Hi. Good day. This is Kathee Littrell, Head of Investor Relations at Jazz. I want to thank you all for joining for our Xywav Investor Update. Before we begin the webcast, I will point out that we will be making forward-looking statements today, including statements regarding our plans and expectations for the Xywav commercial launch in the U.S., potential Xywav revenue opportunity, and our other development plans and opportunities. Our forward-looking statements are subject to risks and uncertainties described in our quarterly report on Form 10-Q for the quarter ended June 30, 2020, and our other filings with the Securities and Exchange Commission, and actual results may differ materially. We undertake no duty or obligation to update any forward-looking statements we make today. Finally, we are not confirming or updating any other guidance, and actual results may differ.
I'll remind you that you can send in questions at any time during the presentation, and we will address those after the presentations are over. So, at the very end of the presentation, we will answer all the questions, but feel free to submit at any time that you all have a question pop into your mind, and we will address it at the end of the presentation. Please also note that the slide deck from today's presentation is available for downloading from the investor section on the Jazz Pharmaceuticals website, at jazzpharma.com. With us today from the management team are Bruce Cozadd, our Chairman and CEO, Dan Swisher, President and COO, Renée Gala, our Executive Vice President and CFO, Rob Iannone, our Executive Vice President, R&D, Kim Sablich, Executive Vice President, General Manager, North America, and Phil Jochelson, VP, Therapeutic Area Head for Neuroscience.
We are also joined today by Dr. William White, a well-known researcher with extensive expertise in preventive cardiology, clinical hypertension, and cardiovascular drug safety, and Dr. Richard Bogan, a well-known sleep expert and President of Bogan Sleep Consultants and Associate Clinical Professor at the University of South Carolina School of Medicine. As you can see, we have a great agenda today, starting with Bruce Cozadd introducing our presentation, and then Dr. White will speak to us on sodium, blood pressure, and cardiovascular health, and then Rob Iannone will follow with an update on the Xywav label and narcolepsy overview, followed by Kim Sablich, who will again talk on the narcolepsy launch plans and commercial landscape, and then many of you have asked a lot of questions about idiopathic hypersomnia, so we're really excited today that Dr. Bogan is also going to address a disease overview.
And then Rob will talk briefly about our phase III study, followed by Dan Swisher, who will close us out with a commercial overview discussion around idiopathic hypersomnia. And at that point, we'll take Q&A. So, at this point, I'm going to turn the call over to Bruce Cozadd.
Terrific. Thank you, Kathee, and thank you all for joining our webcast today. You know, I'm really excited about the momentum of Jazz Pharmaceuticals right now as we continue our revenue diversification with two of five key 2020 and 2021 launches underway and the launch of Xywav next week, providing multiple near-term value-enhancing catalysts, with another two launches targeted for next year. Let's go to the next slide. So, as we look at our sleep franchise, we are poised for continued growth and diversification. We now have three approved sleep products, with Sunosi and Xyrem marketed, and Xywav about to be launched. The year 2020 has been all about execution, positioning us for sustainable growth and durability in the neuroscience business. Just this year, we submitted the NDA for Xywav for narcolepsy, received Priority Review with an approval in July, and launched next week following our REMS implementation.
At the same time, we completed enrollment in our Xywav phase III study in idiopathic hypersomnia earlier than expected, received U.S. Fast Track designation, announced compelling top-line data in October, and are planning for our sNDA submission in the first quarter of next year, with launch targeted later in the year. Next slide, please. I'm really excited about what we've done with Xywav, our first product taken all the way from concept to launch in-house at Jazz. And this really reflects the investment we've made in transforming our R&D capabilities. We listen to patients and physicians and prioritize Xywav as the major advance in the treatment of narcolepsy, giving narcolepsy patients a new option that tackles the lifelong burden of high sodium intake. This has been a goal of ours for nearly 10 years.
It's important to remember we've been focused on and dedicated to the health of patients in this space for 15 years now. We've harnessed this experience and knowledge to develop Xywav to improve the lives of narcolepsy patients and continue to develop Xywav and IH to improve the lives of significantly more patients. Next slide, please. We expect a majority of oxybate patients will be on Xywav by 2023. Xywav is the lower sodium oxybate for the treatment of narcolepsy, with 92% less sodium than Xyrem. It's indicated for the treatment of cataplexy and EDS in patients seven years of age or older with narcolepsy. And I will point out that this drug does have a black box warning as well, and it's important that patients understand how to use the product safely, including discontinuing alcohol using Xyrem or Xywav.
Narcolepsy is a chronic disease associated with increased prevalence of cardiovascular and cardiometabolic comorbidities. We're excited about our label, which has clear instructions for patients transitioning from Xyrem to Xywav, and Rob will walk you through the label a little bit later in today's presentation. We are expecting strong adoption of Xywav, priced at parity to Xyrem, and with patients able to start at the same doses. We see an opportunity to add patients previously not prescribed Xyrem based on sodium concern, and we're focused on providing strong patient assistance programs and patient payer access. Note that in IH, we have the opportunity to reach a new significant group of patients with an estimated diagnosed prevalence of approximately 37,000 patients in the U.S., although we're confident that understates the true opportunity. At this point, let me introduce Dr.
William White and thank him for joining us today to provide an overview of sodium, blood pressure, and cardiovascular health. Dr. White has been a Professor of Medicine and Chief of the Division of Hypertension and Clinical Pharmacology at the University of Connecticut School of Medicine, with expertise in preventive cardiology, clinical hypertension, and cardiovascular drug safety for 40 years. Dr. White has a longstanding interest in clinical hypertension and pharmacology, particularly in the areas of ambulatory blood pressure monitoring, clinical trials of antihypertensive drugs, and the impact of non-cardiac drugs such as analgesics, hormones, NSAIDs, neuropsychiatric agents, and analgesics in cardiovascular disorders. He has extensive experience as Chair of Data Safety Monitoring Boards, cardiovascular endpoint committees, and interacting with the FDA as a cardiovascular safety consultant.
He is a Fellow of the Council for High Blood Pressure Research of the American Heart Association and was the President of the American Society of Hypertension from 2012 to 2014. Dr. White is the author of over 480 original articles and five books in the field of cardiovascular medicine and pharmacology. Dr. White, thank you for joining us today, and I'll now turn it over to you.
Thanks very much for that kind introduction, and good afternoon, morning, or evening to all the listeners today, depending on your time zone. I'm going to try and give a brief overview of some of the salient interactions between sodium via salt intake, blood pressure, and cardiovascular health in this presentation. I kind of outlined the presentation as a little bit of information on salt consumption and some definitions to get everybody on sort of the same wavelength. Some impact of salt reduction on heart and cardiovascular disorders, a little bit of information on some of the guidelines and how they got developed for present-day recommendations, some information on sodium in medications, and then I'll provide a summary. Let me just start out by saying that most of us eat too much salt in the United States.
Just to give you sort of an idea of how much sodium is in salt and how much salt we eat, if you take just a teaspoon and you fill it with salt so that it is flat, not heaping, that is 6 g of salt and is equivalent to 2.5 or 2,500 mg of sodium. That's kind of the formula. 1 g of salt equals a little under 400 mg of sodium. You'll see that I'm showing 1 g of salt and 3 g of salt throughout this presentation. Three grams of salt is 1,164 mg of sodium. A lot of people don't realize that. They think it's the same thing, but you've got sodium and you've got chloride, or you've got sodium and citrate, so it doesn't really actually, it's never equivalent. We eat most of our sodium.
A lot of people think it's from adding salt to food that's being prepared, but actually, most of it's what's already in foods, and you see here a laundry list of some of the things that are obviously high in sodium, like pizza and cold cuts, cheese. Some things are not as obvious, such as sandwiches and breads and so forth, but it's out there, and we don't like food that doesn't have a fair amount of salt in it. It just kind of tastes blah, so we unfortunately become so used to it that we don't like to eat food without it, and so I have a lot of trouble converting people from a high-salt diet to a low-salt diet just simply because of that, and just one word on salt substitutes that are out there. They are typically made of about a 50/50 potassium-sodium mix, and it's bitter.
Potassium is bitter, and if it's fully potassium, almost no one can tolerate that. There is a little bit less sodium in salt crystals, such as sea salt, only because it takes more volume and so forth, but it's still about 75% or 80% of the sodium that regular table salt has. So, in view of some of the concerns that really started many, many years ago about salt and blood pressure, the American Heart Association created one of their scientific statements or call to actions, and this was published almost a decade ago, where it was recognized that blood pressure is one of the, i t actually remains one of the most common attributable causes of mortality in the world, despite everything else that's going on.
It sort of stays there in the number one or two position because it's common and because it often is not adequately managed or treated on a global basis, and we now know that starting at about 115 over 75 and moving upwards, there's some graduated risk as you go up from that number. Now, there was a study just the other day that said it's even lower than that, but that was not based on a whole lot of cardiovascular outcomes, so that's sort of TBD, if you know what I mean, but I think right now we're looking at anything from 115 to over 75 to 130 over 80 as being a little bit increased risk with each sort of decile of blood pressure, and certainly it goes up, the slope of morbidity goes up a lot more after 130 over 80.
The American Heart Association, in conjunction with the American College of Cardiology, has actually taken a more stringent stand on what they think should be the target amount of sodium in a given day and it's 1,500 mg. Not that easy for many people to achieve, and we'll get more into that. Now, this happens to be, I think, the only medical student slide I'm going to show you. I know there's some physicians listening in, but there's also some non-physicians, so I'm going to kind of walk you through this. Excess sodium intake has a number of physiological or pathophysiological functions.
It causes activation of a complex system in the body known as the Renin-Angiotensin-Aldosterone System , which has been targeted for many decades by drugs to reduce this activity, such as the ACE inhibitors and the angiotensin receptor blockers, because when this system is activated or staying in overdrive, it causes a lot of negative things to happen. Renin causes volume retention, angiotensin causes vasoconstriction or blood vessels to constrict, increasing blood pressure, aldosterone causes salt and water retention, and also is known to cause actually primarily damage to the kidneys and to the heart, so that all happens as a result on that side of the equation, and then there's some other things that happen from salt that's sort of independent from blood pressure, and that includes the exposure to cytokines that damage blood vessel walls and actually lead to dysfunction of the blood vessel itself.
I'm sorry if you're hearing a little buzz. And then, from the clinical perspective, all of this stuff ends up causing target organ damage, such as blood vessels getting overly stiff and not functioning properly, kidney disease with the loss of protein, larger hearts, which actually ultimately become dysfunctional and lead to MI, stroke, heart failure, and chronic kidney disease. So, this is what we're talking about, and this is what we're trying to mitigate by sodium reduction. Okay, so let me give you some research studies that I think will elucidate some of the concerns that I certainly have, and so do most of my colleagues, about the effects of high salt intake. Now, this study was done in New York City.
It was referred to as the Northern Manhattan Study, and it would involve a very diverse population of individuals, almost 3,000 participants started up in the study, and when they first came in, they had a dietary assessment that was carefully done to put them in a different typical category of salt intake, and that was continued to be monitored, and they were followed up for 10 years, and during that 10 years, there were a number of cardiovascular events that occurred. The group was focusing on stroke because stroke is a very consistent adverse outcome of elevation in blood pressure, more so than myocardial infarction, although that goes up to some extent with hypertension as well, and the other big one is cardiovascular mortality, so these two things, stroke and cardiovascular mortality, in study after study, always seem to have a fairly robust relationship with blood pressure.
When they characterized the people and analyzed the data, they looked at first the highest group of sodium intake, which was 4,000 mg per day or higher, which you might think sounds like it's a lot, but it's not on the U.S. basis. If you compare that to the reference group, which were people who were obviously on their extremely best behavior and were hovering around 1,500, the risk of a stroke was about 2.6x greater in the high salt group than it was in the reference group. The combination of the major adverse cardiovascular events, also known as MACE, is 1.7x higher. That included stroke, myocardial infarction, and cardiovascular death. There was clearly a higher risk in this population of salt and bad outcomes.
Now, I would like to talk a little bit about a study that I think is really one of the most prominent and important studies in the area of reducing sodium intake in the United States because it was based on a variety of studies and populations, including Framingham, in which they had good data on salt, and cardiovascular outcomes were measured quite precisely. Now, the study was published in the New England Journal of Medicine about 10 years ago, and I still haven't seen anything quite as good as this study happens to be, and the senior authors from California, but you'll notice the last author, Lee Goldman, he was a longtime guy at Harvard, friends of mine, and then went to New York City to be a president of one of the big healthcare systems there.
What they did in this study is they developed a coronary heart disease model, which allowed them to define forward risk of various kinds of cardiovascular outcomes according to all the things that are typically used in risk calculators, such as the Framingham risk calculator or the American College of Cardiology risk calculator. They used age and gender, blood pressure and antihypertensive drug use, smoking status, cholesterol, and diabetes. They were able to break it down further based on race and age and gender within the population that they were putting together in this very complicated analysis.
And just to give you kind of the top-line results, if an individual, this is based on the model, reduced their salt intake, so this is salt intake of 1 g , remember that's 400 mg of sodium, or 3 g , which is about 1,160 mg of sodium, then the blood pressure impact would be a reduction of somewhere between 1-2 mm of mercury, estimated, for people with high blood pressure, and less than that for all others, about 0.6- 1.2. But you'll note that in the Black subpopulation, and they really need to focus on this because in the United States, African American populations have much more morbidity when they do develop increases in blood pressure than non-Black patients. And that was higher, so that was about 1.8-3 by just reducing sodium by 400 mg per day.
Over to the right part of that graph or table, you'll note that in the reduction of 3 g , which is 1,164 mg of sodium, the range for people with high blood pressure was 3.6-5.6, as it was for older people because older people are typically more salt-sensitive than younger people. For the normotensive middle-aged, it was about 1.8-3.5 mm of mercury. Again, in the Black subpopulation, everything was magnified. There was a much bigger impact of salt reduction in Blacks than it was in Whites. Now we can look at it to some extent in a pictorial fashion. What we have here is the impact on reductions in cardiovascular events given a 3 g daily reduction in salt. So, that's again 1,164 mg of sodium, and it's by age, gender, and race.
The left-hand graphic is all coronary heart disease parameters, such as unstable angina, MI, coronary bypass surgery, and other coronary interventions. And you'll note that right off the bat, the big picture shows that Blacks had a lot better reduction or bigger reduction to salt reduction compared to non-Blacks. And women and men were about the same for this particular parameter. It's really a mirror image for myocardial infarction, which of course is also a big component of incidence of CHD. But one of the things that's missing here is there's just not a whole lot of impact of age when it comes to salt reduction and coronary disease. All ages benefited, young and middle-aged and old. Now, when we take a look at stroke on the left and then mortality on the right, and that's all-cause mortality, that's not cardiovascular mortality per se.
If we look at stroke first, we see that once again there's a larger benefit, if you will, in Blacks, particularly Black women, compared to non-Blacks. We'll also note that women had a bigger stroke benefit of salt reduction compared to men. Here we also see a trend that the older you are, the bigger the benefit of salt reduction. This is kind of making sense as it relates specifically to stroke. Over to the right-hand panel, the gender and age categories have a very different pattern. When looking at all of things in totality, there is a reduction in mortality with 3 g of salt reduction, more prominent again in Blacks versus non-Blacks. You'll notice that when we get to the folks who are 65 and older, the benefit of salt reduction is much more modest than in the younger groups.
Of course, that's because this is all-cause mortality, so there's a lot of competing reasons why people are dying in these age groups versus in the younger age groups, which cardiovascular disease is more prevalent. To sort of provide a summary from a population perspective from this outstanding analysis is a table which shows salt reduction in grades of 1, 2, 3 g , which translates into about 400, 800, and 1,200 mg of sodium reduction. You'll see the changes in coronary heart disease, MI, and stroke are benefited even with the 400 mg, but it's bigger with 2 g and 3 g , obviously, for all of these significant cardiovascular events. Let me move now to some of our guidelines that are out there and have been out there for a number of years.
The guidelines for reducing sodium intake and its projected impact on blood pressure have been sort of championed by both the AHA/ACC, and they've worked together on this, and then the National Academy of Sciences, Engineering, and Medicine, and they got more interested in providing sort of daily recommendations for every kind of mineral or cation, not just sodium, so just going for the AHA first, their recommendation and guideline was that lowering sodium by 1,000 mg a day is expected to reduce systolic blood pressure in most individuals, normotensive and hypertensive, by about 2 over 3 and 5 over 6 mm of mercury, respectively, and then from the National Academy of Sciences, Engineering, and Medicine , they felt and reported that for a sodium intake range of 2,300-4,100 mg a day, 1,000 mg reduction is expected to reduce chronic disease risk, or CDRR, for cardiovascular disease and hypertension.
They established a recommended sort of upper limit of normal of 2,300 mg from their assessment of the literature. This is a huge group of people who spent a lot of time doing these analyses. On a worldwide basis, there are some differences, for sure. I would say that the AHA and ACC have always been the more conservative, trying to recommend that the targeted sodium intake should be 1,500 mg a day, not that easy to achieve. The FDA said 2,300 mg. I do not know exactly why they did that, but I think they coordinated with the U.S. Department of Agriculture. Everybody else kind of felt like the upper limit is somewhere around 2,300 mg per day. We should certainly be seeing it staying lower than that.
I can tell you, as a clinician, if I have a person with significant heart disease, particularly heart failure or resistant hypertension with kidney disease, as far as I'm concerned, the lower I can get in salt, the better because it just mitigates drugs and it causes a lot of hassle with maintenance of control of blood pressure in those populations of individuals. Now, how does this all compare to reality in the U.S.? Well, on the left is a bar graph showing the ideal and the sodium upper limits that we just talked about. And just right next to that is what people are actually eating on average.
You can see by age, it runs from about 3,500 mg a day in kids to about 3,700 mg in middle-aged and young and middle-aged people, and about 3,300 mg in people over the age of 51, probably because they're starting to get reasons for why.
Can you hear me?
Hello, Kathee, I can hear you. I don't know, can you hear me?
Yes, I can too. It's Dan.
Okay, Dan, you can hear me. This is Rob.
Hello. Yeah, I think everybody's getting reconnected. Hi, this is Bruce. If I'm live, can somebody message me?
I'm here. Hi, this is Dr. William White.
Rick Bogan here.
Yeah, I just want to get a confirm from somebody on my team that on the webcast they can hear us. Okay. Okay, people can hear us. So those of you that are on the speaker line, mute if you're not speaking.
To everyone listening in, we sincerely apologize for the technical glitch. We're going to have Dr. White pick up at slide 24, which is when I became aware that people couldn't hear. I promise you there's lots of exciting content ahead. So with that, Dr. White, back over to you.
All right, thank you very much. So I think perhaps you heard a little bit of this slide, but just in case, I'm just going to make the comment that the average sodium intake on a daily basis in the U.S. is far in excess of that that is recommended as the upper limit by more than 1 g . And to the right is the Gaussian distribution of intake, which really ranges from exceedingly low, about 1,000 mg a day, to very high of 8,000 mg a day.
This is sodium we're talking about, so it's really like 20 g of salt. And if you think that that doesn't happen, it does. Take it from me, I grew up in the Deep South. All right, so now I'd just like to spend a couple of minutes talking about some of the studies that I've reviewed for high-salt-containing medications and start out with a randomized crossover trial of an effervescent form of paracetamol in people with hypertension and osteoarthritis, in which the amount of sodium in each one of these paracetamol pills is 545 mg. And the way this study was done was that half the patients were assigned to the high-salt paracetamol and the other half to a low-salt paracetamol. And they stayed on that for three weeks, and then they had both clinic and ambulatory blood pressure.
Ambulatory blood pressure is done with a little device that can record your blood pressure about every 15 minutes throughout the day and the night and give you a beautiful profile of blood pressure behavior and typical whether or not the blood pressure declines at night or it doesn't decline. And it's extremely reproducible from this perspective of clinical trials such as this and allows for smaller sample sizes and so forth. And there's really no placebo effect or white coat effect associated with ambulatory blood pressure monitoring as there would be with doctor's office pressure. So if you look at the middle panel, which is the white in between the two gray bars, that shows the 24-hour blood pressure, and it demonstrates about a 4 mm increase on the effervescent sodium containing paracetamol versus the non-effervescent paracetamol.
And that is magnified in people taking antihypertensive drugs, particularly ACE inhibitors, angiotensin receptor blockers, and diuretics, in which the increase is more like 6 mm of mercury. And now we're talking both 24-hour awake types of blood pressure, so it's a big jump in blood pressure on this amount of sodium in just about a three-week period. So I'd like to digress for a second and really review what the importance is of small differences in systolic blood pressure. And this is really based on a couple of types of data quality. One is epidemiological, but this is really from clinical studies and clinical trials in which people have investigated hundreds of thousands of people and put it together with outcomes that were adjudicated, such as stroke deaths, coronary heart disease deaths, and overall mortality.
As you can see in the table below the graph, a 2 mm reduction in systolic pressure, which is actually clinic-derived blood pressures at this stage, was a 6% reduction in stroke mortality, and a 3 mm reduction is just 8%, and the 5 mm or a 14% reduction. It's clear that in a population, small reductions in blood pressure that were seen in that previous study are clinically meaningful. Now, one might ask about the individual patient, which is legitimate. The way these things work, and I've done a lot of these kinds of studies, is that it's not that 100 people out of 100 have a 2 or 3 mm reduction in blood pressure. It's a distribution, and some of them go up on a drug that raises blood pressure by 20 mm of mercury or 30 mm of mercury, and some have absolutely no change.
So obviously, it's the ones that go up by 20 or 30 that are the high-risk group that actually cause the event, and that's exactly what you see in these kinds of analyses and studies. Another example of where low or small-looking changes in blood pressure have been impactful are from the HOPE study, which was the Heart Outcomes Prevention Evaluation. This was conducted in the 1990s, and in the 1990s, and was published in 2000 in The New England Journal, in which people who were a combination of normotensives, mostly normotensives, and hypertensives, but with other kinds of cardiovascular risk, like they were overweight or they had maybe a high cholesterol or low HDL, etc. , and the blood pressure reduction was 3 over 2 mm of mercury over a period on average of about five years.
This resulted in a 22% reduction in cardiovascular death, MI, or stroke, the composite, and each of these endpoints was significantly reduced. ALLHAT, which was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial in over 40,000 people, compared four different kinds of drugs on outcomes, and it historically had a treatment arm known as doxazosin. That's an alpha blocker. It actually was stopped early because it was not doing well as far as stroke outcomes, and it turned out that people who were taking the diuretic, that's chlorthalidone, had a 3 mm l ower blood pressure than the individual randomized to doxazosin, and that accounted for the 19% reduction in stroke on the diuretic, or you could say the 19% increase in stroke on the doxazosin, and 25% reduction in overall combined CV disease.
When looking at people who finished the study on the ACE inhibitor, lisinopril, or the diuretic chlorthalidone, in which blood pressure was lower on chlorthalidone by 2 mm of mercury, it was a 15% reduction in stroke and a 10% reduction in combined cardiovascular disease. So I think that there's powerful evidence that small changes in blood pressure, like by reducing it by 2 or 3 mm of mercury, will yield substantial reductions in cardiovascular events. And I showed you that to some extent from the Bibbins-Domingo paper, which was a model of about 30,000 people, but here are actual data from clinical trials that prove the point.
Now, the last thing I wanted to show you was another study that was sort of a nested case control study done from the United Kingdom, in which they have this beautiful U.K. Clinical Practice Datalink , and it actually has 1.3 million persons in it, and they followed people for over seven years who were taking at least two sodium-containing formulations, and it turns out that in the formulary of the British National Health Service, they have 24 drugs with high salt and 116 that they know have low salt, and so they compared the outcomes in these different kinds of populations. They had 61,000+ people who had a cardiovascular event, and when looking at the odds of having such an event on a high-salt medication versus not being a high-salt medication, the composite was increased by 16%, and that was driven primarily by stroke and mortality.
As you see, myocardial infarction was not different, which again is probably related to all the multifactorial things that cause MI. So I would conclude as follows. I think sodium intake is grossly excessive in the United States. We all know that, and it's not like it's that easy to do anything about. They did a lot about it in the U.K., by the way, and it certainly has resulted in less hypertensive emergencies and less admissions to the hospital for stroke and heart failure. There's evidence for cardiovascular risk and untoward cardiovascular outcomes when we are exposed to high-salt diets as well as high-sodium-containing meds. And I think clearly that the totality of evidence for the beneficial impact of sodium reduction on CV health is substantial. I don't think that is controversial at all.
And finally, clearly, it's important for everyone, but certainly our patients who have underlying health concerns like heart disease, kidney disease, or if you are African American and salt-sensitive, it's even more problematic. The amount of salt people are already getting in their daily diets, whether it comes from food that they are already eating, salt that they're adding, or medications that have a large sodium content. So that's the end of my discussion. I really appreciate your listening with our technical problems, and I'll turn the slides over to our next presenter. Thank you.
This is Bruce, Dr. White. Thank you so much, particularly for rolling with the technical glitch there. I think my blood pressure went up quite a bit during that time. I'm pleased to say we still have 178 folks on the call, so we did not lose very many.
I'm now going to turn the call over to Rob, but before I do that, just a reminder that if you have questions for Dr. White or any of the speakers today, go ahead and put those in Q&A, and we'll address questions at the end. Here's Rob to provide an overview of narcolepsy and Xywav's label.
Thank you, Bruce, and thank you, Dr. White, for that great presentation. I want to start with an overview of narcolepsy. Narcolepsy is a chronic sleep disorder predominantly characterized by five symptoms: excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, sleep-related hallucinations, and sleep paralysis. Symptoms can appear as early as childhood, and because there is no cure, treatment is typically lifelong.
Research has shown narcolepsy to be associated with cardiovascular and cardiometabolic conditions, and these include obesity, diabetes, dyslipidemia, hypertension, and an increased prevalence of cardiovascular outcomes such as stroke, myocardial infarction as compared to controls. As shown in this photograph of an in situ hybridization in the hypothalamus of a patient and a control, Type 1 narcolepsy is believed to result from autoimmune destruction of hypocretin neurons. Although less well- understood, hypocretin dysfunction may play a role in Type 2 narcolepsy as well. In addition to its role in sleep, hypocretin may also regulate appetite, insulin secretion, and blood pressure. In preclinical studies, such as the one shown here, there is a suggestion that hypocretin protects against the development of atherosclerosis due to sleep deprivation. In addition, recent clinical research has demonstrated an association between CSF hypocretin level and severity of disrupted nighttime sleep in patients with narcolepsy.
Loss of hypocretin and its ability to regulate sleep, metabolism, and blood pressure may in part contribute to increased prevalence of cardiovascular comorbidities in patients with narcolepsy. Along these lines, clinical data have also shown that patients with narcolepsy have disruption of the so-called nighttime dipping, the normal nighttime dipping in blood pressure. The disruption of nighttime dipping or non-dipping pattern is considered a predictor of increased cardiovascular risk. This slide shows results from a clinical study of nighttime blood pressure in untreated patients with narcolepsy and cataplexy compared to individuals without narcolepsy. If I can call your attention to the right side of the slide, the study demonstrated that narcolepsy patients had a blunting of the normal nighttime dipping in blood pressure compared to the control group. This phenomenon provides additional evidence that may in part explain the increased cardiovascular risk in narcolepsy patients.
Multiple studies, as summarized here, have characterized the increased cardiovascular and cardiometabolic risk in narcolepsy patients. These risks include obesity, hypertension, diabetes, and dyslipidemia. This slide specifically details the cardiovascular risk in narcolepsy patients based on the BOND Study. The BOND Study used U.S. insurance claims data to analyze comorbidities in over 9,000 patients with narcolepsy and compared them to over 45,000 controls who were matched for key factors such as age, gender, geography, and insurance type. This study showed that narcolepsy patients are at increased risk for stroke, myocardial infarction, cardiac arrest, heart failure, and had an increased odds ratio across these factors of 1.6-2.6. As shown here, Xywav was approved by the FDA in July of this year for the treatment of cataplexy or excessive daytime sleepiness in patients seven years of age and older with narcolepsy.
Notably, unlike Xyrem, the Xywav label does not have a warning related to high sodium and the requirement to monitor patients with heart failure, hypertension, or impaired renal function. The Xywav label also includes information indicating that some patients may see better responses with unequal doses at bedtime and two and a half to four hours later. Thank you for your attention. I will now turn the presentation over to Kim Sablich, EVP, General Manager of North America.
Thanks, Rob. Today, I'm happy to share with you a summary of our brand launch efforts and high state of launch readiness. Just last week, we held our launch meeting to train our sales team on all of our launch strategies and tactics, and I can tell you that they left the week energized, confident, and ready to go.
For the launch of Xywav, we've established four critical success factors that drive all of our efforts. The first is about building both healthcare provider and patient awareness of the lifelong burden of high sodium intake and the prevalence of certain comorbidities in patients living with narcolepsy. Second, we will ensure broad and rapid patient access to Xywav via a combination of strong payer formulary coverage and extensive patient assistance programs. The third critical success factor is all about achieving rapid adoption of Xywav for newly diagnosed patients, current Xyrem patients, and prior Xyrem patients who discontinued treatment. To achieve this, we will have a comprehensive set of promotional and support programs for both healthcare providers and patients. And lastly, we are fully committed to delivering an improved patient experience via enhanced patient services that we deem integral to bringing the launch strategy to life.
So let's start by talking about our patient education efforts. These efforts aim to establish that narcolepsy is a lifelong condition that often requires long-term therapy, that patients with narcolepsy are at increased risk of comorbid conditions, and that excess sodium intake is detrimental to health. Featured here is our More Than Tired disease education campaign , which has already been live in the market for months. It's an omnichannel campaign supported by the website morethantired.com, a CRM program, and Veeva triggered emails. Our unbranded patient efforts also include a sponsorship with the American Heart Association, live patient education programs conducted by key opinion leaders, and collaborations with patient groups. Now, at launch, our patient efforts will shift to educating patients about Xywav via branded omnichannel campaigns and programs.
As part of this, the Central Pharmacy will play an active role in making current Xyrem patients aware of Xywav through multiple efforts, including a mailer insert in every patient shipment of Xyrem bottles. For healthcare providers, our disease education goals are largely the same that they are for patients. Our branded HCP education campaign was launched earlier this year and is focused on narcolepsy as a lifelong disease, the increased prevalence in cardiovascular comorbidities among patients living with narcolepsy, and sodium being a modifiable risk factor for narcolepsy patients. This campaign is being brought to life through multiple channels: digital and print ads, a revamped Narcolepsy Link website, a satellite broadcast attended by over 150 HCPs, and a three-part webinar series.
The branded HCP campaign we'll be launching with will pull through key aspects of the disease education campaign, namely the increased prevalence of cardiovascular risk in narcolepsy patients and high sodium intake being a modifiable risk factor, and will highlight Xywav as the first and only lower sodium oxybate for narcolepsy patients. Now, our medical affairs activities have been ongoing, including scientific exchange with KOLs, publication and Congress activity, and IME support, and we've supported both awareness of lifelong cardiovascular risk for narcolepsy patients as well as the clinical data supporting Xywav. In addition, the primary manuscript for the Xywav phase III study in narcolepsy is now published, and three posters with additional analyses were presented at the APSS meeting held virtually in August. Our sales force promotion of Xywav will be just as efficient as it was for Xyrem.
At launch, we're going to be highly focused on HCPs who already believe in oxybate and are comfortable prescribing it to narcolepsy patients. We'll focus our efforts on the 1,600 HCPs who today drive 80% of current Xyrem volume. 100% of our promotional efforts will be on Xywav. In addition to current Xyrem prescribers and patients, we will also be focused on discontinued Xyrem patients, as approximately 40% have expressed interest in market research and learning more about Xywav and reconsidering oxybate therapy on a lower sodium medicine. Our MSL team has reported they've heard from many KOLs that they are excited about Xywav and that after FDA approval, already have identified and counseled several Xyrem patients on Xywav to prepare them to transition.
As mentioned earlier, we are raising our game when it comes to improving the patient experience by enhancing our patient support services for the launch of Xywav. This includes a significant advancement in the patient welcome kit and creation of a digital-based myWAV with resources designed to meet a patient where they are in the patient journey. For the first time, we will offer omnichannel ordering and refills to enable patients to order through the channel that is most convenient for them. We will also launch a pilot of the first field nurse educator program in sleep. Finally, everything we are doing is designed to support HCPs and their patients through their journey from the moment they decide to initiate treatment with Xyrem. This begins with ensuring that patients can obtain affordable access to Xywav.
We price Xywav at parity to Xyrem in order to facilitate broad and rapid access on payer formularies. We are very encouraged by our ongoing payer discussions for Xywav and have already signed a favorable contract for the commercial lives of one of the three major PBMs in the U.S. While we wait for the broad national access that we are anticipating to kick in, we have in place an extensive set of patient access programs for commercial patients, including a coupon that allows a patient to pay as little as $5 for Xywav and a voucher and bridge program that enables commercial patients to obtain Xywav for free for a few months. To support HCP and patient-initiated transitions from Xyrem to Xywav, the Central Pharmacy staff has been increased, and a dedicated team has been created to manage the anticipated demand for Xywav.
We've also increased by 30% the size of our team of account reimbursement managers who are responsible for facilitating access once a script has been generated. Lastly, the joint REMS program for Xyrem and Xywav is efficiently designed such that current Xyrem patients do not need to re-enroll when starting Xywav. This should expedite time between prescription and first fill. Last, we have a clear set of goals for the launch and a core set of metrics we'll be monitoring internally to track our progress and signal any potential issues that require an action plan. Three of these key metrics we plan to share with you on a quarterly basis: the percent of commercial lives with coverage for Xywav, the adoption level of Xywav among existing oxybate patients, and the average number of active patients on Xyrem and Xywav.
We are now only one week away from launch and fully ready to bring this advanced treatment to the patients who can benefit from 92% less sodium. I will now turn it back over to Bruce.
Thank you, Kim. You know, in addition to our approval of launch of Xywav in narcolepsy, last month we were excited to announce positive and compelling top-line data for Xywav in idiopathic hypersomnia, and we look forward to submitting an sNDA in the first quarter of next year, targeting launch in the fourth quarter. With that in mind, I'll next turn the call over to Dr. Richard Bogan, a highly regarded sleep expert who will provide an overview of idiopathic hypersomnia. Dr. Bogan is the President of Bogan Sleep Consultants, LLC.
He is the Chairman of the National Sleep Foundation, an Associate Clinical Professor at the University of South Carolina School of Medicine, and Associate Clinical Professor at the Medical University of South Carolina in Charleston. He serves as Chief Medical Officer of SleepMed, the largest sleep diagnostic company in the United States. Dr. Bogan received his bachelor's degree in chemistry from Wofford College and his MD from the Medical University of South Carolina. He served his internship and residency as well as was Chief Medical Resident at the University of Alabama Hospital and Clinics in Birmingham. He then completed a fellowship and assistant professorship in the pulmonary division of the Department of Medicine at the University of Alabama School of Medicine. He has been certified by the American Board of Sleep Medicine, American Board of Internal Medicine, and American Board of Pulmonary Disease. Dr.
Bogan has served as principal investigator on numerous clinical trials in the past and continues to do so. He has a variety of publications and research interests that focus on topics such as narcolepsy, insomnia, sleep apnea, shift work sleep disorder, restless leg syndrome and periodic limb movement disorder, chronic fatigue, fibromyalgia, and circadian rhythm abnormality. Dr. Bogan, thank you so much for joining us, and I'll now turn the call over to you.
Thank you, Bruce. I appreciate it, and it's a pleasure to be here. I hope everybody can hear me. Let's move on to idiopathic hypersomnia. As we know, there are individuals who are sleepy no matter how much sleep they get.
Of course, you've had an introduction to narcolepsy Type 1 and Type 2, but there are another group of individuals out there who are very sleepy, and we've given them the diagnosis of idiopathic hypersomnia. It's a central disorder of hypersomnolence that's characterized by excessive sleepiness, but some of these individuals are long sleepers and we'll talk about that. The sleepiness is the symptom that really interferes with these individuals, and they tell you that when they wake up, the sleep is not refreshing to them. It's very difficult for them to awaken in the morning. Many of them will say, "I've set multiple alarms, but I still can't wake up," so the sleep inertia is a big problem, especially if you have to get up in the morning, get the kids ready, or get to work. It really bothers these individuals.
We don't know the pathophysiology yet. There's a lot of interest in exactly what's going on in these individuals, and I'll reflect on that in just a little bit. The prevalence, we don't really know. It is idiopathic. Some of the prevalence data you see here is based on claims data, but there are no drugs approved to treat this, and many of the drugs we use actually are off-label drugs. So the incidence and prevalence is not really clearly known. In my practice, I treat about as many people with idiopathic hypersomnia as I do narcolepsy, but that's in my practice. So we're going to learn a lot more as we have new drugs that are available to treat these individuals and as they become more apparent in presenting to the clinic. As I said, it's more common in females than males.
We're not really quite sure why that's the case. We can speculate on that. But typically, it occurs in young females. Oops, my slide moved. Let's get back to where we were. It typically occurs in young females, and the symptoms sometimes do present in childhood. As you remember, in narcolepsy patients, typically the peak is in the teenage years, right around 15, 16 years old. It can occur in younger age groups, and there's been a delay in diagnosis. I think there's a longer delay in diagnosis of this disorder because many times they don't have the features of narcolepsy with the REM dissociative symptoms that sort of call into focus that there is an abnormality. There are significant diagnostic challenges that delay these individuals. They don't know how sleepy they are. They've kind of grown up sleepy.
This is a chronic disorder, though we occasionally see some patients where the sleepiness remits, which is quite fascinating. The Hypersomnia Foundation group, particularly out of Georgia, Emory University, Lynn Marie Trotti, and others have characterized these sleepy patients. And as you can see, narcolepsy Type 1 is pretty obvious. They're sleepy, and they have these REM dissociative symptoms that Bob talked about earlier, including vivid dreams and paralysis and disrupted sleep. And of course, Type 1 has cataplexy. And most of these individuals don't have sleep inertia. In fact, they're pretty good nappers. They can take a short nap and feel better. So they're not really what we would consider long sleepers. And in fact, some of the questionnaires that we use, if they can't wake up easily in the morning, that's a negative in terms of making a diagnosis of narcolepsy, though some of them do have trouble.
The T ype 2 is a blend. They don't have cataplexy. They oftentimes do have the REM dissociative symptoms, so vivid dreams, paralysis, hallucinations, disrupted nocturnal sleep. Oftentimes, they do have those, but maybe not quite as much as the narcolepsy Type 1. But what about the idiopathic hypersomnia? We see a blend, but most of the patients with idiopathic hypersomnia will tell us they have sleep inertia. They're long sleepers. They have trouble waking up in the morning. If they take a nap in the daytime, they will nap for hours. When they wake up, they don't feel rested. They sometimes do have the vivid dreams or the sleep paralysis or the hallucinations that might occur, but primarily, they have this sleep inertia characteristic to them that's apparent. So how do we make the diagnosis in these individuals?
I'll show you in a minute the nosology. Our definition has really evolved. Right now, the International Classification of Sleep Disorders III, which is our current sort of dictionary that we use for our nosology, is that these individuals have daily periods of irrepressible need to sleep or daytime lapses into sleep. Now, chronic means three months by definition. Cataplexy is absent. When we evaluate those individuals in the sleep lab to see what's going on with their sleep, and then the next day we do the nap studies, typically what we do with narcolepsy patients as well, many of those patients are sleepy. So they have to have at least one of the following, which means they have to have a mean sleep latency of less than eight minutes. They fall asleep quickly. They are measurably sleepy.
But we also see a group of individuals who are long sleepers. These individuals sleep over 11 hours per day, and yet they still don't feel rested. Now, many of those long sleeper types may not describe lapses into sleep or napping or their nap added into their total sleep time. It goes over 11 hours. But some of the long sleeper types are not profoundly sleepy the way some of the shorter sleepers are. Of course, we have to rule out other sleep disorders. Insufficient sleep or circadian misalignment are really important to rule out. So when we take these individuals, we evaluate them. What's their clinical status? What medicines are they taking? Are they in training? And of course, then we'll proceed with polysomnography and the nap studies to see if we can characterize what's causing their sleepiness. There clearly is heterogeneity in these individuals.
As I pointed out, some of them, they sleep eight to nine hours, and they're still sleepy. They're able to wake up in the morning. Then we have those long sleepers. But we don't really have a good biomarker in these individuals, much as we don't have a good biomarker in narcolepsy except for the low CSF hypocretin, which we don't normally do lumbar punctures in most of our patients in the U.S., at least, in terms of making the diagnosis of Type 1 narcolepsy. So we do rely on the clinical presentation as well as doing the sleep study and the Multiple Sleep Latency Test. There's a lot of interest in actigraphy.
Actigraphy would be like your Apple Watch or your super Fitbit in terms of sleep-wake processes, but those are not exactly as pristine and accurate as we would like for them to be in terms of facilitating the diagnosis. So I talked about these two phenotypes, with and without long sleep time. And when you look at these individuals in clinical practice, the IH folks without long sleep time, they're sleepy sort of like the narcolepsy patients. In other words, they sleep. Many of them don't have the REM dissociative symptoms such as the paralysis and the hallucinations that might occur at night, but they may have disturbed sleep with awakenings, but they're able to go back to sleep. But in the morning, they have trouble waking up. But finally, they do wake up.
They have sleep inertia for a long period of time, so it really takes them a considerable period of time to really get going. And then they're still sleepy, so they have these lapses of spontaneously dozing during the day. And the associated symptoms of excessive sleepiness in terms of executive function and mood and motivation and workplace performance are big problems in these individuals. The long sleepers are amazing. I mean, they can sleep for long periods of time but can't wake up to the alarm, and they end up sleeping 10 or 11 hours and then napping during the day. So they have marked difficulty with these awakenings. So you're going to hear the term sleep inertia a good bit in patients with idiopathic diagnosis considerations. If you look at the nosology on the left, you see it's evolved.
The International Classification of Sleep Disorders I, II, and III, as we've evolved over the years, we used to say these folks had a mean sleep latency of less than 10 minutes and in narcolepsy less than five. We evolved into the two phenotypes, ICSD II, where the MSLT was less than eight minutes, the same as narcolepsy, but we have the two phenotypes with a 10-hour cutoff. As more studies have been done, and we recognize that the general population sometimes doesn't sleep much during the week, and they try to catch up on the weekends. The cutoff point now is for our ICSD-3 is that now the 11 hours is our alternative objective measure. If someone consistently is sleeping 11 hours per day, they will fall into that diagnosis. As I pointed out, there are no really good biomarkers.
We use hypocretin in our narcolepsy Type 1. The prevalence of the HLA phenotype is the same as the general population. There's no REM sleep instability in narcolepsy Type 1. Many of those patients will have short REM latencies. They go into dreaming very quickly, and of course, we've incorporated that into the diagnosis in the nap studies because you shouldn't dream in the daytime, at least not quickly, and so we see that in the narcolepsy patients as sort of markers or things that have a high degree of specificity for narcolepsy patients, but there are hypotheses about what happens to these folks, and some of the hypotheses relate to the brain sleep-wake processes, so during the day, the brain is making these neurotransmitters to keep you awake, and then at night, the brain makes a neurotransmitter, GABA-A, which turns off the awake circuits, and we sleep.
And then in the morning, that's supposed to turn off, and we start again with the neurotransmitters that keep us awake, orexin being one of those neurotransmitters that's the key to stimulating or activating the awake processes. So it could be that the GABA-A persists into the daytime. And some of the patients will tell you that's how they feel, that they feel like they've taken a sleeping pill in the daytime. There are also some interests in terms of how do these awake neurotransmitters and neural processes affect energy utilization in these folks. There's all kinds of debate in terms of what might be causing these individuals to be sleepy but not have narcolepsy. There are diagnostic limitations.
And again, some of these signals are not easy, but because you can imagine if I put you in the lab and every two hours I turn the lights out and I said, "Okay, take a nap," and you've got stuff going on. So the Multiple Sleep Latency Test can have some variability to it. And in fact, we know from clinical experience, patients with narcolepsy Type 1 who have low CSF hypocretin levels may have a false negative nap study. So it is a somewhat fragile study, and patients can move back and forth from having dreams or not having dreams depending upon their clinical status. They also are on medications, and many of the medicines can affect REM penetration, for example, antidepressants or REM suppressing. So we can have some confusion.
And quite frankly, we've been frustrated in the clinical arena using the Multiple Sleep Latency Tests, but it is what we use, and we clinically correlate it with these individuals. The other is that if you do nap studies in the general population, you're going to find some people who fall asleep in less than eight minutes on their nap studies. And so who are these people and what's going on is another question. That's why clinically we have to correlate with these individuals in terms of the chronicity of the disorder, again, the acuteness of the disorder, and the comorbidities of these disorders, and concomitant meds. When we do a sleep study in these individuals with long sleeper types, this is an evolution of current interest. And the Europeans are doing a good bit of work on this. Of course, some U.S. sites are as well.
And doing prolonged sleep studies in these individuals, given an opportunity to sleep as long as they can in a 24-hour period of time or in a 36-hour period of time, how long can these individuals sleep? So this is an evolving area of interest in terms of looking at extended polysomnography to make a diagnosis, 32 hours of optimal recording time, and what happens to the sleep in these individuals. What about actigraphy? So actigraphy, as you well know, is an accelerometer. So it's looking at movement. It also can look at heart rate and heart rate variability. Are they dipping at night? So we can see if a person is moving. Is their heart rate slowing down? Is there changes in heart rate? It can be associated with REM sleep. So we're trying to get some idea. Is the person awake? Are they asleep?
And how much time are they sleeping in a 24-hour period of time? And document that over a period of time as a surrogate signal. And this is currently under investigation to try to help us define who these individuals are. Well, how do we treat? What's our current treatment paradigm in these individuals? And as you know, there are no FDA-approved drugs pharmacologically that are available. We oftentimes, as clinicians, use medications that have been used to treat patients with narcolepsy, but third-party payers are not anxious to reimburse. So really, some of the plans only approve FDA-approved medications. In the previous published guidelines, these are small studies, not necessarily well-controlled. They're more observational studies or small studies, but there was some early evidence that showed that sodium oxybate helped some of these individuals.
I'm not going to go over some of those publications because what has evolved is that, and you saw this in the press release, is that now we have a study where Xywav has been used in patients with idiopathic hypersomnia based on very specific inclusion and exclusion criteria that did show some improvement, obviously statistically significant in certain domains that were reflective of hypersomnia. One of the scales that was used is an Idiopathic Hypersomnia Severity Scale. We have fatigue scores. We have insomnia scores. We have the Epworth score to tell us how sleepy someone is. We have the Karolinska, how sleepy are you right now? And this scale was developed to help us understand the symptoms that these individuals have. So this Idiopathic Hypersomnia Severity Scale was developed as a valid tool with good test, retest probability, and clinical relevance in terms of the symptoms.
This has shown efficacy in these individuals. It was developed looking at the domains where these individuals have problems. 14 specific questions. They're weighted. There's a Likert score of never or lots of times. There are different weights to these scores, but it's 14 self-administered questions. As you can see, nighttime sleep symptoms are important in these individuals. What is their sleep like? Do they have a lot of sleep inertia the next day? Their daytime sleep symptoms and how that affects them in terms of mood and productivity and other issues. The impairment of daytime function due to the hypersomnia. How is it affecting these individuals? We can get a score, a valid score that will help us quantify the degree of symptoms and help us qualify. Are these patients, do they fit a diagnosis of idiopathic hypersomnia?
We're looking for a questionnaire that would be very sensitive and highly specific for these individuals based on the frequency of these symptoms. Of course, higher scores indicate more severe symptoms, and we've used that scale to help us, again, qualify and quantify these individuals and use it as a measure because it should be a measure of how the patients are responding to the symptoms, so these psychometric properties and its responsiveness to treatment have been demonstrated as a valid tool, and it can differentiate patients with idiopathic hypersomnia from patients with NT1. And the IHSS, as you can see, once you get a score, cutoff value of 22 over 50, tends to have excellent specificity and sensitivity for these individuals to separate from controls or normal individuals, and then the narcolepsy cohort, NT1 particularly, it scored 29 out of 50. It has correct sensitivity but lower specificity.
So we, as clinicians, are still very important in terms of making the diagnosis in these individuals, but these tools can certainly help us with symptom severity and also to look at how patients might respond to therapy. So with that, I will stop and hopefully answer questions later on. Thank you, Bruce.
Thank you, Dr. Bogan. And just as a reminder, everyone, feel free to type in questions for any of the speakers today, and we'll address questions at the end. And I'll now turn the call back to Rob, who will take you through our phase III trial in IH.
Thank you, Bruce. I would like now to step you through the pivotal IH trial with Xywav and the top-line results. The phase III IH study enrolled patients into an open-label treatment titration and optimization period, which lasted between 10 and 14 weeks. Patients were on a stable Xywav dose for two weeks prior to entering the two-week double-blind placebo-controlled randomized withdrawal period. The primary endpoint of Epworth Sleepiness Scale, ESS, was measured at baseline, at the end of the stable dose period, and again at the end of the two-week randomized withdrawal period. The key secondary endpoints, Patient Global Impression of Change, PGIC, and Idiopathic Hypersomnia Severity Scale, IHSS, were measured after the stable dose period and again after randomized withdrawal period. After the two-week stable dose period, patients were then entered onto an open-label extension, which is ongoing. This slide summarizes the impressive top-line results from this study.
Patients who entered the trial were typical in terms of excessive daytime sleepiness severity. As described in the prior slide, all patients were treated with Xywav during the open-label treatment titration and optimization period, and clinically meaningful improvements in the ESS were observed. At the end of the double-blind placebo-controlled randomized withdrawal period, patients who were administered Xywav showed clinically meaningful maintenance of efficacy for the primary ESS endpoint and the key secondary endpoints of PGIC and IHSS. P-values for all three endpoints were less than 0.0001. The safety profile was also consistent with that of Xywav, with no new safety signals observed in the idiopathic hypersomnia patient population. Regarding key events and next steps, Xywav has received orphan drug designation as well as fast-track designation for idiopathic hypersomnia. We expect a supplemental new drug application in 1Q 2021 with the objective of launching in 4Q 2021.
Now I'd like to turn the presentation over to Dan Swisher, President and Chief Operating Officer.
Thanks, Rob. Hope everybody can hear me. Just going to be a few more slides, and we're going to get to questions. So let me start just with a little bit of an overview here. There's a lot on this slide, but the key point as referenced by Dr. Bogan is that these patients have excessive sleepiness and living with idiopathic hypersomnia. They're consumed by that sleepiness, and their activities of their daily life are severely affected. The sleepiness manifests itself in many ways, as described earlier, so I'm not going to go through that list. For those that are suffering from IH, their symptoms lead to challenges professionally, and idiopathic hypersomnia patients often have trouble completing even the most simple household tasks or being able to maintain a job or even an active, well-rounded social life.
Currently, with no FDA-approved therapies, there's a number of common coping mechanisms IH patients use to help them manage through their day, but we hear from patients that while these may help slightly, often only for a short period of time, there remains a significant need for effective pharmacologic treatment, so in terms of the market characteristics, we believe this is a very significant and underserved market. Based on the claims data, there's approximately 37,000 people diagnosed with IH in the U.S., but given the mis and underdiagnoses without any approved treatments, we believe the patient market size to be even bigger. We also know that the majority of this diagnosis has been generated by only 800 prescribing physicians, and there's a 90% overlap of these IH prescribers or diagnosers and treaters with our current call universe for Xywav.
For any future launch in this market, Jazz would be able to fully leverage its existing HCP relationships, its field forces, customer services, and other non-personal efforts. While we've been highlighting recently Xywav's IH data, which is very compelling, and we look forward to advancing this indication to the market in 2021, as well as other updates, this call is really focused on the Xywav launch in narcolepsy, and Xywav is a major advance for narcolepsy. You can see that with the 92% less sodium than Xyrem. Dr. White put this in very nice context of cardiovascular health and the consequences of high salt intake, and as you heard from Rob Iannone, the cardiovascular risk factors among narcolepsy patients with this lifelong condition, so we believe it will become the treatment of choice. We are targeting a majority of oxybate patients to be on Xywav by 2023.
Our near-term focus is to support a launch strategy focused on strong adoption, both for existing oxybate patients who can transition seamlessly gram for gram from Xyrem, as well as naive patients, along with patients who are unable to take Xyrem due to sodium concerns. In terms of the adoption, narcolepsy patients who couldn't previously take Xyrem will now have this new treatment option. So focus is on seamless access to Xywav beyond the efforts around patient and physician education to fully understand the burden of lifelong high sodium intake and the unique product attributes. We're ensuring seamless access to this therapy with a suite of patient assistance programs alongside a market access strategy to ensure broad payer coverage, as Kim referenced.
We're very excited to be officially in full launch mode for Xywav, the first and only lower sodium oxybate, and we look forward to providing future updates on the progress of this very important initiative, and with that, I'll turn the call back to Bruce.
Thanks, Dan. We're excited about launching Xywav next week for the treatment of cataplexy or EDS in narcolepsy. Given that narcolepsy is a lifelong condition, reducing sodium intake is a significant advance for patients. We've heard from both HCPs and patients that they're looking forward to having a lower sodium oxybate product available. Separately, we're also excited about the IH opportunity and look forward to bringing Xywav to IH patients and plan to submit an sNDA in the first quarter of 2021, targeting a launch in the fourth quarter of 2021 following FDA approval. We'll begin the Q&A now, starting with questions that were addressed to our scientific and medical experts, Dr. White and Dr. Bogan. If you have additional questions, please submit them. I'm, in general, going to try to read questions as they were written, but I may occasionally combine a few questions if they're highly similar.
So with that, I'll ask Dr. White to come off mute and let me throw a couple of questions your way.
Okay. Thank you.
Can Dr. White discuss examples of physicians choosing between drugs to avoid sodium intake? And is there an example of regulatory action by the FDA on drugs to address the sodium issue, for example, safety trial requirements for high sodium drugs?
First of all, amazingly, most of the high sodium medications in the U.S. and in Europe are in analgesics and in calcium supplements that actually have sodium in them as well, such as calcium, vitamin D, and there's a lot of salt in those. And these are all the effervescent products that happen to have a lot of salt in, but that's over-the-counter things like Alka-Seltzer. So we don't have another bona fide sort of experience with a chronically administered medication as we do with sodium oxybate to really contrast the two different issues. As far as I know, I haven't heard of an FDA-related regulation. However, I can tell you that they're exquisitely sensitive to drugs that raise blood pressure when they're particularly used for subacute or chronic conditions.
In recent times, as well as one year ago, maybe a year and a half ago, there was a very major presser meeting held at the FDA through Duke-Margolis and the Cardiac Safety Research Consortium, in which they presented their guidance and actually demonstrated at that time that any drug that has a hint of raising blood pressure will have to do thorough ambulatory blood pressure monitoring studies and could get a black box warning if it's, in fact, found to raise blood pressure by 2 or 3 mm of mercury. It doesn't sound like a lot, but they're taking it very seriously because of the general risks that I showed in my talk.
And I'll just add, for context, something I've said for quite some time, which is, of course, the sodium becomes an issue if there's a lot of sodium in the drug, and there aren't many drugs that have ever had the amount of sodium as Xyrem, and if they're taken on a basis. And so this is much less relevant for drugs that start with less sodium or that are taken acutely. For Dr. White, it seems there's a lot of compelling data on the benefits of lower sodium intake, reducing blood pressure, and improving CV outcomes that would drive physician prescribing behavior with Xywav. But when generic Xyrem ultimately becomes available, will payers find that benefit important enough?
Are there examples from the other drugs you've mentioned on how easy it is to give lower sodium options to patients and if there's payer support for that, or if physicians would go through the hoops to ensure patients can get the lower sodium drugs? Dr. White, take this or not, depending on how comfortable you feel commenting on payer behavior.
I'm comfortable on payer behavior for other reasons. I think I can forecast relatively easily. I mean, clearly, part of payer behavior has to do with penetration of a drug within a particular market or region, depending on who it is. For example, in the upper Midwest, there's payers that basically cover three or four states, and Kaiser has their rules and so forth and so on. But I would say that this is a fairly dramatic difference in these two products and that the benefit of taking 1 g less of sodium per day is clinically meaningful.
And therefore, it would translate in many instances to them accepting the difference, particularly if there's any untoward effects of a higher salt content, or perhaps there's been resistance to starting the drug in the first place because of high salt intake, because, let's say, somebody has a history of edema or they happen to be 45 years old and they're starting to develop some high blood pressure, or maybe they have other cardiovascular concerns. That would basically put them in sort of a high-risk category, and therefore, they might be chosen first, and therefore, the others who are normotensive might be chosen second. I mean, I could see that kind of tier thing happening legitimately, but again, that would be a test case.
We've had lots of experience with a variety of drugs which have become preferred versus intermediate versus kind of full pay, depending on the perceived benefits by the payers and also the combination of that, plus how it got penetrated into their market, into their patient population.
Thank you. And Dr. White, you are very familiar with the increased CV risk and comorbidities with elevated intake of salt, but how well does that message resonate with non-cardiologists, or rather sleep specialists in this case, as they manage these patients? Are other physicians sufficiently educated, given most specialists are focused on their own disease types? And Dr. Bogan, I may come to you with this one as well.
Yeah, I was going to say we should both address this. I think this is a good question for both specialties. Well, certainly, I think that I was listening that Dr. Bogan is a sleep specialist, also an internist. We're all internists, actually, at one point in time, and we are all very cognizant of the fact that high salt intake translates into higher blood pressures and higher cardiovascular disease burden. So I don't think that this would be something that would be flying past the mindsets of the physicians who are prescribers of a drug like this, and this is mostly going to be prescribed by people who are specialists or experts, and they typically want to get a really good handle on all of the efficacy and safety of the drugs they're prescribing to their patients.
I don't consider this to be a problem from my perspective.
Dr. Bogan?
Yeah, I would say, as you say, we appreciate the problem with sodium and its cardiovascular effects. What I would say as an addition, however, is that maybe we don't know as quantitatively the clinical relevance. So I think the message that was delivered is actually quite a powerful message, and so I suspect that if there is a deficit, the deficit will be recognizing the impact of just reducing sodium intake by 1 g . It's just amazing.
Great. And I've got another question that came in for Dr. White, but I may ask you both to weigh in on this one too. Is disrupted sleep a higher risk factor for CV risk, like in the BOND Study, or is high sodium a bigger CV risk?
Yeah, I love this question, actually. I think it's really interesting because just to give a little background, the individuals who have obstructive sleep apnea have obviously significant sleep-disordered breathing problems. And it's been known for a really long time that there's increased cardiovascular risk in this population. And it's a mixture of things. It's the problems with sleep architecture, but it's also problems with kind of the ups and downs of the adrenergic nervous system during sleep. So clearly, it's a risk factor from a cardiovascular standpoint. Now, the question is hard to answer because it's sort of, how would you know which one is worse? Having a high salt intake that lends itself towards hypertension that's not well- controlled or not well- recognized, that's certainly a risk factor all by itself, independent from everything else, as is the disrupted sleep.
But I think that they're, I guess the question would be, if you're taking a high sodium oxybate for disrupted sleep, and you make the disrupted sleep better, you lower some risk, but you also increase it with the sodium. So the obvious thing is that take the low salt formulation. It's kind of like a double whammy. You're improving sleep architecture and having less problems with disruption of sleep, and you're not giving a high salt load. So I think that would end up being a good educational area to explore with prescribers when the drug is launched or when the program gets set up.
Dr. Bogan?
Yeah, I would say you can't quantify. I don't know which is yin and yang, which one is the most significant, but as clinicians, we take all those things into account in terms of exercise and weight and sleep and sodium intake, etc., but I don't think I'm not comfortable quantifying which one is more important compared to the other, and I think that's going to be highly variable with the individual as well.
Great. So Dr. Bogan, given the phase III results for Xywav, would you use Xywav on your IH patients prior to approval? Do you use Xyrem on any IH patients currently off-label?
The answer is yes. We have many patients that have narcolepsy features and only have one sleep onset REM episode on the Multiple Sleep Latency Test. So technically, they don't have narcolepsy based on our nosology. So the International Classification of Sleep Disorders III says those who fall asleep in less than eight minutes on average and have two sleep onset REM episodes to have narcolepsy. So we have a fair number of patients who have only one sleep onset REM episode or are obviously IH patients. They don't have any sleep onset REM episodes. But we've been successful with a few payers because nothing really has worked in these individuals. We've been pretty desperate. And so we do have some experience in this particular disorder. And of course, I did participate in the research study, which was a maintenance of effects study.
We had the opportunity in the open-label phase to treat patients as well to see how they did. Before we did the double-blind withdrawal period, the two-week blinded period. So I do have some experience, and I do use the drug in patients, Xyrem, in patients with IH. I don't have Xywav yet except in the clinical trial. Did I answer your question?
Great. One more question. Well, it's not my question, so I'm going to say yes. One more question on IH. Can you comment on the real-world incidence of IH relative to narcolepsy? What's the current diagnosis and treatment rate of patients, and how is that likely to change with the availability of an FDA-approved treatment?
Yeah, that's a great question because there's a lot of question about long sleepers and the distribution of long sleepers, short or normal sleepers, and their degree of sleepiness. What I will tell you clinically is that in my clinic, my impression is that the prevalence, I would be surprised if the prevalence is not comparable to what the prevalence is of narcolepsy patients, quite frankly. We have a lot of individuals who have only one sleep onset REM episode who are pretty sleepy, and they don't have other reasons to be sleepy. They have adequate opportunity to sleep. They don't have other sleep disorders, and yet they're particularly sleepy. So I think the prevalence we're going to see as we get more experience with this disorder, we'll see the prevalence increase. As far as treatment interventions, many of the payers won't let us treat the patients.
They'll just say, "There's no FDA-approved drug. We can write a prescription for a drug," and they just won't approve it. What we've been able to do is use the classic Schedule II stimulants , and we've been able to use modafinil in some of the patients because the American Academy of Sleep Medicine does have guidelines to treat patients who are sleepy, and amongst those, there was some early little bit of evidence that showed modafinil might be beneficial in some of these patients. My impression is that these individuals are really pretty profoundly sleepy, and these medications, while they're helpful, this fogginess that the individuals have is really substantial, and they've been very difficult to treat.
So to have an FDA-approved drug, which I'm hoping will happen, but the opportunity to have an FDA-approved drug that showed the biological signal that was seen in the clinical trial is really pretty exciting.
Dr. Bogan, can you speak to whether 10%-15% of sleep apnea patients with sleep inertia could be candidates for Xywav assuming an IH approval?
Probably not. I mean, the ICSD-3 talks about there's not another reason for the patient to be sleepy. They have an adequate opportunity to sleep, and they don't have another sleep disorder. Having said that, we know that narcolepsy patients have a higher prevalence of obstructive sleep apnea as a comorbidity. So we can have patients who have both obstructive apnea and narcolepsy. And of course, in those patients, we will use Xyrem, protecting the airway because Xyrem could theoretically affect the obstructive sleep apnea. But we don't have a lot of experience with females, particularly. Most premenopausal females have a low prevalence of obstructive sleep apnea. So it's unlikely that we're going to see patients with both idiopathic hypersomnia and obstructive sleep apnea as a comorbidity. Now, having said that, when women reach the perimenopausal years or postmenopausal, they do develop more obstructive sleep apnea.
But by that time, we probably would have made the diagnosis. So the sleepy OSA patients are not likely to be treated with Xywav.
We've heard from physicians that many patients get misdiagnosed as IH. Can you comment on the current criteria of diagnosis of Type 2 and IH patients and potential overlap? I think you've hit some of this, but we'll see if you want to add anything.
Yeah, I think the main thing is the Multiple Sleep Latency Test is not the most reliable test. And if I do the test on the same person two or three times, they might bounce back and forth. And so I don't think it's a matter of misdiagnosis as it is the study technique itself of the Multiple Sleep Latency Test is a challenging test to do. And so we may see some patients meet criteria for one diagnosis, and then if you retested them later on, they may move to another diagnosis. And some of that is affected by current medications because most of these patients want to be treated. They don't feel good, and they're on medications, and the medications themselves may affect the Multiple Sleep Latency Test later on.
I think the misdiagnosis is really more the difficulty in making the diagnosis and recognizing that the test is not a good, it's not our ideal test. It's what we use based on our nosology, but it's not the best test in the world. We need a biomarker if we could.
Amen. For Dr. Bogan, do you see Xywav being prioritized in patients with long-form of IH, or would you use the drug more broadly irrespective of disease phenotype? If long-form only, can you estimate what percentage of IH patients have this as a predominant symptom?
Yeah, that's another great question because it depends on which investigator you talk with because some of them. I mean, they're very interested in these long sleepers. But in the clinical trial, most of the patients. Some of them were long sleepers, don't get me wrong. But most of them were able to get up in the morning. They had sleep inertia, so they might have trouble getting up. But they were sleepy like our narcolepsy patients. So they had high Epworth scores, which is our scale for sleepiness, but some of the long sleepers may not have a high Epworth score. What's their chance of dozing while they're sitting and reading and watching TV? They don't feel good. They're foggy, and they have this sort of inertia. They just want to. They're tired. They just want to sit there, but they may not doze off.
There's a lot of discussion about those particular phenotypes. In my practice, I would say I have a—for me, it's almost 50/50 in terms of the long sleeper as well as the people who are more normal sleepers still have the sleep inertia, but their chance of dozing in the daytime is high. They have a high Epworth score. I think both phenotypes really benefit. The study design and the research picked out patients who had abnormal Epworth scores, and some of the long sleepers might not have been in that group, but there were some long sleepers in there. Yeah, I think both phenotypes are amenable to be treated by Xywav.
Dr. Bogan, what sort of CV comorbidity is there with IH patients? Is it lower than it is with narcolepsy because it's more prevalent with younger women? Trying to understand the importance of a low sodium formulation in this patient population, also considering when generic Xyrem will become available and how that might be used for IH.
Yeah. Well, I think I'd start with that this is a chronic disorder, and I think in any person, any adult, and any child for that matter, I'm going to recommend that they have a lower sodium intake than what most of them are consuming, particularly those of us from the South. So no matter what comorbidities they may or may not have or be at risk of, I think the lower sodium choice is going to be the obvious choice. As far as the comorbidities and idiopathic hypersomnia, that's yet to be determined. This is a poorly studied disorder compared to narcolepsy. But at the moment, I would say that the comorbidities we see with narcolepsy may not be there. I think, again, it remains to be seen. These are sleepy individuals. They may not be as active.
They may not feel as good as working out and staying healthy. What's going to happen to their weight, and does that contribute to comorbidities? All of those are factors that we have to consider as we evaluate these individuals and learn more as we go forward.
Dr. White, I don't know if you want to jump in on that one too since I think the question is in part, is there anything special about IH, but it's also just going to sodium consumption in general?
I'm going to have to admit that I know very little about this disorder. As a matter of fact, I don't think that it was really something that was labeled when I was going through my formative years of training. I don't like normally to punt, but unless you had something very specific that was cardiovascular in nature, I'm not sure what I could add.
Yeah. And I'll just remind all our listeners, part of the reason we wanted Dr. White to present on this call was just to make sure people understood that there really isn't any patient group for whom the high sodium consumption is something that would be a good idea long- term.
Oh, yeah. I mean, if that's the context with which you're asking, that's certainly true. I mean, as I mentioned, the population that had the high-salt paracetamol only, they were 121 over 69 when they started into the study, and their blood pressures clearly came up pretty substantially. So some of them were controlled hypertensives, and some of them were normotensives. So it's not as if you're scot-free just because you happen to have a pretty good blood pressure before you get started on the treatment.
For Dr. Bogan, why haven't there been more drugs studied or approved in IH? And what's your expectation for the number of diagnoses or growth of this market once we have an approved drug? I think you've got the second part you've hit already, but why not more drugs studied or approved in IH?
Yeah. I think you saw the definition evolve over time. And so I think our clinical knowledge of who these people are, what's the pathophysiology, how do we define them to recognize them and intervene? All of those have been rate-limiting steps in terms of new drug development. It's a very real disorder. It's clinically meaningful to these individuals. Now we're getting better tools to both diagnose and see a signal in terms of using the Idiopathic Hypersomnia Severity Scale. We have tools available to us now to better quantify the response to therapy. So I think we've been struggling with the diagnosis, and now we have our arms around the diagnosis better. I think the opportunity for drug development improves with that.
Dr. Bogan, has Sunosi been considered as an option for people with IH?
Certainly. I think as I think I said earlier, as clinicians, we try to use everything we do for our other sleepy people, narcolepsy. And so certainly, that would be a strong consideration. So anything that's going to promote wakefulness in these folks would be a reasonable consideration. And of course, the advantage of the Sunosi is it doesn't interact with birth control pills. The disadvantage is it's not approved by the FDA to treat IH. It's approved for narcolepsy patients and patients with obstructive sleep apnea who are still sleepy despite using their CPAP. So it's not approved by the FDA, but it certainly would be a reasonable drug to consider.
Okay. Thank you. Kim, I think I'm going to come to you with a few questions now. There's a lot of questions around payers. I'm going to combine a couple of them as I go, and you've addressed some of this in your presentation. But how are you thinking about payer engagement evolving for smooth uptake? We've had people asking about whether Xyrem is already getting use in IH patients. Hang on. Let me see. Well, why don't you just talk about payers a little bit?
Sure. So what I will say, as I'll reiterate, that our pricing strategy really was selected because we do want broad and rapid uptake on the payer formulary. So we were very confident when we selected that parity pricing strategy that we would be able to achieve that goal. And again, I'll reiterate that we've had ongoing discussions with payers for a number of weeks now and are very encouraged and have already signed a contract for the commercial lives of one of the three major payers. I had thought some questions regarding treatment of Xywav versus Xyrem. We really do anticipate with this pricing strategy equal treatment of Xywav and Xyrem by payers, meaning, for example, comparable utilization management and prior authorization criteria. So we're feeling very confident on that front heading into launch.
In terms of IH, I don't have hard quantitative data, but we have heard anecdotally quite a bit from specialists who have tried to obtain Xyrem for their IH patients that it's extremely difficult to do. Once in a while, you can get it approved. But largely, given the price and the fact that it's not currently indicated, it's usually the exception rather than the rule that they can get it covered by a payer.
Okay. There was another question that came in with two parts, one of which I think you just hit, which is really about parity pricing and parity access. The second part of the question, I'm just reading it as it came in, how do you market the sodium risk without killing the safety of Xyrem? To market Xywav is essentially to say that prescribing Xyrem for all these years has been putting patients at risk, and I just want to address that head-on. The benefit-risk balance for any drug is what determines whether it should be on the market and used. I think you heard some comments from our KOLs already in the Q&A about FDA's concern about sodium, about blood pressure, black box warnings. That doesn't mean the drug shouldn't be on the market. It means it's important to understand the benefits and understand the risks.
We're excited to have the benefits of Xyrem with the oxybate moiety without that additional sodium risk. So I hope that's a clear answer. Kim, can you talk about the willingness of patients to switch? What will be the impetus for physicians to switch an existing patient from Xyrem to Xywav? Will it require a patient visit?
Okay. So let me start with the patients. From our market research with patients, we really believe that patients are very interested in Xywav. In fact, when we show them the product profile and market research for Xywav, nine out of 10 current Xyrem patients indicate that they plan to ask their doctor about it. So we believe that this high-level patient interest and intention to take action is actually going to be a very major driving force of Xywav adoption out there in the marketplace. Furthermore, our market research with HCP shows that 75% of the time that a current Xyrem patient requests Xywav, the HCP intends to grant the patient that prescription. So again, we believe this high grant rate is a reflection of HCP's very favorable response to the value proposition of Xywav.
It's really the working together, both the patient and physician, the combination of the patient and the physician receptivity to Xywav that will be very synergistic in driving the demand and ultimately the adoption of Xywav in the marketplace.
Yeah. Bruce, this is Rick. I would echo that. I mean, I've been talking to my patients about it as soon as the drug was approved. And I typically see these patients every three months, three to four months, just to monitor their progress. And almost all of them, when you introduce the concept, they're like, "Okay. I'm ready to change. When's it going to be available?" So of course, that's an N of 1 as far as healthcare practitioners are concerned. Kind of a no-brainer.
Let's see. There are some questions about patient assistance, Kim. Will Jazz consider giving the first monthly prescription of Xywav to patients free of cost to help acclimate them to the new therapy? Where's another one? How could you use patient assistance to drive Xywav use? Will you still provide equal patient assistance for both products, or could copay assistance represent a lever to help encourage switching?
Yes. Okay. So as I mentioned before, we have a very broad set of patient assistance programs designed to provide access and affordability to patients, including buying their copay down to $5 a month through our coupon. In terms of providing a free month, we've got a bridging and voucher program that is going to be available to any patient that doesn't have coverage yet for Xywav and that they're going to be able to get a few months of product free while we're waiting for that broad coverage we anticipate to kick in. And then lastly, in terms of patient assistance, similar to Xyrem and actually identical to Xyrem, we will offer a patient assistance program for both Xywav and Xyrem. So basically, equality in terms of that program.
We don't so much look at that program as a vehicle to drive adoption, more so to be there to support patients who can't afford their prescription.
Kim, there have been a couple of questions that I think are trying to get at gross to net and how that might compare. It's asked different ways by different people. It's either asked in terms of, does price at parity mean net price per prescription will be the same initially and over time, or how should we think about the spread between gross and net sales for Xywav relative to Xyrem?
Thanks. So what I'll say is our strategy is a parity pricing strategy. So we'll be priced at the gross level, the two products comparable. And we were out, as I mentioned, talking to payers and negotiating contracts. So again, our strategy is net price parity. Where we ultimately end up depends on how those negotiations go. But I would anticipate that the Xyrem and Xywav access and contracts with payers will be quite similar. So given that, you can expect that we will have discounts to payers and a difference between the gross-to-net and the gross selling price in our financials.
As we do with Xyrem as well. With some of the patient assistance at launch, we do expect some widening of gross to net, at least in the short- term, right? That's as patients are adopting Xywav and as we're finalizing these negotiations.
Yeah.
Kim, what? Go ahead.
I was just saying I think we plan to talk more about gross to net in future calls.
Yep. What specific claims or language in the Xywav label do you have with language that can point to Xywav being a healthier version of sodium oxybate versus Xyrem? What can the sales force speak to?
Sure. What the sales force can speak to is basically what I laid out for you today in our slides, talking about the fact that narcolepsy is a chronic condition whereby all patients, by virtue of their diagnosis, are at increased risk for cardiovascular events and disease, the impact of sodium on cardiovascular health, and showing that that is well- established, and emphasizing there's broad scientific consensus that reducing sodium consumption, which is a modifiable risk factor, is associated with clinically meaningful reductions in blood pressure and cardiovascular disease risk. So given that narcolepsy is a lifelong condition, we therefore believe that reducing sodium intake versus the standard of care by 92% each and every day is a significant advance for these patients.
We've seen in market research that when HCPs are presented with this information and line of messaging, that many feel compelled to both start their newly diagnosed patients on Xywav and transition existing patients from Xyrem to Xywav where appropriate. I mentioned earlier that we also have the patients out there with a very strong interest to ask their doctor about Xyrem based on that line of messaging.
All right. Kim, just how meaningful is the number of patients not prescribed Xyrem due to sodium content concerns? What percentage of these patients have been left on the table? And how many patients are there that have discontinued Xyrem over the years? And what portion of those do you think is because of the high sodium content and potential cardiovascular issues?
Okay. I'll try to address that with one piece of data that we have from a small research study. We've seen that physicians reported that up to 20% of their patients in their practice who were otherwise eligible for Xyrem were not prescribed Xyrem due to its high sodium content.
I'm going to jump in and take a couple of questions here. Should we think of 50% Xyrem decline from peak as triggering generic entry? If no, can you provide better understanding of the dynamics as you may reach 50% switch ahead of 2023? We'd love to hit that ahead of 2023 to be clear. I can't give you more specifics on the market decline provision than we've already given. Here's a question. I'm just going to read it as written. For the content that Dr. White is sharing, were any of the patients actually diagnosed with narcolepsy included in these studies? Over the past 20 years, have there been significant issues with Xyrem patients and salt that have not been made publicly available, such as increased stroke for Xyrem users? A little bit of a negative tone to that question.
I'll just say we obviously do all the required pharmacovigilance. That data is all with us and with FDA. Of course, that's all available. We see higher cardiovascular risk and morbidity and mortality in narcolepsy patients. That's not specific to Xyrem treated or not Xyrem treated. We just see that background rate. So relative to healthy normals, definitely yes. There were a couple of questions that went even beyond gross to net that were really trying to figure out how much—and I'm just reading the questions as written—how much will you lose on Xywav versus current in year one? Can management provide any additional details on the proportion of patients who will be eligible for free drug for a few months? Clarity on how to think about revenue impact.
I'll just say to all of those, in terms of revenue financial guidance, we'll do that when we give guidance for 2021 across the business. There was a question about, given the obvious health benefits and talked about patient demand for low sodium, then why is the target 2023 for the majority switch and not 2022 or before that? One of the reasons we gave that as a target is we were trying to help people understand how we think the marketplace could change over time, including entry of additional products. I wanted to go out far enough in time to take that into account. That would include an extended-release version of oxybate with higher sodium. It could include authorized generics. I mean, we intentionally went out to 2023.
So that was the purpose for giving that date as opposed to being a specific commentary on rate of adoption. So Rob, I think I may come to you with a couple of questions. One is, have we reached a sufficient number of months post-Xywav approval to effectively rule out that drug receiving Orphan Drug Exclusivity ?
Thanks for that, Bruce. So what I would say is, given everything you've heard tonight about narcolepsy and the risk of sodium and Xywav, we certainly believe that Xywav should be considered clinically superior and eligible for ODE. Typically, the FDA will make a determination on this after approval, and sometimes it takes several months, but there's no set timeframe that they're required to do so in.
Great. Rob, is there any reason why FDA would not grant Priority Review for the IH sNDA filing?
No. Just to review how the process goes with FDA, we have Fast Track designation, which suggests the FDA agrees around the disease severity and the potential for Xywav to meet this significant unmet need. Priority Review, as you know, is determined by the FDA only after the NDA submission at the end of the 60-day validation period, so that's when we would expect, and we certainly would be requesting this of the FDA.
Rob, what sort of magnitude of benefit did you see in the IH phase III trial? Would highly statistically significant translate to highly clinically meaningful? Can the benefit be compared with what you saw in the Xywav narcolepsy phase III?
Yeah, so as the highly statistically significant results suggest, and by the way, this is across all three key endpoints, we believe the results are clinically meaningful, and we do plan to publish the detailed results in an appropriate upcoming Congress and ultimately in a peer-reviewed journal.
And Rob, doctors in the Xywav IH trial were allowed to titrate the patients up. What proportion of the doctors' patients were a single dose of Xywav or two? And with respect to the sleep disruption contribution to cardiovascular risk versus sodium content, which is more likely to be important in the physician's opinion? A single dose of high sodium oxybate or two doses of Xywav?
So for the first question, we haven't disclosed that level of detailed results yet, but we certainly will at the appropriate time in the upcoming congress or certainly in the peer-reviewed publication. Getting to the second question, I would say that, again, everything that's been discussed here today really substantiates that the lower sodium Xywav is the right choice for all patients, either with narcolepsy or idiopathic hypersomnia.
I think we have said, Rob, that most patients got twice nightly.
Okay. Great, then. Thanks for that reminder. I didn't know what we had said, and I don't know if we've gone into any more details than that. And that's not necessarily surprising. And we know from our patient experience more broadly with narcolepsy that the twice nightly actually affords a lot of flexibility and is preferred by most patients.
I will say I've seen a couple of notes based on prior data that has nothing to do with this trial that some people are assuming the amount of oxybate used in IH patients would necessarily be lower than in narcolepsy. And I don't think that's a well-founded assumption. I think your assumption should be relatively similar use. Rob, two questions. When do you plan to take your low sodium once nightly into clinical development? And what are your expectations for Xywav receiving an ODD? I think you hit the second one already. So when do you plan to take your low sodium once nightly into clinical development?
Yeah, so as mentioned, it's already in clinical development. This summer in August, we evaluated it in healthy volunteers, and our goal is, while we believe that the twice nightly Xywav is preferred by most patients, we want to support all narcolepsy patients, and our goal is to provide a low sodium option for that subset of patients who may prefer it.
So Dan, I'm going to come to you with a couple of questions. To what degree was IH embedded in the prediction around the percentage of sales by 2023 goal? I believe the prediction came before the top-line readout. Where or when can we expect IH results to be published or presented?
Yeah. Thanks, Bruce. We did make that comment in the context of the narcolepsy market before the IH results were going to read out at our Q2 earnings. Yeah. That being said, we had signaled we were optimistic about getting to good IH results. And we do think that the IH market opportunity is a significant one. And this would be the one and only approved therapy for it if we succeed with the FDA. In terms of, I think Rob mentioned it too, we're going to be presenting at an upcoming conference and publication. And we'll let people know when those results are ready or available.
Dan, where are we? I'm not sure I can read this correctly. Question about diagnosis of IH. How many are diagnosed in the U.S.? How many are treated? What are they treated with? I think that's all been covered. How do I think about the slope of expected launch trajectory for Xywav and IH? What's the potential peak commercial revenue opportunity? Somebody else asked, came at it a similar way. What percentage of IH patients could be on Xywav three years after the IH launch?
Yeah. I mean, we're just now with clinical results going to test to understand the market research and market demand, but I will say we think IH is a real market that is crying out for therapies, and a good example is the pace of the clinical trial accrual that we had, and importantly, just a very small number of patients had Xyrem before, so we know there's IH patients that can be diagnosed and looking for pharmacologic treatment, which Xywav would be appropriate for, and like narcolepsy would be a lifelong condition, so we're, and maybe just the one other context is 75,000 diagnosed narcolepsy patients, currently 15,000 on Xyrem. We do think the 35,000 we know from claims is probably understated, but again, it'll take some time for market development, market education, and then the adoption of the therapy by patient and physician.
The good news being that the vast majority of the physicians are very familiar with oxybate therapy. So that gives a leg up for moving into IH.
Dan, this may have been addressed already, but there's a question. My sense is that some investors worry that IH is already being treated with Xyrem and therefore not truly a franchise expander. How would you address this concern? And then a different question. Do you have any data from insurers or otherwise that proves there are, in fact, IH patients out there today that are getting oxybate prescribed but rejected because it's not officially approved?
Yeah. And just triangulating on a few things. We don't have that sort of claims data triangulated in that sense yet, though that's some work we can do. But we know anecdotally in the field that it's very difficult for a true IH patient to get therapy given the price and payer requirements and utilization factors that payers use. So in the rare exception, there's some KOLs that can sort of push it through, particularly if there are some overlapping narcolepsy. But that's the vast minority. Of the 156 patients, a single-digit number of them were coming into the study with prior Xyrem. So again, I think there's a very big untapped market. And with an approved indication, it really changes the dynamic with the payers.
Dr. Bogan, I'm going to come back to you. There's a question I didn't hit before around IH. What successes have you seen with currently available various generic wake-promoting agents? And how do you anticipate uptake of Xywav will look like across sleep specialists across the U.S. over the next 12- 24 months?
Yeah. I would say, again, my opinion is that these folks are very difficult to treat. They certainly get better with stimulants. We use Schedule II drug stimulants a fair amount because that's about all we can dose them. They get a response, but it's still not optimal. I would say the majority of the individuals are still foggy. They have the sleep inertia. In fact, sometimes the spouse or parents have to wake them up to give them the medication so they can wake up an hour later. The sleep inertia is a big problem. I think the Xywav results were clinically relevant. Most clinicians, myself included, are pretty excited about the opportunity to use the drug.
Great. I'm going to ask Dan one more question. And then Dr. White and Dr. Bogan, I'm just going to let you guys wrap up with any other comments you'd like to make to clarify or any final points you want to make. But before I do that, Dan, how many sales reps are you adding to launch Xywav or any plans to realign the sleep sales force as it stands today?
Yeah. At this point, for the market launch, which is underway as of today, we haven't made any changes to the field force. And we think we're well covered right now with narcolepsy. And again, the overlap with IH would be the same physician audience.
Great. Thanks, Dan, so Dr. White, thank you again for making time to be with us, not only for your presentation, which turned out to be more complex than we thought it would be with the glitch, but also for sticking around for questions, and I just wanted to give you an open opportunity if there's anything you want to add in conclusion.
I guess from a clinical perspective, if you think about reducing anybody's sodium intake by 1 g in a day, it's going to bring a lot of people down to what would be considered a good daily sodium intake. And if they're starting out at 3,000, you bring them down to 2,000, they're going to be in a good range for those people who are going to end up switching from the high sodium oxybate preparation to the one which is essentially devoid of sodium. And we didn't talk about it, but it's through the addition of other salts, which are actually probably good for you, such as potassium and calcium, and in quantities that are just about right, by the way. And that's another thing that we didn't get into.
But just for the people listening still, a little extra potassium in one's daily intake is actually good for the heart. So I just wanted to make that a little statement from a clinical perspective as well. So I think that as time will go on, there'll be more data accumulated from various mechanisms about drug safety and this drug safety as well. And it's going to, I think, really be illuminating.
And Dr. Bogan, same softball to you. Anything else you want to add that you want to bring out or summarize with?
Yeah. Just to summarize, I think myself and others, and especially our patients, are excited about a low salt preparation for our narcolepsy patients. And at least in my clinic, we plan on transitioning as many that we can over to the Xywav. And why not? Because of the bioequivalence. The other is the IH. It's hard to get your arms around these sleepy people because of the two phenotypes, the long sleeper and the not long sleeper. But these folks are really significantly impaired. And I think the idea of taking a pill in the middle of the day is sort of how they feel. And they feel foggy. And they're extremely difficult to treat. Right now, using many off-label therapies, to have a drug with this amount of signal biologically is pretty exciting. So I'm waiting to see how this evolves. And I'm pretty excited about it.
Terrific. Well, thank you to Dr. Bogan for making the time and sticking around for questions. I just want to wrap up and thank all of you who stayed on the phone through the audio difficulties and through the Q&A portion. We hope you found this helpful, and just to reiterate, Xywav will be officially launched November 2nd, and I think that will complete our call. Thank you, everyone.
Very good. Thanks.