfolio, which is complemented by a robust pipeline of late and mid-stage compounds. We view our oxybate franchise as one of the company's value drivers, along with our oncology franchise and Epidiolex. We previously announced a corporate objective of completing 5 key commercial launches in 2020 and 2021. With the launch of Xywav for idiopathic hypersomnia in November, we will accomplish that goal. I'm proud not just of this achievement, but also the level of excellence we've maintained with respect to our execution as evidenced by the best-in-class adoption for Xywav in narcolepsy, the successful launch of Zepzelca, which is rapidly becoming a standard of care for second-line small cell lung cancer patients, and more broadly, the performance of our entire commercial portfolio. This slide also highlights the significant transformation our business has overgone over the past several years. If we look back at the second quarter of 2020, Xyrem represented approximately 80% of our revenue. Now we have a diversified portfolio of commercial products and are tracking to meet our goal of generating 65% of revenue in 2022 from these recently launched or acquired therapies. As we noted previously, we are investing in the launch of these products, which are long-lived assets with broad IP protection, to drive growth and realize their full value. In addition to the progress we've made on the commercial front, I want to point out that we fundamentally reshaped our R&D organization and expect we will continue to build on the recent successes of Xywav and Rylaze, both of which we brought from concept to commercialization through in-house efforts. Slide 7 outlines both the history and our forward-looking view of the oxybate franchise. There are 3 distinct areas that contribute to the overall durability of oxybate. First, continued adoption of Xywav in narcolepsy with EDS and/or cataplexy; second, the growth of Xywav in adults with idiopathic hypersomnia; and third, legacy Xyrem sales coupled with meaningful royalties from authorized generics of Xyrem, which increased significantly over time. Over the past 15 years, we've established oxybate as the standard of care in narcolepsy. First, with the introduction of Xyrem, and now we're continuing to advance patient care with Xywav, a lower-sodium oxybate. For patients with narcolepsy, for whom oxybate is a lifelong therapy, a 92% reduction in sodium with every dose of medicine is clinically meaningful in managing the known risk for cardiovascular disease. According to FDA, which published a summary of clinical superiority findings for Xywav in the treatment of narcolepsy, and I quote, "Xywav is clinically superior to Xyrem by means of greater safety because Xywav provides a greatly reduced chronic sodium burden compared to Xyrem." FDA's summary also stated that the differences in the sodium content will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated. We believe this is something that physicians and patients value, with approximately 5,100 narcolepsy patients benefiting from Xywav therapy as of the end of the second quarter. Along with FDA findings of clinical superiority, we received orphan drug exclusivity, or ODE, for Xywav in narcolepsy, which runs through July 2027. We also have a patent estate that includes multiple Orange Book-listed patents, which extend into 2033. The approval of -- in IH offers an opportunity to make Xywav available in a new patient population that can benefit from therapy. There are approximately 37,000 patients with idiopathic hypersomnia in the U.S. actively seeking care. In addition to 5 years of exclusivity based on new chemical entity, or NCE, designation, Xywav in idiopathic hypersomnia is eligible for ODE, and we have patents on the use of Xywav for IH extending to 2033. Finally, we have meaningful economics on authorized generic versions of Xyrem, which will be indicated for narcolepsy, but not IH. Oxybate is a core component of our value, and I want to reiterate that we expect the majority of all oxybate patients will be on Xywav in 2023, which accounts for both branded and generic oxybate competition. It also factors in that Xywav is the only oxybate therapy approved to treat IH. Given these changing dynamics in the oxybate marketplace, beginning with our fourth quarter and year-end reporting, we will be updating our quarterly metrics for our oxybate franchise. We will continue to provide the total average number of oxybate patients as well as the total number of patients benefiting from Xywav exiting each quarter. In addition, we will share the breakdown of the number of Xywav patients based on their diagnosis of either narcolepsy or IH. Turning to Slide 8. For nearly 2 decades, Jazz has been advancing the treatment of sleep disorders. Xywav highlights our philosophy of putting patients first. We prioritized development of a lower-sodium oxybate because for patients taking medication for chronic diseases, sodium matters. We are recognized by health care providers, advocacy organizations and patients as a leader in sleep science, and we are grateful for the trust they have put in us. With the best-in-class launch of Xywav in narcolepsy underway, we are now excited to also be able to deliver the first FDA-approved treatment for idiopathic hypersomnia to patients in desperate need of therapeutic options. Delivering the first therapy indicated to treat IH reflects our commitment to addressing the needs of underserved patients. I'm very proud that our team has brought Xywav from concept through to commercial availability, first in narcolepsy and then quickly following in idiopathic hypersomnia, demonstrating the value we are creating for patients. I want to take this opportunity to thank the investigators, office staff and study coordinators who contributed their time and talents to advancing this new therapy for patients with IH. I also want to recognize the Jazz R&D team who first identified a true patient need and then worked to deliver a groundbreaking therapy that can help adults with idiopathic hypersomnia. Most of all, I want to express our gratitude to the IH patient community for their contributions to the development of Xywav to treat this debilitating sleep disorder. We've had the opportunity to collaborate with patient organizations to better understand the challenges that patients with idiopathic hypersomnia face, and we'll continue to work together to address those needs. We've also had the privilege to hear from patients with IH directly, and our team has certainly been inspired by their stories. We're excited about the potential of Xywav to provide patients with a much-needed therapy that we believe will become a standard of care for the treatment of idiopathic hypersomnia. It's now my pleasure to introduce a brief video featuring Casey and Cindy, who are participants in our idiopathic hypersomnia clinical trial. We're very appreciative that they were willing to share their stories with us. I hope that Casey and Cindy's experience provide you with a perspective on how idiopathic hypersomnia can impact someone's life and what appropriate and effective therapy means to them. For those of you on the webcast who have the slide presentation in full screen view, you will need to exit out of full screen to see the video on your screen. Operator, please start the video. [Presentation]

Our thanks, again, to Casey and Cindy. While our team can discuss the patient need for new idiopathic hypersomnia therapy, no one can articulate the impact of this disease more than someone who experiences it every day. Now I'm very pleased to introduce Dr. Richard Bogan, who will provide an overview of idiopathic hypersomnia, including his perspectives as a physician who treats patients with IH. He will also review key findings from the Phase III Xywav idiopathic hypersomnia clinical trial. Dr. Bogan, over to you.

Thank you, Bruce. Hope you can hear me all right. I'm a little bit nervous. I'm used to doing Zoom calls where I can see everybody. But anyways, let's talk about central hypersomnias with a specific reference, obviously, to idiopathy hypersomnia. This has -- this is a disorder much like the other central disorder of hypersomnia called narcolepsy because it causes excessive daytime sleepiness. So the primary symptom is excessive daytime sleepiness, but it's different. The diagnostic criteria requires that the patient be sleepy, but they also tend to have sleep inertia. They have a lot of trouble awakening in the morning. The brain is very slow to awaken -- I'm referring to Slide 11, by the way. The brain is very slow to awaken in the morning. They take naps. They take long naps in the day. And when they awaken from the nap, they don't feel very rested. Many of these individuals are long sleepers. When you talk to them, they all sleep 11 hours or more per day. So they spend a lot of time sleeping or desiring to sleep. They have some other symptoms, some autonomic complaints, not always, but headache, orthostatic disturbance, some temperature dysregulation and maybe Raynaud's Syndrome, which -- where they have cold hands when they're exposed to cold. We don't know exactly what the physiology is. There are a lot of speculations, including speculations about GABA, a neurotransmitter, which is open for discussion. The onset is typically in young females often before the age of 30, and many of them actually are treated for depression, but it's more prevalent amongst women. There are diagnostic challenges because individuals who are sleepy have other associated symptoms, including fatigue and executive dysfunction and mood changes. So many times, they may be mistaken for that. But idiopathic hypersomnia is a chronic disorder. It usually does not go away, but there are some patients who have spontaneous remission. And again, I'm on Slide 12. So let's contrast idiopathic hypersomnia with narcolepsy on Slide #13. Narcolepsy has a different pathophysiology. And as you know, there's type 1 and type 2 narcolepsy. Type 1 has cataplexy. And those individuals oftentimes have disrupted nocturnal sleep with what we call REM dissociative symptoms. So they may have this very vivid colorful dreams, and awaken from the dreams with paralysis, brief paralysis, but they may hallucinate or think the dream is happening. And of course, they have cataplexy, which are episodes of muscle weakness with stronger motion, laughter. So they're awaken, they laugh. It's something they feel suddenly weak. And if severe, they could collapse or sort of melt to the floor. Narcolepsy Type 2 does not have cataplexy, and we see some reduction in the REM dissociative symptoms, but they can still have those REM dissociative symptoms. They normally don't have much sleep inertia, type 1 certainly. If they take naps, they can take a brief nap and feel better, but it's not enduring. They still have difficulty with sleepiness that recurs. Whereas the idiopathic hypersomnia are different. These individuals, as I said, they are sleepy but they tend to be long sleepers. They have a lot of sleep inertia. Naps are not very restorative. So they clearly are a different phenotype. The data from -- I'm on Slide 14, has actually been presented to our peers. So the pivotal trial data has been presented as well as some of the data on the open-label extension has been reported to the American Academy of Neurology, which is coming up as a virtual meeting at the SLEEP 2021 meeting, and pending publication. So we have had the chance to present some of this data to our peers and hear their response. Now let me talk about the study trial. This is an important study, Phase III design, on Slide #15. In this particular trial, we took individuals who met the diagnostic criteria for idiopathic hypersomnia. Some of them actually were treated off-label with Xyrem, and some are actually on Xyrem plus stimulants, and some are already on stimulants because we had no FDA-approved drugs, but we did have principles of treatment from our academy, the American Association of Sleep Medicine (sic) [ American Academy of Sleep Medicine ] gave us some criteria for treatment. So some of the patients were on stimulants but some were naive. This is the largest study that's been done in a well-controlled, well-designed study because these patients are pretty profoundly sleepy. And I call this a maintenance of effect. So we had an open-label treatment titration period. So as investigators, we could initiate Xywav. We could adjust the dose to response and tolerance until we reach a stable-dose period. And then when they're on this stable-dose period, we actually use that as the baseline for 2 weeks, and we ask them how sleepy they were, and we use some other parameters, but the Epworth score was the primary outcome measure, how sleepy are you? The Epworth score gives us an objective measure. My Epworth score is 6. If I'm over 10, I'm sleepy. So we use that as an indication of how sleepy these individuals are. We also had the idiopathic hypersomnia severity scale, which is a new scale and looks at parameters or aspects of quality of life and sleep and sleep inertia that's very specific for idiopathic hypersomnia, and we use Patient Global Impression. And I'll show you another one as far as sleep inertia. But what happened after they were on stable-dose periods, then we blindly transition individuals to a placebo solution that looked and taste like Xywav or continued on Xywav, and we did that for 2 weeks and then asked them how sleepy they were. And I'll show you that data in just a moment. But importantly, after that 2-week period of time, blinded, we had a chance to see if there is a statistical signal comparing Xywav to placebo. And then we had an open-label extension period, which gives us some idea of long-term efficacy and safety of the use of Xywav in these individuals, and that was, as you can see, 24 weeks. So that was the study design. Let's look at the results. And looking at Slide 16, this is a very important slide because as you can see, 10 is considered relatively normal as an Epworth score, but you can see these individuals were typically above 15. And as you initiated Xywav at week 1 and then we titrated to effect. So we started at typically 4.5 grams and then titrated. You can see when they reached the stable-dose period, the Epworth score is now normal, which is amazing to me clinically because sleepy people are hard to get to a normal period. But they remained stable in the stable-dose period, you can see in the blue area, the Epworth score remained within normal limits. And then when you randomized them and looked at them 2 weeks later, you can see that the individuals who were randomized to the placebo group, the Epworth scores went up. They were more sleepy compared to the ones who remained on Xywav, again, blinded. And of course, when you use a statistical -- this is a predefined endpoint, and the statistical analysis clearly shows a major difference here that is statistically significant out of p-value that you can see is 0.0001. So again, a signal there that the Xywav certainly improved the sleepiness in these individuals in a double-blind fashion. When you go to Slide 17, this is asking the patients, "All right, what is your impression of your change when you were randomized to placebo or stayed on Xywav and compared to that stable-dose period?" And what we saw is in the Xywav, individuals, these individuals showed very much or much improved or no change in comparison. But when you look at the individuals who were randomized to the placebo group, 88% of the individuals showed they got worse. So again, an important signal from the patient perspective that there is a big signal. Again, this is clearly clinically relevant and significant that these individuals were much worse based on the Patient Global Impression. Going to Slide 18 in the trial, we looked at the idiopathic hypersomnia severity score, and we consider anything below 22 on that score as showing a good therapeutic effect. And as you can see, these individuals on the scale score were well above 30. And then when we put them on Xywav in the stable-dose -- or not stable-dose, but the titration period, you can see the time course of improvement in week 1, week 4 and week 8, they reached a stable-dose period in the light blue period, you can see the score certainly reduced below that 22 level. And then when we randomize them to the double-blind withdrawal period, again, those that were randomized to the placebo, you can see that the score increased in the placebo group, whereas it remained stable in the Xywav group. So again, when you do -- and this is, again, a predefined endpoint statistically, you can see there is a significant difference in the Xywav compared to the placebo group at the 0.0001 level. Again, statistically significant. And when you go to the sleep inertia group, we looked at a visual analog scale. So we asked the patients at baseline, tell us how hard it is for you to awaken in the morning? And many of these patients will tell you, they'll set multiple alarms across the room or loud alarms. It's just hard for them to awaken in the morning. Their brain -- and it takes a long time for them to awaken. They're foggy in the morning. So we asked them to put this on a visual analog scale where 100 is just very severe, and their score was 54. There's no normative data on this, but we were looking for a change. And what you saw over the stable-dose period that these individuals said, I can awaken better. On the visual analog scale, I improved. And then when you went to the double-blind randomized withdrawal period, you can see that the placebo group again worsened. There was no rebound. They didn't get worse than they were at the baseline, but they did get worse. And again, that was statistically significant, highly significant at the 0.0001 level. So again, these are all signals blinded that indicated that there was a significant difference. And of course, that's on Slide #19. Sorry about that. Now we go to Slide 20 about the adverse reactions. Was anything unexpected this being an oxybate molecule? And the side effect is very similar to Xyrem in terms of all the oxybate molecule. Nausea was one, headache, anxiety, some dizziness, insomnia is interesting with some sweating and vomiting. And you can see these -- nothing popped up that was unexpected compared to the oxybate. And then when you look at any adverse event that occurs during a research trial, we're going to capture that and report it. And so we looked at adverse reactions that had a greater than 2% of patients treated with Xywav in the open label and stable-dose periods in the study. So this is a way of looking at potential side effects. And I typically tell my patients, headache, dizzy, nausea, anxiety or things I want you to let me know about. Those are the ones to be considered amongst the other ones. What about the serious adverse events? There were 4 participants who reported serious adverse events. And none of these were thought to be related to the drug. One was rhabdomyolysis in a fellow who worked out aggressively, kidney stone, some noncardiac chest pain. But again, these were not related to the investigative drug or to placebo. There were 17 participants who reported treatment-emergent adverse events, 11%, that led to discontinuation, and the discontinuation occurred -- could occur at any point during the study, open-label titration or stable-dose period. But as you can see, anxiety, 4; insomnia, 3; nausea, 3; and confusion, again, things that we see with oxybate molecule as a potential side effect. So Slide 22 really is -- are the key takeaways. This was a well designed, I would say, compassionate or empathetic study design because these individuals are very sleepy. And the patients who are entering the study had baseline excessive sleepiness as you saw in the Epworth score. And the study met the primary endpoint, which was an improvement in the sleepiness based on the Epworth score with a statistically highly significant value of the 0.0001 Xywav versus the placebo. And the key secondary endpoints were important. The Patient Global Impression. The patients told us that Xywav made them better. When they were randomized to the placebo, they got worse. And importantly, this new scale that is specific for idiopathic hypersomnia, the Idiopathic Hypersomnia Severity Score, showed improvement with Xywav, and then worsened when they were randomized to the placebo group. And of course, we have that exploratory endpoint with the visual analog scale looking at sleep inertia because these individuals really complained of a lot of sleep inertia. In the end, the safety profile of Xywav, there are no new safety signals. So with that, Bruce, I will stop and turn it over to Robert, I guess.

Yes, Rob, take it away.

Thank you so much, Dr. Bogan. Thanks, Bruce. Dr. Bogan, that was a great overview of where we are today in treating idiopathic hypersomnia and the potential for Xywav to address a critical unmet patient need. I'll begin my comments on Slide 24. Xywav is not only a drug we advanced from concept to commercialization, as Bruce mentioned earlier, it's also one where we again demonstrated our commitment to patients with sleep disorders. In the case of IH, our experienced R&D team identified a true patient need, determined that Xywav had a high probability of having a clinically meaningful effect and then designed and executed a development program that resulted in getting an FDA-approved therapy in the hands of patients. As Dr. Bogan noted, the findings in our trial were statistically significant and clinically meaningful across objective measures and patient-reported outcomes. Given the robust observed effects, we are excited that adults with IH will now have access to Xywav. I'm very proud that Jazz prioritized this program and thankful to our external partners who contributed to the clinical trials, and especially thankful to patients and families who participated in the clinical trials. We are pleased that FDA recognized the need for patients and granted both fast track designation and priority review. All of this enabled us to run a very efficient development program and deliver Xywav to patients with IH on an accelerated time line. I'll be presenting several additional data analyses that underscore the clinical benefit of Xywav for IH. Before we go to the data, I want to introduce a brief video that shows the impact of idiopathic hypersomnia. As a preview, the individual featured in the video has IH. He has profound difficulty waking, and staying awake despite sleeping for long periods, including naps, which are hallmarks of idiopathic hypersomnia. This, despite being on a wake-promoting agent. For those of you on the webcast, who have the slide presentation in full screen view, you will need to exit out of full screen to see the video on your screen. Operator, please start the video. [Presentation]

That's a powerful example of how debilitating idiopathic hypersomnia can be. Earlier in the webcast, Dr. Bogan provided an overview of the key findings in our Phase III clinical trial, Xywav in idiopathic hypersomnia, which showed a robust treatment effect for Xywav in patients with IH. Beginning on Slide 26, I'm going to expand on that discussion with several important analyses from the clinical trial. As Dr. Bogan noted, our clinical trial showed meaningful improvements in 3 separate and distinct endpoints. The Epworth Sleepiness Scale, ESS; Patient Global Impression of Change; and the Idiopathic Hypersomnia Severity Scale, IHSS. On the next few slides, I'm going to focus specifically on ESS and IHSS. So I think it's worth providing some additional background from those diagnostic tools. The Epworth Sleepiness Scale measures the general level of daytime sleepiness. It's a well-validated patient-reported scale that asks the respondent to rate his or her propensity to doze or fall asleep during 8 common daily activities to determine the overall level of daytime sleepiness. Propensity for dozing is rated for each situation on a 4-point scale, from 0 indicating would never doze, to 3, indicating high chance of dozing. Adding the scores for each of the 8 questions yield a total score of 0 to 24. An ESS score greater than 10 suggests excessive daytime sleepiness, or EDS. An ESS score of greater than 16 suggests a high level of EDS. For reference, the baseline mean ESS score of patients in our Phase III trial was 15.7. So these patients had significant disease burden. This was despite the majority of patients being treated with wake-promoting agents, traditional stimulants or other therapies to address their IH symptoms. The Idiopathic Hypersomnia Sleep Scale (sic) [ Idiopathic Hypersomnia Severity Scale ], IHSS, is also a well-validated patient-reported scale, which is composed of 14 questions made up of 5 focused nighttime sleep symptoms and sleep inertia and 9 focused on daytime sleepiness or performance. Items are scored on either 0 to 3 or 0 to 4 scale, with a total score that can range from 0 to 50. A score of less than 22 is typical for people without a sleep disorder. Higher score indicates more severe and frequent symptoms associated with idiopathic hypersomnia. The mean IHSS score for patients in our Phase III trial was 31.6 baseline. Similar to ESS baseline scores, the IHSS score for trial participants indicated a significant level of disease burden. Dr. Bogan discussed the patients who remained on Xywav during the double-blind randomized withdrawal portion of the trial, maintained the improvement in their ESS and IHSS scores, while those switched to placebo worsened. On Slide 26, there is a sub-analysis of those measures comparing participants who have long sleep time and those who do not, a common way of characterizing patients with IH. In this trial, approximately 20% of patients were identified as long sleepers, defined as sleeping more than 11 hours per day. The remaining 80% participants were defined as non-long sleepers. A key takeaway here is that on both the ESS and IHSS there were clinically meaningful differences between the Xywav group and placebo group in participants with long sleep time as well as those without long sleep time. These subgroups had comparable baseline severity and comparable improvements after Xywav treatment, showing that Xywav was efficacious regardless of sleep duration. Slide 28 (sic) [ Slide 27 ] displays data from a sub-analysis looking at trial participants stratified by prior treatment history. As these graphs clearly show, participants had similar results on Xywav regardless of whether or not they were taking other medications, such as wake-promoting agents, to treat their IH symptoms. The consistency across both ESS and IHSS measures indicates that, one, treatment being used to address IH symptoms prior to entering the trial do not appear to be particularly effective since the 2 groups' baseline scores are comparable; and two, we have the opportunity to improve outcomes for patients regardless of their prior treatment regimen. Please note that very few patients, 6 out of 154, have been treated with Xyrem prior to study entry. Now moving to Slide 28, there are graphs showing improvements on 3 measures assessed on the IHSS in the Phase III trial. While these measures speak to waking, general health and intellectual function, improvements observed in these 3 domains were representative of the improvements we saw across all 14 measures on the IHSS. Seeing improvement consistently across all 14 measures on the IHSS speaks to the overall patient experience on Xywav. Each of these measures, difficulty waking in the morning, impact on general health and impact on intellectual functioning, track patients' responses from the IHSS questionnaire over the course of the trial. The questionnaire was administered at the start of the Phase III trial on day 1 or at baseline, which is the bar at the far left of each measure, and then again at several time points throughout the trial with the final administration at the conclusion of the double-blind randomized withdrawal period. What you see from day 1 through the end of the stable-dose period, which is labeled SDP on the graph, is that scores steadily improved with Xywav therapy. Then to the right of the dotted line on each graph, you see the results of patients when they are randomized to either stay on therapy, this is noted as LXB, or receive placebo labeled PBO. As is clear across all measures, the group remaining on Xywav maintain their improved scores, while there is a worsening for patients who are randomized to placebo. The IHSS is an important tool for us to assess the clinical meaningfulness of the therapy. Across all 14 IHSS measures, we saw a clinically meaningful reduction in symptom frequency, intensity and consequences with Xywav treatment. On Slide 29, we'll review the Xywav labeling for IH. I think it is critical to highlight the indication statement, which is for the treatment of idiopathic hypersomnia in adults. While straightforward, this is a broad indication that represents the totality of the data from our clinical trial across multiple different assessment measures, including the ESS, Patient Global Impression of Change and the IHSS. Our Phase III clinical trial data showed statistically significant and clinically meaningful benefits across the primary and key secondary endpoints, and this is reflected in the indication statement. The safety profile of Xywav in idiopathic hypersomnia is comparable to the safety profile in narcolepsy, and we did not observe any unexpected adverse events. Xywav has a boxed warning for risks associated with CNS depression and potential for abuse and misuse, and has a REMS program that includes distribution by a single specialty pharmacy. Based on known risks associated with oxybate therapy, oxybate is contraindicated for use in combination with sedative-hypnotics, in combination with alcohol and in patients with succinic semialdehyde dehydrogenase deficiency. The most common adverse reactions in adults with narcolepsy or IH occurring at a rate equal to or greater than 5% were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue and tremor. I will conclude my remarks on Slide 30. As you've seen and heard through the course of today's presentation, idiopathic hypersomnia is a debilitating sleep disorder that has a profound impact on people living with this condition. As a longtime leader in sleep, we are pleased that we can now provide this first and only FDA-approved treatment for IH in adults, the patient group that has been underserved for far too long. On this slide, we've included a statement from the FDA press release on the approval of Xywav for IH that encapsulates many of the points we've been discussing today. To quote the Deputy Director of the Office of Neuroscience at FDA, "Idiopathic hypersomnia is a lifelong condition, and the approval of Xywav will be instrumental in providing treatment for symptoms such as excessive sleepiness and difficulty waking, and in effectively managing this debilitating disorder." I'd like to reiterate our thanks to the trial investigators, site coordinators and most of all, patients, for contributing to the clinical program and to the FDA for their collaboration in the review process. I'll now turn the webcast over to Kim to discuss our commercial strategy. Kim?

Thanks, Rob. I'm excited to share our commercial strategy for Xywav in idiopathic hypersomnia. I'll begin on Slide 32. We have developed a very targeted commercial strategy that includes robust disease education and showcases the clinical benefits of Xywav to health care professionals, patients and payers. Our market research indicates that HCPs are looking for more information about idiopathic hypersomnia and a clearer understanding of what success looks like in managing the condition. Our goal is to provide in-person and online resources and education that highlights the robust clinical benefit of Xywav in IH, where there has not previously been an approved therapy. We will be focused at launch on driving awareness and adoption among the already diagnosed patient population and existing oxybate prescribers. In parallel, we will be working to optimize both the physician and patient experience by ensuring that existing coverage of Xywav in narcolepsy expands to include IH, and that utilization management policies are medically appropriate and enable access. We are also tailoring our existing Xywav patient access and support programs for patients with IH. Moving to Slide 33. The majority of diagnosed patients are being treated by a relatively small group of approximately 1,300 health care providers, most of whom our field teams have been calling on historically and have existing relationships, which allows for an efficient approach for our launch promotional efforts. Approximately 90% of the HCPs we plan to engage at launch are on our existing oxybate call plan. There are many benefits to this overlap, including experience with Xywav in our REMS program as well as having background on our patient support services and the commitment we have to patients. The existing relationships that we have built with these prescribers enables us to effectively utilize our current oxybate sales force to launch Xywav in idiopathic hypersomnia. Our in-person and direct education and promotional activities will focus initially on HCPs who are familiar with oxybate and have high idiopathic hypersomnia patient volume. This group of HCPs includes pulmonologists, neurologists, psychiatrists and PCPs, most of whom are board-certified sleep specialists. Our goal of professional outreach is to reinforce the distinctive symptomatology of IH and highlight the significant impact this disease has on people living with this sleep disorder. Now to Slide 34. Idiopathic hypersomnia is a critically underserved disease. There's limited published data on IH prevalence. However, our research on claims data indicates there are approximately 37,000 people already diagnosed with idiopathic hypersomnia in the U.S. who are actively seeking health care. And our initial launch efforts will be focused on these patients. Because there were no approved therapeutic options prior to Xywav, we believe that IH is often misdiagnosed and underreported. Expanding the market beyond the 37,000 diagnosed patients provides us with a longer-term growth opportunity. Based on claims data, market research and input from health care professionals, we estimate that the total diagnosed IH patient population is likely close to the diagnosed narcolepsy market, which is approximately 70,000 to 80,000 patients. Many diagnosed IH patients are treated with wake-promoting agents or traditional stimulants. But as you heard earlier, this is not meeting the needs of patients. The educational component of our launch is critical. We will be activating a branded patient-focused campaign that offers support, resources, patient testimonials and validation. Patients often have a long diagnosis journey and can feel overlooked, often going through multiple misdiagnoses before being properly diagnosed. Patients have expressed the need for validation that idiopathic hypersomnia is a real medical condition and often share that they are discouraged by the lack of information about idiopathic hypersomnia available. We also hear from many people with idiopathic hypersomnia that they felt relief when they were diagnosed, only to feel frustrated to learn there wasn't an FDA-approved medication to help manage the condition. While we know that many HCPs are excited to finally have an effective treatment for their IH patients and that there will be early and fast adopters, we also anticipate it will take time to build this market, and that on the whole, health care providers will discuss Xywav with patients as they come in for their regularly scheduled appointments. Turning to Slide 35. A critical element of a strong launch is supporting patients and ensuring access. While idiopathic hypersomnia is a new indication, Xywav in narcolepsy already has significant commercial coverage in place at over 80% of commercial lives. Based on our work in narcolepsy, payers and plans already have an understanding of Xywav's clinical profile. This has been a very helpful starting point for discussions related to idiopathic hypersomnia indication. And we have ongoing dialogue to educate payers on the clinical presentation of IH, its prevalence and the benefits of Xywav for these patients. As is customary following the approval of a new indication for an existing therapy already on formulary, plans are conducting medical reviews for the use of Xywav in IH. We anticipate Xywav and IH will have similar coverage to narcolepsy and expect this to be in place in the same or faster time frame as narcolepsy, which was within 6 to 9 months of launch. While payers are updating their policies, prescriptions for Xywav can be filled through medical exceptions. We also have patient assistance and access programs in place to ensure patients who want to initiate therapy can do so. In addition to access, ensuring that patients have a positive experience with Xywav from a support perspective is important to us. We are leveraging our experience in narcolepsy and existing patient experience programs to support patients with IH. And now I'll turn the call back over to Bruce for some closing remarks.

Thanks, Kim. I'll close out our prepared remarks on the next couple of slides, beginning on Slide 37. Jazz is a leader in sleep. We believe that Xywav is the best oxybate therapy available for patients and expect that the majority of patients taking oxybate will be on Xywav in 2023 and beyond. We view oxybate as a durable franchise, and we expect Xywav to provide substantial value in both the near and long term. Wrapping up with Slide 38, the approval and launch of Xywav, first in narcolepsy and now IH, is one of several examples of our transformation into an innovative biopharmaceutical company with strong execution-focused capabilities from concept to commercialization. In the past year alone, we've introduced Xywav in 2 indications and received approval for and launched our oncology therapy, Rylaze, both of which were internally developed. At the same time, with the acquisition of GW Pharmaceuticals, we added an exciting new product to our commercial portfolio in Epidiolex as well as a promising pipeline in the GW cannabinoid platform. We also exceeded our expectations for the launch of Zepzelca and are making significant progress across multiple R&D programs. I've never been more excited about the future of Jazz. With a diversified commercial portfolio and robust R&D engine behind it, we are poised to deliver meaningful impact for patients and value to our shareholders. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Our first question comes from Jeff Hung of Morgan Stanley.

Dr. Bogan, are there any reasons to believe that IH patients are more or less likely to seek treatment than narcolepsy patients? Just appreciate any insights you can provide on differences that might impact treatment rates.

Yes. I don't think there's any reason for -- I mean these people are sleepy. It takes a while for them to realize -- because the peak incidence is in young people, they don't exactly know how sleepy they are, that something's wrong until there's some precipitating event or finally, they're tired and they've been treated for other things and they still don't get better. Tired and sleepy, I should say. But no, there's no reason why they shouldn't. Oftentimes, they present as they think they have narcolepsy or they just can't figure out why they're sleepy. And they've been -- they've had all of the tests done and something is still wrong, and they get referred to a sleep specialist. There are no barriers other than these are young people who don't know how sleepy the world should be.

Our next question comes from Marc Goodman of SVB Leerink.

It's Rudy on the line for Marc. I have 2 questions. First, can you provide more color on the diagnosis of idiopathic hypersomnia versus narcolepsy? Since Xyrem is already used off-label in this indication, would the new label support a broader use in both narcolepsy and other sleep disorders? And secondly, you mentioned that now we have like 37,000 patients diagnosed already, but the total population will be around 70,000 to 80,000. So how long it takes for these patients to become active? And what's our plan to target these under-diagnosed patients?

So maybe I'll come to Kim to take this question, both in terms of current off-label use of oxybate in IH as well as the difference between the early focus on already diagnosed patients and the timing for potential market expansion. Kim, are you there?

Yes, Bruce, sorry about that, I forgot to unmute. So yes, in terms of IH patients already being on Xywav, prior to the approval of Xywav, there were no FDA-approved treatments for idiopathic hypersomnia. And other treatments such as wake-promoting agents, stimulants and antidepressants were primarily what were being used off-label, of course. But in most cases, IH patients were not able to access any oxybate treatment due to pretty strong restrictions that payers had in place. In terms of the numbers around diagnosis, we really do believe that we're going to have strong uptake. And we're focusing on the launch of our existing sleep call universe in the approximately 37,000 adult patients who have been diagnosed with idiopathic hypersomnia and are actively seeking health care. We think that's the right place to start. While we know that many HCPs are excited to finally have a treatment option available to them, we do believe most HCPs will be waiting for patients to come in for their regular scheduled appointments to get them started. Expanding the market once existing patients with IH and prescribers have experience with Xywav does provide us with a longer-term growth opportunity. And that's where we think we can start to grow in terms of going after perhaps those 70,000 to 80,000 patients that we think may actually have a diagnosis today.

Kim, this is Rick. Could I make a comment?

Please do.

Please do.

Yes. No, I would say -- I mean 2 things. One is the number of people that entered the trial who were on Xyrem off-label was actually very small. As you remember, it was only about 6 people. And I'm -- personally, I'm converting all my people from Xyrem over to Xywav because of the sodium. I mean you're getting over 1 gram less sodium per day, which has significant, I think, health benefits. So we're converting almost all to Xywav from Xyrem. So in idiopathic hypersomnia, there's no reason not to go ahead and use Xywav, it's the FDA-approved drug. As far as the prevalence is concerned, it's still -- this is an evolving diagnosis that we really didn't appreciate. We knew there were some sleepy people, and we were trying to prove that they had narcolepsy, and we couldn't always prove that. And now we have a lot more understanding. And there's some published data out there from AHI and others looking at the epidemiology. But from my perspective, in my clinic, and I may be bias, but the number of patients that I treat personally are equivalent. I see the same number of people with idiopathic hypersomnia that I see with narcolepsy. And so I think, if anything, we're going to see that prevalence number go up as we get more awareness and now that, especially, we have an FDA-approved drug.

Our next question comes from Ami Fadia of Needham.

Maybe a follow-up question for Dr. Bogan here. How long does it take to correctly diagnose patients? And what are the generally agreed criteria in clinical practice for identifying a patient of having IH? And then I have a different question for Kim.

Yes. I would say it doesn't take long. I mean the patients come in, they're sleepy. Now unfortunately, it takes a long time to make the diagnosis because they have symptoms of fatigue and sleepiness, and they get worked up for depression and attention problems and metabolic abnormalities and all kinds of things. And sometimes with the autonomic instability, they get worked up for neurologic or cardiovascular abnormalities. So it takes a while for them, much like the narcolepsy patient's 10 years delay in making the diagnosis. So there is a delay in making the diagnosis. But once they present to the sleep physician, we record their sleep diaries, how much sleep -- making sure they have adequate sleep and they have, what we call circadian entrainment. I mean they're sleeping when their brain wants to sleep. But then we can do the diagnostic testing with polysomnography to rule out any other sleep disorders and then do the nap studies. So we can make the diagnosis very quickly. It's -- and then at that point, review with the patient what we consider the pathophysiology of the disorder, what we think is going on and review the treatment options based on the American Academy of Sleep Medicine guidelines as well as the FDA-approved drugs.

Got it. The question for Kim is...

And Ami, before we go to the rest of your question, Phil, anything you want to add to that?

No, Bruce. I think Dr. Bogan covered it. I think it's important that the sleep specialists are very focused on ruling this out as part of the diagnosis when they get a sleepy patient. So I think Dr. Bogan did cover that once they get to the sleep specialist, it can be done fairly rapidly and this well-established criteria, including the sleep laboratory test, the MSLT criteria and having ruled out other conditions. So -- and these also are specialized in narcolepsy as well. So I think they're very comfortable with prescribing an oxybate product and now will have an approved therapy to help them. But I think Dr. Bogan already covered that.

Great. Ami, sorry, back to you.

I guess the second question is that you have a very significant overlap, over 90% of your call universe already is seeing a patient with IH. Why wouldn't the uptake be pretty quick when I think a lot of these physicians are already treating patients with narcolepsy and they're already seeing patients, like Dr. Bogan said, half the patients are IH patients. Should we not expect a rapid ramp in the adoption of the IH indication? And then also, I'd like to know what percent of patients actually reached a normal ESS score in the study, just to understand what the persistency would look like?

Yes, I think -- sorry, Bruce, go ahead.

No, I was just going to turn it over to you, Kim.

I think this really centers on what we talked about before in terms of when those patients are going to show up at the doctors' offices. We're hearing really, in this instance, that they are -- while they're excited about the product, they're going to be waiting for those patients to show up for their regularly scheduled visits. So we do think there's a lot of excitement out there, but it's going to take a little bit of time for the market to build, both in terms of patients showing up and as well as us continuing to educate the market a bit more about idiopathic hypersomnia.

I was just going to ask if anyone wanted to say anything more about what we expect in terms of patients staying on therapy once they initiate oxybate for IH.

Well, I'll be glad to make a comment. This is Rick Bogan again. Yes, I mean, this -- when it hits, the patients are kind of like, now I can wake up. When -- Xywav, you take it at night. And when it wears off, boom, then they wake up. So the sleep inertia is dramatically improved, as you saw in that visual analog scale and in the IHSS scale because it asks about naps and executive function and mood and productivity, all of those parameters significantly improve and actually near normalize, which, to me, is more dramatic than narcolepsy patients because these people are pretty profoundly sleepy. So the sleep inertia and the other symptoms are pretty dramatic. And most of the patients are highly motivated to continue on the drug, which is pretty impressive to me. The number of people who did respond, not everyone responds, but the number of people who did respond and had fairly quick results and how quickly they got worse when you withdrew it is pretty impressive when you look at the data from the study.

Phil, anything you'd like to add?

Yes. The one thing that I did want to add to this was, if you look at the patients who make it to the double-blind randomized withdrawal period who then go on to the open-label extension, which Rob had shown in one of his slides, I think it was Slide 27, if you look at the number of patients who continue on to that open-label extension period, which goes on for 6 months, virtually everybody who made it through the double-blind randomized withdrawal period continued into that open-label extension. So I think this speaks to Dr. Bogan's point, those patients that are seeing the benefits are very much likely to stay on it even long term. And this was the beauty of the study is you can -- really reflects the clinical practice where you can titrate it to effect, optimize and dial in the right dose for the -- for each patient. And then once you do that and they see the benefit of it, they tend to stay on the drug long term.

Yes. And I would add, we -- as clinicians, we're always worried about tolerance. And you get used to it and it quits working. And obviously, so we're interested in the long-term efficacy, tolerance, rebound, withdrawal. Those are all -- and this study really afforded us the chance to look at those things. And it just reemphasizes what you said in terms of this molecule treating IH, it's encouraging for its duration of effect and its safety as well and the absence of major rebound and withdrawal and tolerance. So at least based on the data we have, and if I would probably echo that, based on my clinical experience.

[Operator Instructions] Our next question comes from Jessica Fye of JPMorgan.

I feel like there have been a number of questions kind of related to this, but just to ask it directly, can you comment on how you envision the shape of the launch ramp for Xywav in IH?

Yes. Jess, maybe I'll just jump in at a big picture to say this is a little different from the launch in narcolepsy, where we already had many oxybate-using patients experienced in the narcolepsy space, and it was a matter of would they be adopting our new treatment, Xywav, with the 92% reduction in sodium? This is building a new market de novo. Patients won't be switching over at an established dose of oxybate like they were in narcolepsy. These will be people starting at an initial dose and titrating up over time. So we've got some things working for us in that we're the only approved treatment and we know the right physicians, high overlap has been pointed out. But on the other hand, we have some real work to do. Not all these patients are going to come visit their doctor the week after we launch the product. They'll come in over the balance of a number of quarters. And we'll be driving our education messages, both in the physician community and, as we can, out to potential sufferers. But we've got a highly focused launch plan that starts with the physicians we know are already seeing IH patients that are in our call universe. Kim, anything you want to add to that?

No. That covers it.

Our next question comes from Brandon Folkes of Cantor Fitzgerald.

Maybe just on the dosing regimen, just given that you have the once-nightly and twice-nightly in the label for IH, any color on the number of patients who completed the trial on the once-nightly dosing? I think in the label, you say that 23% started the double-blind withdrawal period. And then along those same lines for Dr. Bogan, in practice, how are physicians going to weigh up whether to start a patient on the once-nightly or twice-nightly dosing regimen for IH?

Yes, I'll jump in. The Europeans have -- seem to have more longer sleeper types. And part of that is just the clinical people they see. And some of these folks have such severe sleep inertia, they can't awaken in the middle of the night to take a second dose. So many of the patients were started -- they can only -- they were prescribed 2 doses, but they started out with 1. But after they began to get a response, they could wake up and take the second dose. And based on our experience in narcolepsy patients, in the pharmacokinetics and the pharmacodynamics of the drug, most of us in the U.S. prefer twice dosing. So in the clinical trial, I can't remember the exact percent, but it was around -- it was over 80% ended up in the stable dose period on twice-nightly dosing. But for those who couldn't, we gave them 1 dose, and we could go up to 6 grams, which is not the dose that we typically use, but we could go up to 6 grams in 1 dose. And those patients also showed benefit with taking 1 dose. I mean the parameters, the Epworth, the Idiopathic Hypersomnia Severity Scale, the Patient Global Impression, all of those parameters were statistically significant. I mean they showed response. So we have the flexibility to be able to use 1 dose and 2 doses. But I would say, in my experience, over 80% of the patients are going to be on twice-nightly dosing.

Phil, anything you want to add to that?

Yes. I think Dr. Bogan covered some of the points really well there. I think importantly, we know from patients that flexibility is important both in the IH and the narcolepsy population. So we wanted to give this flexibility to patients, and we designed the study in that way. So -- but we do know that the vast majority do land up on twice-nightly dosing and probably require twice-nightly dosing. And that's been our experience with Xyrem in the past as well and the Xywav in our narcolepsy studies as well. Importantly, there isn't any differences between the patients who, in terms of the baseline demographics or characteristics, that would differentiate between these patient populations that opted for the once-nightly dose versus the twice-nightly dose, and as we mentioned, where the minority demanded a once-nightly dosing at the end of the study. I will say what is important is if we look at the median doses in this study relative to the narcolepsy study, which was a bit similar design, in this study, the median stable dose is about 7 grams in IH, and it's about 7.5 grams in the narcolepsy study. So still showing that they require a reasonable substantial amount of oxybate that's sort of somewhat consistent with the median narcolepsy dose in other studies.

As clinicians, the flexibility in the dosing is amazingly important to us and to the patients. So it's nice to have some experience in a controlled trial with once-nightly dosing, asymmetric dosing, twice-nightly, I mean, the flexibility in the dosing is important depending upon the patient's response. And it evolves over time because the patients, when they respond, become -- they awaken more easily. So flexibility is important.

Our next question comes from Ken Cacciatore of Cowen and Company.

Bruce, at the beginning of the presentation, you had a reiteration of really bullish commentary about your belief that the majority of all oxybate patients will be on Xywav in 2023, and you said which accounts for both branded and generic oxybate competition. So I was hoping you could flesh that out for folks. It's obviously one of the greatest fears is that, that won't be true. So just wondering, is it because of your knowledge of the kind of supply constraints of the generics? Is it just you have such connectivity with the clinicians and via your sales force and the knowledge, is it just surveying the clinicians about the desire to have the low sodium for chronic patients? Can you try to provide a little bit more context on that continued bullish thoughts as we enter into what some folks are believing is a fearful period of generic oxybate?

Yes, Ken, the things I want you to recall are: number one, we have the only low-sodium oxybate product. And the importance of that reduction in sodium has been reinforced by the feedback we've gotten from physicians and patients, by the FDA finding of clinical superiority. And our belief is that benefit for a chronic therapy, a lifelong therapy in the narcolepsy population that's known to have higher cardiovascular risk, to start with, is really important. And I think people recognize the importance of that. On top of that, we now have the launch in IH, where Xywav is the only product that has or will have in the near future an IH label. And so the combination of those 2 things, along with the great performance of our team in terms of education, providing patient services and access, make us confident that we're in a good position now. We've got work to do to continue to grow in narcolepsy now to begin to offer treatment in a brand new market. And our belief is that opportunity in front of us is a long-term opportunity.

Yes, Bruce, I would add, in my clinic, 90% of my narcolepsy patients have converted over to Xywav. That's just me, but that's -- I mean there's no reason for us not to convert everybody over, considering we're reducing their sodium intake by over 1 gram.

And Ken, I didn't mean to leave out a more direct answer to your question. We're really talking about what's good for patients and patient preference, not supply issues. That's not what we're contemplating.

Our next question comes from Esther Rajavelu of UBS.

I guess one quick one. I wanted to clarify what proportion of the approximately 37,000 patients you've identified are under the care of doctors who are part of the Xywav, Xyrem REMS? And if I can squeeze one more in, whether you're planning anything for the OUS markets with Xywav?

So Kim, why don't you take the first part of that question?

Yes. Given the high overlap, about 90% overlap in the 1,300 HCPs that we're going to be calling on, really virtually all of them are signed up for and part of the REMS because they are utilizing Xywav today. So we feel very confident that, that ability for them to start using Xywav in IH will be quite rapid.

And on the OUS part of the question? Sorry.

Well, Dan, why don't you finish on the OUS and then we'll let Esther ask the rest of the question.

So on the OUS part, market conditions are very different on oxybate therapy outside the U.S. We do directly sell Xyrem in U.S. and Canada, and Xywav is only approved in the U.S. We do think with the low-sodium benefit in the IH indication now there is some opportunity ex U.S., particularly as we're seeing an evolving neuroscience and sleep specialties in the Asia Pac region. So that's under active evaluation at this point.

Our next question comes from Jason Gerberry of Bank of America.

I just wanted to come back to the payer access point that was raised at the beginning of the call, the 6 to 9 months, similar to Xywav for narcolepsy. Just more directly, do you expect to have a pretty good broad access at the start of 2022?

Kim?

So again, I'll just repeat. We think it will take somewhere in the range of 6 to 9 months, perhaps faster, for that access to build. Exactly where we'll be in January remains to be seen. I think the important thing to remember is that patients who want to be -- are placed on and want to be on Xywav for idiopathic hypersomnia will have routes to obtain access to it. The fact that payers are working on updating their policies, many of these patients in the meantime will be able to obtain Xywav through a medical exception process. And then we also will continue to make available to Xywav patients with IH our patient assistance and access programs in the meantime. So -- and lastly, our area reimbursement managers who recently supported physician offices on Xywav for narcolepsy will be there and available to help support our customers with their IH patients.

And Kim, if I can just follow up, is that 6 to 9 months from the approval or from the fourth quarter launch? Probably not a big difference, but 3 months or so, just thinking about next year.

Yes. We really think within 6 to -- our goal with narcolepsy was 6 to 9 months of launch, and we exceeded that. And we do believe because of the great foundation we have in place with Xywav with payers today with greater than 80% of commercial lives having access that it should go a bit faster this time.

Our next question comes from Gary Nachman of BMO Capital Markets.

Okay. Great. Just following up with Dr. Bogan on a previous comment. If most patients have IH chronically, any concern with them taking Xywav indefinitely well beyond the 6 months that you saw in the open-label extension of the Phase III? Would you consider taking them off at any point to see if they go into remission? I know there's been good durability with the narcolepsy patients on oxybate. Bruce mentioned earlier, a lot of them stay on for their entire lives. I'm just curious if you think that should be the same with IH, that same kind of durability?

Yes, that's an interesting question because we don't really know. It's rare, in my experience, for it to remit. But as we understand more about the disorder that maybe the standard of care is, hey, we have someone who's doing really well, and maybe we'll start withdrawing drugs. Because the first thing that will happen is they'll quit taking stimulants in the daytime because most of the patients on Xywav are still going to be on some sort of wakeness-promoting medication. So they might give a signal. And some of them don't. Some of them just take the Xywav. But as we follow the patients over a period of time, that may -- that's an interesting question whether we will do a clinical challenge. My impression is probably not. This is considered chronic in most people. And I see this a lot in some of my narcolepsy patients. They may miss a dose here or there or whatever. And then they're like, "Well, gosh, I didn't get that bad. Maybe I don't need it." And they stop the drug, and then 2 months later, they're like, "Uh-oh, now I see where I was." So it's not unreasonable to maybe test people, periodically withdraw and see how they do. But the majority -- well over 80%, maybe 90% are going to be on the drug forever really. And I have patients that have been on Xyrem since the clinical trials, 2002 and -- for narcolepsy, obviously. But yes, these are chronic long-term therapy medications.

Yes. And Gary, I'll just reinforce what Dr. Bogan said, which is in narcolepsy, where we have longer experience, we certainly hear stories about patients who felt so good -- this is relative, of course, but felt so good that they felt they might have, I don't want to say been cured, but they felt this might be behind them, and they have come off drug. They generally end up back on drug at some point, so they resume therapy. And there's sort of a cumulative effect of that over time. On the first night off therapy, you're not going to feel the full cost of being off therapy. Over time, you most likely will. In the cases I've heard about, it's generally been patient-initiated rather than physician-initiated. I haven't generally heard that the physicians have suggested they come off therapy. It's more often been the patient sort of running that experiment.

Your next question comes from Greg Fraser of Truist Securities.

Dr. Bogan, of your patients with IH, roughly what portion have their excessive sleepiness adequately controlled with wake-promoting agents or other stimulants? And what portion are in need of something else and would be good candidates for Xywav?

Yes, that's -- it's very low, to be honest with you. I mean they're helped. And there's always mild, moderate and severe. But the ones that I see, and this is my personal experience, the ones that I see are more moderate and severe. I mean they're hurting. They come to a tertiary clinic to -- for sleepiness. And they've been on all kinds of stimulants. And that doesn't help the sleep inertia, because they have to wake up to take the medication. So they have family members who come in and wake them up to give them a pill an hour before it's time to wake up so they can wake up and get started. And when they do, they will tell you, "Doc, I'm more alert, I'm more awake, but I still need -- I can take a stimulant and take a nap." And so that's the majority of the patients. It's pretty -- I would say it's pretty low probability that the stimulants alone are going to be adequate because of the sleep inertia. It just doesn't get them to where they want to be. That's very different from the Xywav. I would say almost all of my patients who are on stimulants still have an abnormal Epworth score. They're still sleepy. And -- but -- and again, not everyone responds to the Xywav or tolerates it. But when we get someone who responds, it's pretty dramatic. The sleep inertia gets better, the stimulants work better. They have improvement in executive function, thinking and memory. So the effect of sleepiness on motivation and the executive function and mood, et cetera, is improved. It's not treating those. It's treating the sleepiness. But this is what they tell me. And that's what the IHSS score looks at. It looks at those domains of quality of life and those sort of things. And you just don't get that signal with stimulants. Did I answer your question?

Yes. And maybe I can just add a couple of additional points here. Thank you, Dr. Bogan. If you also looked at the data that we presented today on Slide 27 that Rob went through, we showed you the data on patients who were on wake-promoting agents versus those that were treatment-naïve. And you can see the Epworth Sleepiness scores are actually very similar. They're above 15. So that actually shows that despite other wake-promoting agents and stimulants, the sleepiness is not adequately treated. But I'd also like to reiterate that it's more than EDS that we're treating. I think Dr. Bogan did cover that. And the indication that we have was not about treating excessive sleepiness in IH. It's for the treatment of IH because of the effects that we've seen, not just on the Epworth Sleepiness Scale, but also the Patient Global Impressions and Idiopathic Hypersomnia Severity Scale, which covers 14 domains. And while we only presented data on 3 of them today, it was significant across each of the individual domains. So I think the clinical benefit is beyond the sleepiness. And these patients are achieving benefits, as I've mentioned, across multiple domains, and we see which are going to be clinically important.

Operator, I think we've got time for one more question.

Our last question comes from Balaji Prasad of Barclays.

I didn't think I -- just going back to your comment on 50% of patients being on oxybate by 2023, just wanted to understand that a bit better. Does this factor only Jazz patient volumes? Are you factoring in authorized generic volumes? And I'm assuming, of course, that it factors both the indications that you're approved for?

Yes. So all oxybate products, not just our products, and yes, factors in the new indication.

Okay. All authorized, including the authorized generics and potentially FT218?

Correct. Thanks for clarifying. I appreciate that. Okay. Well, thanks for the Q&A. And let me just wrap up with a few comments. As you can hear from our presentation today, we're excited to deliver Xywav to patients as the first and only FDA-approved medicine to treat idiopathic hypersomnia in adults. The commercial launch in idiopathic hypersomnia also represents an important component of the growth of Xywav. I do want to note that we are presenting several posters on Xywav in IH at the upcoming American Neurological Association Annual Meeting, which begins this Sunday, October 17. Abstracts are now available on the ANA website. To wrap up, I'd like to thank our colleagues here at Jazz for their commitment. This is our fifth launch in the past 2 years, enabling us to improve patients' lives and reach a significant milestone for our company. I also want to thank, again, Dr. Richard Bogan for his participation in this call. We look forward to providing updates across our business in November on our third quarter earnings call. Until then, please stay well. And we'll now close the call.

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