All right. Good morning, everybody. Welcome to Harmony Biosciences Inaugural Investor Day. It's exciting to see so many people here in the room. A lot of familiar faces, some new ones. We want to welcome all those that are on the webcast as well. Reminder, I'm gonna be making some forward-looking statements today. So, to look at a more detailed version of the risk factors, please see the SEC filings. With that, I'd like to turn the presentation over to Dr. Jeffrey Dayno, President and CEO of Harmony Biosciences. Welcome, Jeffrey.
Thank you, Brennan. Good morning, everyone, and welcome to Harmony Biosciences' Inaugural Investor Day. To those of you in the room and those of you following on the webcast, I first wanna thank you very much for your time this morning and your interest in Harmony Biosciences. We are here today 'cause we are really excited. My team and I are very excited to share with you a very unique and compelling story, and we hope that you share our excitement and will feel our passion for what we've been building at Harmony over the past year. It starts with our proven track record of success with WAKIX in narcolepsy and one of the most successful orphan rare drug launches in the industry.
You know, and from there, we've taken an innovative, very successful drug in the market, and in our patient-focused drug development strategy, we're working to make it better with pitolisant high dose or pitolisant HD, to address an important unmet medical need in patients living with narcolepsy. From there, we've executed smart and strategic business development deals, fully funded off of our balance sheet. And that's why we're here today. To share with you the new Harmony Biosciences and to demonstrate that we have what it takes to drive durable, long-term shareholder value. It starts with innovation. We are at the center of the science. From WAKIX as a first-in-class molecule, novel mechanism of action, which has been very successful in the market, to our excitement about our orexin-2 agonist compound that we recently in-licensed with our partner, Bioprojet, with the potential to be best in class.
To our patient-focused approach at Harmony, which is not new, which is at our core, part of the fabric of who we are. Meeting patients with rare diseases where they are and the communities that they, you know, that we serve. And again, patient-focused drug development across the span of our pipeline. And a robust, catalyst-rich, late-stage pipeline that we've been building at Harmony, and we're here this morning to open that up for all of you, to show our conviction in the pipeline. And we believe that we have one of the strongest, most valuable pipelines in the industry for patients living with rare neurological diseases. And one of the most important takeaways that I would like you to appreciate from this morning is that Harmony is a profitable, self-funding biotech company.
Based on the cash generation from WAKIX and narcolepsy and advancing our late-stage pipeline of innovative assets, fully funded off the balance sheet. So the takeaway of all this is that Harmony is a very meaningful investment opportunity, and the time is now. So this new ethos, our new identity at Harmony that we're sharing with you this morning, is embodied in what we call neurology. Just as there is balance in nature, there is balance as to how we focus our energies at Harmony. Focus on patients and focus on you, our investors. So welcome to the new Harmony Biosciences, and join us as we embark on the next era of neurology.
Harmony Biosciences is growing, emerging from our successful legacy in sleep- wake, and expanding our commitments into neurobehavioral disorders and rare epilepsies. We are leaving conventional wisdom behind and breaking ground in a new era of therapeutic possibilities. Rooted in deep empathy, novel science, and visionary thinking, Harmony Biosciences aims to empower communities who feel overlooked. Because everyone deserves to feel seen and heard and have science work hard for them. Evident in the therapeutic innovations we advance, the culture we cultivate, and the community programs we nurture. Harmony Biosciences brings together the perspectives and expertise of patients, families, advocates, specialists, innovators, and scientists. We believe that when empathy and innovation meet, a better future can begin for patients with rare neurological diseases.... Harmony Biosciences is taking a fresh approach to helping patients thrive today and into the future. This is neurology.
You just heard the themes of neurology: growth, innovation, delivering meaningful treatments to patients living with rare diseases, and driving strong value creation for our shareholders. And that, that all starts with a strong pipeline, a catalyst-rich pipeline. This was our pipeline at the beginning of last year. And this is our pipeline today. Look at this pipeline. I get really excited when I see this slide. Look at the depth of this pipeline. Three CNS franchises in orphan rare diseases, each with potential peak sales opportunities of $1 billion-$2 billion. Eight assets across 13 development programs, four of which will be in phase III pivotal trials by the end of this year. If we extend this out to the end of next year, twenty twenty-five, we will have up to seven programs in pivotal phase III clinical trials.
I don't think you can find another biotech company with a pipeline this deep, this robust, and this valuable. It is innovation that's driving the growth of our portfolio. Let me share some highlights with you and some exciting, you know, new information, new data that we'll be sharing with you today from each of the three franchises. First, in sleep/wake , some compelling new data that Dr. Kumar Budur, our Chief Medical and Scientific Officer, will be sharing with you from our phase III trial in idiopathic hypersomnia. An update on our next-gen pitolisant HD program, with a target PDUFA date in twenty twenty-eight, out ahead of the WAKIX LOE, out to twenty thirty, driving innovation and addressing an important unmet medical need.
And then some very exciting new data on our orexin-2 agonist that we in-licensed with our partner, Bioprojet, to demonstrate its potential to be best in class in this very exciting space of orexin-2 agonist, the next novel target for narcolepsy. In our neurobehavioral franchise, we'll share with you the innovation of ZYN002, a purely synthetic cannabidiol devoid of THC. The opportunity to bring the first approved treatment option for patients living with Fragile X syndrome. That's about 80,000 patients in the U.S., and that's also a global opportunity for Harmony that we could partner out. And in our epilepsy franchise, the potential to offer a new treatment option in an area of serious, ongoing, unmet medical need in patients living with rare epilepsies that most often are not well controlled.
We'll share some data with you from the ongoing pivotal trial in Dravet syndrome that will demonstrate the potential for a better risk-benefit ratio, risk-benefit profile, compared to what is currently on the market for those indications, Epidiolex, Fintepla and Kumar will share that with you. We'll also share the trial design for nd this is what the team has been working on and is focused and driven to deliver on over the next five years, so beginning in June of this year, the approval of our pediatric narcolepsy indication for WAKIX.
And next year, based on our conviction in the data for IH and the totality of the data, again, Kumar sharing that with you from the phase three pivotal trial, real-world evidence, other data that we have from its use in Europe, patients with IH, and building a very strong benefit-risk proposition in the sNDA for IH, that we are on target to submit later this quarter. In 2026, the target PDUFA date for pitolisant gastro-resistant, part of the LCM strategy, the next-gen formulations, a quick-to-market approach out ahead of the pitolisant HD or high dose program. And then also the target PDUFA date for the Fragile X syndrome program, you know, that I mentioned earlier. If you look out ahead at 2027, 2028, you see multiple target PDUFA dates coming out of our current pipeline.
Starting with pitolisant high dose, pitolisant HD, as I mentioned earlier, and the target PDUFA date in 2028. Our ongoing phase three trial of pitolisant in Prader-Willi syndrome, a program that we've been advancing since the early days of Harmony, when that patient community approached us when we were first started as a company in October 2017. As a little side note, in December 2017, I went down to the NIH with the patient community. They saw potential utility after Wakix was approved in Europe, of using pitolisant in patients with Prader-Willi, not for hyperphagia, but for the sleep disturbance, the excessive daytime sleepiness and the behavioral symptoms that occur in that patient population.
Then from our other two franchises, target PDUFA dates for Dravet syndrome and Lennox-Gastaut syndrome, the phase three pivotal trial that we're on track to initiate later this quarter. In addition, the follow-on opportunity in our neurobehavioral franchise was ZYN002 with 22q deletion syndrome, which has a similar market potential as Fragile X, about 80,000 patients in the U.S. for that indication. Also, a global opportunity that we could partner out. This adds up to one or more new product or indication launches each year over the next five years. A deep, catalyst-rich, near-term and long-term pipeline that we are very excited to advance and share with you this morning.
Today, I can tell you with confidence that we are building a leading CNS company at Harmony Biosciences, and it's based on the foundation of strong revenue generation for WAKIX in narcolepsy, a $1 billion-plus opportunity in narcolepsy alone, out to twenty thirty. The expertise across our organization, the same team that has driven our proven track record of success thus far, and we continue to add really talented individuals to meet our, you know, our growth going forward. Now, with a robust, catalyst-rich, late-stage pipeline with the potential to deliver multibillion-dollar revenue going forward. I also wanna highlight something unique about Harmony, our commercial model that we will leverage to launch multiple orphan rare CNS indications going forward: scalable, innovative, data-driven, and Jeffrey Dierks, our Chief Commercial Officer, will shed more light on that shortly.
So what does it take to be a leading CNS company? First, you must deliver on our promise to patients and the potential, the opportunity to deliver innovative treatments to hundreds of thousands of patients living with rare neurological diseases, which is what we have been building and focused on at Harmony. This is why we do what we do. And when you deliver on value to patients, you deliver value to shareholders, starting with the revenue generation and the success of WAKIX in narcolepsy and a robust, late-stage, catalyst-rich pipeline that again, we believe is the best, the deepest in the industry for patients living with rare neurological diseases, which is poised to deliver, as I just shared with you, one or more new product or indication launches each year over the next five years. The plan is clear and the trajectory, and that's what we're focused on.
So with this pipeline and with our team, we are well-positioned to achieve north of $3 billion in net revenue going forward. And my team is excited to share with you this morning how we will achieve that. So as I, as I said earlier, the takeaway? Harmony is a very strong investment opportunity, and the time is now. So thank you for your attention, and to begin our discussion on our sleep/wake franchise, I'd like to introduce Jeffrey Dierks, our Chief Commercial Officer. Jeffrey?
Thank you. Appreciate it. Good morning, everyone, and thank you for all those who came out, as well as those participating on the webcast. Most of you in the room probably know about the success of WAKIX in narcolepsy, and if you're new to the story, I'll catch you up here in the next couple minutes. The key takeaway is that the sleep/wake franchise at Harmony Biosciences is far more, and so much more than just WAKIX in narcolepsy. WAKIX is our potential billion-dollar-plus foundational opportunity in narcolepsy. We have an exciting opportunity with WAKIX and idiopathic hypersomnia. We have two meaningfully differentiated life cycle management pitolisant products in development: pitolisant Gastro-Resistant, GR, and pitolisant high dose, or HD, and a potential best-in-class orexin-2 agonist.
What that spells is we have a very exciting, innovative, near-term, catalyst-rich sleep/wake franchise that's poised to deliver patient growth and durable revenue out to the mid-2040s. So as Jeffrey shared, WAKIX has been one of the most successful rare orphan launches in the industry, generated durable double-digit revenue growth for the first five years on market, with a compounded annual growth rate of almost 45% over that time. We've seen strong momentum in 2024, and we've reiterated our guidance for $700-$720 million in net sales at the end of this year. So key takeaway, we have confidence in WAKIX being a potential blockbuster product in achieving over $1 billion in net sales. Now, our ability to achieve this is only predicated on our ability to help patients, right?
That's why we got into this business: to help people living with rare disease. At the end of the second quarter, we reported approximately 6,500 average patients on WAKIX, and we reiterated our guidance of approximately 7,000 patients at the end of 2024. Now, this launch that we've had has been one of the most successful, but it compares extremely favorably to the oxybate launch back in 2002. Now, oxybate has been held as probably the gold standard launch in this category. But if you look at the first five respective years of their launch and the first five years of our respective launch, we have more average patients on WAKIX every single year in the first five years than oxybate did. Oxybate's a good drug.
It's helped thousands of patients and achieved over $1.5 billion in net sales at its peak. So it gives us a lot of confidence in our ability to achieve that billion-dollar milestone. So what is it going to take for WAKIX to achieve $1 billion in net sales? We're going to need to achieve approximately 9,000 average patients on product. Guiding towards 7,000 at the end of this year, we only need 2,000 more patients between 2025 and WAKIX LOE in 2030. Given the strong track record of success and the future outlook for the brand, we see that achievable well before WAKIX LOE. And what gives us so much confidence in our ability to continue to grow this franchise is looking at the remaining diagnosed patient opportunity in this market.
Now, although narcolepsy is a rare disease, it's a pretty unique, rare disease, and in fact, it has a large diagnosed patient opportunity. There's nearly 80,000 people diagnosed with narcolepsy and another 90,000 thought to be living with the disease. Now, the market's been growing at a diagnosed rate of about 2% annually, which is adding new patients every year and new potential for WAKIX. So with a strong track record of success, the need to get to 9,000 patients and a large remaining diagnosed patient opportunity, we're extremely confident in our ability to get to $1 billion. Another unique thing about the narcolepsy market, again, a large diagnosed patient opportunity, but those individuals are managed by a pretty concentrated group of healthcare professionals. There's about 9,000 healthcare professionals that see and treat almost 100% of the diagnosed patient opportunity.
But within that 9,000 prescribers, it's a bifurcated audience, predicated on a physician's willingness to want to enroll in the oxybate REMS program and write oxybate. And that provides a pretty unique and durable opportunity, not only for WAKIX, but also for the next generation pitolisant assets. Now, there are about 4,000 doctors that have been enrolled in the oxybate REMS program. These are physicians who write all the scheduled medicines and non-scheduled medicines. Their sleep specialists tend to be early adopters, and it probably doesn't surprise anybody here in the room and on the webcast. WAKIX is highly penetrated in this audience. The growth we're seeing in this audience is coming from depth of prescribing. I mean, these physicians have had initial experience.
They're prescribing it for their second, their fifth, their tenth, their twenty-fifth patient for WAKIX, and we're seeing durable growth in the depth of prescribing in this audience. Now, there's another 5,000 healthcare professionals who've chosen not to prescribe oxybate and not enroll in the oxybate REMS program. And these are physicians and healthcare professionals who traditionally don't prescribe scheduled medicines. They may write some wake-promoting agents or refill another physician's prescription. But these are individuals who are looking for non-scheduled treatment options, and we've seen very strong adoption from WAKIX in this audience. And this provides us an insulated group of prescribers to tap into while the oxybate churn in the market continues. You've got introduction of once-nightly, low sodium, generic, full sodium. These 5,000 healthcare professionals cannot and will not prescribe any of those oxybates.
So as I said, a very durable and very unique and insulated prescriber audience that we continue to tap into every quarter. We've seen relatively consistent growth in this audience and new prescribers going all the way back to COVID. We're about 40% penetrated in this audience, and we continue to see growth in new writers every quarter. So when you look across this, our ability to call on the broad 9,000 healthcare professionals gives us access to the full diagnosed patient opportunity. Fueling our growth, we will continue to grow our prescriber base and continue to grow the brand north of $1 billion. Now, what we know about the WAKIX product profile is it appeals broadly to this entire universe because it has a very unique product profile. And we brought WAKIX to market in a way to address the unmet needs in the marketplace.
We did research back in 2018, prior to WAKIX approval, to get an understanding of what the key unmet needs were in this marketplace. Even with the availability of numerous treatment options, there were a number of key unmet needs in the marketplace. If you look at the left-hand side of the slide, the top unmet needs that were cited from both healthcare professionals and patients back in 2018 included: the need for non-scheduled treatment options. At that time, every product that was FDA approved was a scheduled medicine. The need for more tolerable and effective treatment options, novel MOAs, and a little bit easier products for them to take, once daily dosing treatment options, as most of the products are either BID or TID.
And if you look at the right-hand side of the screen, based upon the FDA-approved product labeling for adult narcolepsy, you can see linearly how well some of the features and attributes of WAKIX align to the unmet needs that existed back in twenty eighteen. WAKIX offers a differentiated and meaningfully differentiated product profile for these patients living with narcolepsy. In addition to the product profile being a key driver of performance, another key driver of our performance is our commercial team. We have a best-in-class sales force, deep experience in CNS and rare orphan, established relationships in the industry. And the commercial team that I get a pleasure of working with every day is best in class, many of which I've worked with in the past. But the other unique thing about our commercial model and our commercial team is our commercial model.
Many of you in the audience are probably looking at the slide and saying, "Jeffrey, this looks like every other model I've seen for specialty pharmacy." You know what? On the surface, that's probably true. It's what we do with this model and how we use the data that makes it not only very unique, but a competitive advantage. When a WAKIX prescription is written, it's sent into our centralized patient hub. It's not sent into an EMR system or a prescription given to a patient and taken to one of the 53,000 retail pharmacies in the U.S. Every script comes into the centralized patient hub, and all of the data on that prescription is captured: demographic information, insurance information, past and current narcolepsy treatments.
We opt patients in for future communications 'cause we wanna make sure we can communicate to them when their prescription's approved, and we also get their consent to conduct reimbursement on their behalf. Once that prescription's approved, from the hub, it's sent securely and safely to one of our three specialty pharmacies, where the pharmacy works to dispense the product directly to a patient's home. It's mailed right to their front door. It's left without a signature because it's a non-scheduled treatment option. And trust me, we had no idea how effective this model was gonna be until we ran into a global pandemic in March of 2020. We launched this drug in November of 2019, and within three to four months, we literally were in lockdown. This model allowed patients to receive their medicine with a no-touch service, and that model continues to be resilient today.
But as that SP dispenses that medicine to the patient, they also capture data. They capture dispense data, dosing information, refills, patient medication behavior, compliance, persistency, when patients discontinue and where appropriate, why patients discontinue. And so all of these data that are generated at the hub and the SP, we capture that data and bring that in to the Harmony Advanced Resource Platform, or what we call it Harmony HARP. And HARP is a single source, cloud-based data warehouse. Now, HARP was actually developed and began development back in December of 2017 by our head of commercial operations, almost immediately after the founding of Harmony. And it's because of his experience and expertise in data management, aggregation, and deployment, we've turned what's kind of a traditional cloud-based data warehouse into a proprietary business intelligence engine.
As I said, we've got data that's coming in from our hub, patient information, healthcare professional information. That goes into HARP. All the prescription data, patient medication behavior data from the SP goes up into the cloud. In addition to those data, we also bring in third-party longitudinal patient claims data. We bring in marketing initiatives, our email campaigns, speaker programs, sales force activities, digital initiatives. All of that is integrated and mastered into one single source database that is actionable for all the members of my commercial team based on their role and their job and their function. HARP takes all this data, and it is refreshed and updated every day. Many companies rely on weekly data, monthly data. The activity and prescriptions that are written today, the sales calls that are written today, will be in my dashboard tomorrow morning at 5:00 A.M.
That 360-degree landscape of data that I get every day, and my team gets every day, allows us to make timely, data-driven decisions on investment deployment, sales force activity, marketing campaigns. And what comes out of all this data is actionable business intelligence. So let me share a couple of examples of what we do with this data. So we can take patient engagement data, looking at patient medication behavior, data we get from our hub and our SP, and we can actually use that data to cadence how and when the hub and the specialty pharmacies cadence and reach out to patients based upon when patients may lapse in therapy, to try to keep appropriate patients on therapy. So after 28 days, if a patient doesn't pick up a phone for a refill...
There's a flag sent to the SP that we need to make a phone call. If two days go by, there's a flag for the hub, and the hub reaches out, so that way we can capture these patients and not have them lapse in therapy. We've been extremely successful in capturing more than 50% of the patients who lapse in therapy through this closed-loop catch. It may not sound like a lot, but let's fast forward about a month or two, and we get into the election. How many people in here are getting robo calls, 800 numbers? Patients don't pick phone calls up. I may not actually have the 800 number of my specialty pharmacy in my phone, but you know what I do have on my phone?
I have the phone number from my hub, because when I have my welcome call with you, the hub tells me to put that phone number in their phone and link it in as RareMed, our hub. And so that way, when Susan hasn't received her call from the SP and gets a call from RareMed, "Susan, we noticed you've lapsed in therapy." "I know, I'm getting a lot of robo calls. I'm not answering my phone." "Well, good news, Susan. I'll warm transfer you right now over to our specialty pharmacy. We'll get your prescription filled." Because we have all that data, we can cadence those calls to make sure we don't lapse patients. We use patient longitudinal data with AI predictive modeling to understand when a physician is actually going to be ready to prescribe a branded treatment option.
Through the longitudinal data, we will get sleep test information, MSLTs, PSGs. We know when those are done on patients. We can see when generic antidepressants, generic wake-promoting agent, and stimulants are written. And we can then flag physicians in our Salesforce database and have them call about 28 days later, after that generic is written, to call in a healthcare professional when that physician is open to writing a branded treatment option, when that patient's insurance will cover a branded treatment option, to be far more efficient and effective in deploying probably the most valuable resource we have in our commercial engine. We also have the ability to use that with our marketing initiatives.
If you've been to the Wakix.com website, we have a link for our prescription referral form, and that form is used and filled out by a physician and sent to our patient hub for a prescription. We tag that link, and every time a physician clicks on that link and downloads that form, it sends an automated email to a representative, alerting them that a physician in their geography has downloaded that referral form, deploying them to that office within twenty-four hours. We've seen a high rate of conversion from intent to prescription because of our ability to act real time. As I said, this data refreshes every day. Lastly, some of the things that we're using with the opt-in.
As we know, narcolepsy, sadly, is a lifelong, incurable neurologic disorder that patients have for decades, in a lot of cases, if they're lucky enough to get diagnosed early. As Dr. Corser and I were talking about, he was telling me about it, a couple of people he met in their sixties that are still waiting to get diagnosed. But these individuals have these for decades, and we know that this is a polypharmacy market. We know that patients cycle through medicines. So because we have all the prescription data, we know when patients stop taking the medicine, and we know why they discontinue, and we have them all opted in.
We can reach out from our hub and contact patients who have discontinued WAKIX for all other reasons other than an adverse event and see whether they'd be interested in restarting WAKIX, based upon the time in which they discontinued. We can call them six months after DC, a year after DC, two years. It probably doesn't surprise anybody. We've had a high level of interest raising their hand to say, "You know what? I might actually be ready to go back and talk to my doctor." Even more important than that, we've been able to connect a lot of these individuals with their doctor and get them then started back on WAKIX therapy. Now, this model is really important as you think and fast-forward to our next-generation pitolisant lifecycle management franchise.
Because we're gonna have the ability to access this entire database to recontact every single patient who's opted in on WAKIX to see if they actually might like a next-generation product that has more meaningful, enhanced benefits. This is a significant competitive advantage. Everybody in pharma wants this model. Nobody else has it. This is a competitive advantage because the companies that want this can't go back and rebuild this because their infrastructure is already built. You have to build this on day one. This is artificial intelligence that powers my entire commercial team's activities, behaviors, and it drives our success. And importantly, within this, HARP is scalable.
Not only we have the ability to do this with WAKIX, but we're gonna be able to do this with every future WAKIX indication, our next-generation pitolisant assets, our neurobehavioral, our rare epilepsy franchise, and any other business development asset that's a specialty pharmacy, rare orphan focus. Scalable, data-driven, unique commercial model that is positioned to drive value for the remainder of our pipeline. We obviously have a potential billion-dollar blockbuster product in the making. We have a very unique and scalable commercial model. We have all the recipes for success for lifecycle management with pitolisant. We brought WAKIX to market to meet an unmet need that we saw back in twenty eighteen, as we said. When we came to the market, we looked and said: You know what? All the FDA-approved treatment options are scheduled medicines.
There's only one FDA-approved treatment option that was approved for both EDS and cataplexy, and that was a Schedule III triple attestation REMS program. And more than half the patients cited frustration with their current medicines based on side effects. So introduce WAKIX, the first non-scheduled treatment option, approved for both EDS and cataplexy, and a pretty well-tolerated product. And so this is a foundation from which we build, and we're thinking about our pitolisant lifecycle management programs. WAKIX is a great product, but even with the introduction of WAKIX, there is still significant unmet need in this marketplace.... And so we go to work using WAKIX as a foundation to not only modify but enhance the formulation against unmet needs in the marketplace.
Now, lifecycle management for everybody in this room, you're like, "Jeffrey, everybody does it." But again, traditionally, what happens in lifecycle management is everybody focuses on function. I'm gonna take a TID and make a BID, take a BID and make it once a day. I'm gonna look at, you know, the delivery method. I'll take a, you know, an IV and make it an oral. I'll take an oral and make it a dissolvable tablet. Or there's something in my product, I'm gonna take it out to make it better. But very few companies look in the marketplace at patient unmet need and build lifecycle management around unmet need. The WAKIX pitolisant lifecycle management program is predicated on patient-centric drug development and looking at unmet needs.
The first product that we looked at is pitolisant Gastro-Resistant or GR, 'cause in addition to what we saw with WAKIX, what we see in the marketplace is almost 90% of narcolepsy patients report GI disturbances as part of their disease. One of the things that we've learned is that orexin in the brain controls the vagus nerve, and the vagus nerve is responsible for gut motility. As orexin depletes in the state of narcolepsy and doesn't activate the vagus nerve, patients with narcolepsy report GI upset, nausea, dyspepsia, vomiting, diarrhea, nine out of ten of them, and this is just a function of the disease. We know that every one of the products in this category requires some form of titration, and many patients just either cannot or will not go through a titration to get clinical benefit.
And we also know that once you get patients on product, nearly one in five of them cite nausea as a side effect of their medicine. So introduce pitolisant GR, keeping all the great features and benefits of WAKIX, but adding a Gastro-Resistant coating, not because WAKIX has a high incidence of nausea, because 90% of these patients are predisposed to having GI disturbances. And we are also gonna end up introducing GR, starting at a therapeutic dose, eliminating the titration to allow patients to get clinical benefit sooner. pitolisant GR is a quick-to-market bioequivalent product that we are looking for a target PDUFA date in 2026, and the goal and the strategy with this product is to be able to not only capture new patients, but also patients who may have discontinued WAKIX due to nausea or potentially not getting the clinical benefit.
But we don't want to just stop there, because you know what? There's even more pressing unmet needs in the marketplace. 75% of patients on narcolepsy treatment report residual symptoms, even while on treatment, that disrupt their lives, and this is based on data that Lindsay McCullough presented from Rush University Medical Center back at a sleep meeting. Nearly six out of ten patients report untreated fatigue, which is different than excessive daytime sleepiness. Introduce pitolisant HD, high dose. Looking to push the dose to drive greater efficacy in EDS and cataplexy. We're gonna be looking at a very unique indication for fatigue and narcolepsy, in addition to keeping the Gastro-Resistant coating, starting at a therapeutic level, non-scheduled treatment option, indicated for both EDS and cataplexy, and a well-tolerated treatment option. Target PDUFA, as Jeffrey shared, is 2028.
Both of these products have provisional patents out to 2044. So we went and did some research, specifically with the pitolisant HD formulation, both with physicians and payers. We did research with 25 sleep specialists that have at least 25 patients under their care, and they prescribe WAKIX to at least five of them. We introduced the target product profile, higher dose, greater efficacy in EDS and cataplexy, untreated fatigue, Gastro-Resistant formulation, the ability to start at a therapeutic dose to drive clinical benefit earlier. Physicians' feedback: It offers significant value over WAKIX, and they see this product as a superior product profile, and they anticipate strong uptake across their entire universe of patients. New patients, current WAKIX patients that are better but not well, having residual symptoms. As I shared on the last slide, nearly 75% of patients have residual symptoms, even on treatment.
Fatigue indication could drive significant value for some doctors. It's an underdeveloped market, but the physicians who see this understand the value of this. So when you look at pitolisant HD, the opportunity, the real opportunity here is maintaining and growing the patient base, driving durable patient growth and revenue out into the 2040s. This product launching in 2028, 18-24 months before WAKIX, which allows full time for these physicians who express interest to want to transition WAKIX patients over to HD prior to WAKIX LOE. So to try to understand whether the physicians were gonna be able to do some of the things they shared in research, we did research with payers.
Seven payers that cover about 50 million lives, or about 15% of the sample size universe, about 80% commercial covered lives, 15% Medicare, 5% Medicaid, so pretty representative of the narcolepsy sample payer. Really interesting with this, payers saw value with pitolisant HD prior to WAKIX LOE, and they believed, and they expressed, patients would be able to get HD without stepping through WAKIX prior to WAKIX LOE. They're gonna be on the same shelf. If you're a doctor, if I have the ability to choose HD over WAKIX, I'll have the ability to do that. But what's even more interesting is that payers saw value in pitolisant HD after WAKIX LOE. Save patients that are de novo and have no experience with WAKIX at all. Those patients are gonna have to go on generic pitolisant.
But nearly every other patient that has any type of experience with WAKIX, current or past, will have the ability to get pitolisant HD without a generic step. If you're a pitolisant HD patient, you can maintain on product and not have to be stepped back. If you're a current WAKIX patient and better but not well, your patient can transition you over to HD without a step back. If you have previous WAKIX experience, you'd be considered pre-stepped. And if a physician doesn't have the electronic look back in the last twelve months, guess who has all the data? We have every single prescriptions written since August of twenty nineteen. If that physician asks us, we can provide that data to be able to get to the insurance to pre-step that patient.
If you look at the landscape for pitolisant HD, high physician interest, superior product profile in their minds, unimpeded access from managed care, both pre- and post-WAKIX LOE. To summarize, I want you to see the pitolisant franchise as three distinct, meaningful products. First is WAKIX, a potential billion-dollar-plus opportunity in adult narcolepsy alone. First and only non-scheduled treatment option. Then you have two meaningfully differentiated lifecycle management pitolisant-based products. The first, pitolisant GR or Gastro-Resistant, target PDUFA in 2026, provisional patent filed out till 2044. The goal of this brand is to expand the patient base, being able to grab new patients and tap into our opted-in, discontinued patients to add a couple thousand patients to the pitolisant base. We see this as a $300 million-$500 million potential opportunity to expand our pitolisant base.
pitolisant HD, high dose, greater efficacy, unique indication for fatigue. See this as driving and maintaining and growing the patient base and extending durable revenue out into the mid-2040s with provisional patent filed out to 2044. This franchise helps solidify and strengthen our leadership in sleep/wake . But importantly, when you take a step back and think about the sleep/wake franchise, I want to leave you with this: We have a potential blockbuster in WAKIX and narcolepsy. We have an exciting opportunity for idiopathic hypersomnia next year. We have two meaningfully differentiated pitolisant lifecycle management assets, with target PDUFAs in 2026 and 2028. We have a potential best-in-class orexin-2 agonist. If you look across this, we have an exciting, innovative, near-term, catalyst-rich sleep/wake franchise that has the potential to extend durable patient growth and revenue out to the 2040s.
Thank you very much for your attention. I would like to now invite our Chief Medical and Scientific Officer, Kumar Budur, up to stage to share data on these exciting programs. Kumar?
Thank you, Jeffrey.
Dr. Budur.
Good morning. Good morning, everyone.
Good morning.
Great. Thank you. Thank you. All right. Look, it is with great pleasure and indeed great pride. I'll be walking you through the Harmony Biosciences R&D portfolio. Jeffrey Dayno mentioned earlier that we have one of the industry-leading late-stage neuroscience portfolio. It's not just industry-leading, but it's really exciting. It's really fascinating. Four phase III studies in four different indications by the end of the year. Not many can say this. Today, along the way, I'll be sharing some key proof points and some new data that support our confidence to launch one or more new indications or new products each year for the next five years.
This is important and helps hundreds of thousands of patients living with rare neurological disorders for whom either there are no approved treatment options at all, or they do have some treatments with significant limitations in terms of efficacy, safety, or tolerability. With that said, let's start with pitolisant HD. We are very excited about pitolisant HD. Why are we excited about pitolisant HD? Because here we have an opportunity to bring a new product with better efficacy, but not compromising on the safety or tolerability profile. We know that, and Jeffrey Dierks mentioned earlier, seven to eight out of ten patients with narcolepsy, despite the available treatments, have residual excessive daytime sleepiness. Here we have an opportunity with pitolisant, because pitolisant has clearly shown a dose response and exposure response when it comes to efficacy. It's not just increasing the dose.
What is important is also optimized PK profile, and we shared some of this data at our last earnings call. An optimized PK profile with pitolisant HD, which increases the relative bioavailability, decreases the interindividual variability and other PK parameters that have a direct impact on the clinical profile. So a combination of higher dose, optimized PK profile equals better efficacy. What it means from a patient perspective? From a patient perspective, as a clinician, I see this helping more patients being more awake during the daytime, more patients being able to participate in their day-to-day activities, less incidents of dozing off to sleep while driving or while at work. I mentioned about safety. These are new data, by the way, we are sharing today.
In anticipation of pitolisant HD program and to establish safety margins at really high doses of pitolisant, much higher than what we anticipate with pitolisant HD, we did this phase Ib study, started about 18 months ago and recently concluded, a randomized, double-blind, placebo-controlled study to evaluate safety, tolerability, PK, and impact on QT at very high doses of pitolisant, started at 60 mg cohort and went all the way up to 180 mg. One hundred and eighty milligram equates to approximately five times, five times the highest labeled WAKIX dose. What we saw is very promising. Safety profile is similar to established safety profile of WAKIX. No serious AEs were observed, and no new safety or tolerability issues were observed. We will present this data at the upcoming safety meeting.
Through this study, we noticed that the safety and tolerability profile of pitolisant up to one hundred and eighty milligrams, approximately five times the highest labeled dose of WAKIX, is very similar to the established safety profile of WAKIX. The combination of optimized PK profile, higher dose, the safety profile that we have established, gives us high level of confidence of meeting this target product profile: higher dose, better efficacy in excessive daytime sleepiness and cataplexy, target indications like fatigue. As Jeffrey just mentioned, 60% of patients with narcolepsy have fatigue, and for that, there are no approved treatments. We talked about optimized PK profile. Gastroresistant coating inherently is designed to address some of the common GI issues seen in patients with narcolepsy. Differentiated indications.
We'll be going after differentiated label, fatigue in narcolepsy, sleep inertia in idiopathic hypersomnia, fatigue and excessive daytime sleepiness in patients with myotonic dystrophy, which, by the way, we announced top-line results from our proof of concept study late last year. Some of the impressive data that we have seen, both in fatigue and excessive daytime sleepiness. Of course, we have filed provisional patent, and the patent protection is expected to be until 2044. Now, pitolisant HD is designed to address unmet medical needs in this patient population with a potential IP until 2044. We are on track. We are on track for PDUFA in 2028. Switching gears, idiopathic hypersomnia. I know there is a lot of interest to hear about idiopathic hypersomnia, and today we'll be sharing a lot of new data.
You'll see that our submission, which is on track by the end of the year, is based on data. It is not based on hope or belief, but it's based on data. Based on strong data, durable data that we'll be sharing for the first time today. This juxtaposed with the established safety profile of pitolisant in the context of high unmet need, where there is only one drug that is approved, which happens to have a REMS program, a scheduled controlled substance, Class three, with somewhat of a cumbersome method of administration. In this context, pitolisant offers a very favorable benefit risk profile for patients with idiopathic hypersomnia. Let's start with the design of the study. This is the INTUNE design. Eight weeks of open-label period where all patients get pitolisant.
This is followed by four weeks of randomized withdrawal, where responders are randomized either to pitolisant or to placebo. At the end of the randomized withdrawal period, patients have an option to participate in the long-term extension study, and this study, by the way, is still ongoing, and we continue to collect safety and effectiveness data from these patients. So let's look at each phase of the study, starting with open label phase. So what happened in the open label phase? The data we saw in the open label phase were pretty impressive. These patients started at about 16.5 mean ESS score, which means they were moderately to severely sleepy.... What we saw is that within first week, a 3-point decline or improvement in sleepiness. That's 1 point more than what ASM considers as clinically meaningful. By day 22, the mean ESS score was in the normal range.
At the end of open label phase, day 56, we saw a mean improvement in ESS of approximately 9.4 points, which is approximately 5 times what is considered as clinically meaningful. 8 out of 10 patients, in fact, 83%, to be precise, were considered as responders, defined by a 3-point improvement in ESS. These are some of the best data ever generated in patients with idiopathic hypersomnia. Now, these patients were randomized either to placebo or to pitolisant. So what exactly happened during randomized withdrawal period? You know that we did not meet statistical significance. What happened was primarily the persistence of efficacy in placebo arm.
These patients came with a mean ESS score of around 16.5, and after seeing an improvement of 9.4 points on the ESS scale, when they were randomized to placebo and out, not just one or two weeks, for four complete weeks, we anticipated worsening by about six to eight points. But what we saw was only a modest decline of about four points. Since it speaks to the prolonged pharmacodynamic effect of pitolisant, possibly related to histamine modulation and the downstream effects. Not only that, in the patients who were assigned to pitolisant, there were few outliers who believed that they were assigned to placebo, indicating a possibility of the expectation bias, and this was confirmed via exit interviews, which is part of the schedule of assessment.
The relatively benign side effect profile of pitolisant means patients always speculate whether they are assigned to placebo or pitolisant, and the lack of AEs, because of the benign side effect profile of pitolisant, some of them assumed they were assigned to placebo, and they responded accordingly. Primarily, it's the persistence of efficacy in the placebo arm, and the decline of only about four points in the placebo arm resulted in lack of statistical significance. What happened in the long-term extension study? Nine out of ten patients who completed randomized withdrawal period elected to participate in the long-term extension study, and here are the data. One year out in the long-term extension study, all the way to day 382. What do we see? A strong and durable improvement in excessive daytime sleepiness. Patients continue to be in the normal ESS range.
The mean ESS scores show that we continue to see an improvement by approximately nine points compared to their baseline scores. What happened with Idiopathic Hypersomnia Severity Scale? The same thing. Strong and durable improvement on IHSS scale as well. This is something that measures idiopathic hypersomnia symptoms in a very comprehensive way, and we see patients continue to be in the desirable range more than one year into the long-term extension study. How about sleep inertia? A key symptom in patients with idiopathic hypersomnia. We see the same: strong and durable improvement in sleep inertia. Now, in our sNDA submission, we have multiple levels of evidence and multiple data sets. These are the data from our clinical trial. What are the other data that we have? These are the data from Dr. Yves Dauvilliers' lab. Anyone who has worked in idiopathic hypersomnia probably know Dr.
Yves Dauvilliers, a very well-recognized name in idiopathic hypersomnia, has a large clinical practice, has a large database of patients with idiopathic hypersomnia, and this is a real-world, independent database analysis, independent data analysis conducted by Dr. Yves Dauvilliers. He followed 64 patients over a period of 14 years, 314 unique clinic visits. And this is what he saw. About 40% of the patients were stable, got better, and remained stable with pitolisant as monotherapy alone, and just over 20% of the patients benefited and remained stable with pitolisant as adjunctive therapy. Overall, more than 60% of the patients experienced benefit from pitolisant. Another set of data. These come to us from Bioprojet's compassionate use, where just over 300 patients accessed pitolisant for narcolepsy and for idiopathic hypersomnia. Amongst these 300 patients, just over 100 patients took pitolisant for idiopathic hypersomnia.
Obviously, it's a compassionate use study. The data are not collected in any systematic fashion. So that's why it's real-world evidence. What we saw here in a subset of sixty-one patients on who we have good data, we again saw about approximately four points drop in the ESS score, which is two times what is considered as clinically meaningful. So what do these data say? In a clinical trial setting, highly structured, or a clinical practice, a semi-structured setting, or real-world unstructured setting, pitolisant consistently showed efficacy in patients with idiopathic hypersomnia. Just a quick word about Voice of the Patient report. Many of you know about external-led, patient-focused drug development meetings that happen. And the meeting on idiopathic hypersomnia happened in the month of April, where typically FDA also attends, and in this instance, the head of psychiatry division, Dr.
Tiffany Farchione, not only attended, she actually spoke at this event. One of the important outputs from this meeting is the Voice of the Patient report. Why is it important? It's important because FDA actually provides input in finalizing the report, and FDA often uses this as a reference document when they have to make important decisions, when they see the files come in front of them. What does this Voice of the Patient report highlights? It says we need more research and awareness, the need or the desire for non-stimulant treatments, frustration with current treatments, and the hope for new treatments. Now, pitolisant, with its unique benefit risk proposition, has the ability to fill many of the gaps that were identified not just by patients, caregivers, and providers, but the agency itself. So to summarize, we are on track to submit sNDA by the end of this year.
We have a strong case based on the totality of the data, not just from the clinical trial, but several layers of evidence from a large clinical practice, from real-world use of pitolisant. We have a very unique benefit risk proposition, non-scheduled drug, once a day, simple dosing regimen, and of course, the Voice of the Patient report, where patients, caregivers, providers, and the agency alike highlighted the need for new treatments in patients with idiopathic hypersomnia. All right. Shifting gears onto our new asset, BP1.15205, a potential, potentially best, best-in-class orexin two receptor agonist. BP stands for Bioprojet because we in-licensed this asset from Bioprojet, and I do want to acknowledge Olivier Venault. If you could raise your hand or stand up. He's the head of R&D from Bioprojet. Thank you, Olivier, for joining us today. Great collaboration the past seven years, and the collaboration continues. All right.
Speaking of innovation, with WAKIX, we often say we work with the seat of innovation because Dr. Jean-Charles Schwartz was the one who discovered histamine receptors and actually went on to develop WAKIX. With our orexin receptor agonist, BP1.15205, this originated in Tokyo at Teijin Pharma. This was a collaboration between Teijin Pharma and Professor Yanagisawa, who, if you don't know, he's the one who discovered orexin receptors in nineteen nineties and went on to describe the impact of orexin on sleep/wake cycle. This has a unique structure and chemical scaffolding. Based on leveraging the lessons learned from other orexin receptor agonists. Huge clinical potential based on potency, selectivity, and potential once a day dosing regimen. All right. We often mention that it has novel chemical scaffolding.
It has a differentiated structure compared to the usual pyrrolidine sulfonamide bicyclic moieties that is often seen with other orexin receptor agonists. The distinct scaffolding from known ligands with drug-like properties using scaffold hopping technology and structure-based drug discovery led to the lead optimization candidate of BP1.15205 that confers unique properties and clinical benefits, and also it helps with the efficient and expedited synthesis of the product. Some real data. The in vitro pharmacology data showed this is highly potent. We are talking about potency in nanomolar range, 0.015 nM range. This potency was consistent across species. Similar potency in mouse, similar potency in non-human primates, and greater than six hundredfold selectivity over human orexin-1 receptor, and more importantly, more than one thousand-fold selectivity over more than 150 biological targets.
Here we compare the potency, selectivity, and dosing regimen of our orexin receptor agonist with other orexin receptors based on the data that is publicly available. We have the most potent orexin receptor agonist based on the data that we know of in the public domain. BP1.15205 is the most potent orexin receptor agonist. What does that mean? The novel chemical structure, high potency, good selectivity, and the PK profile confer some unique benefits, which could make this potentially best-in-class orexin receptor agonist. The potent on-target effects, the high potency give us the flexibility with the dosing to cover not just all the central disorders of hypersomnolence, potentially beyond central disorders of hypersomnolence based on the emerging evidence. The ability to dose once a day is highly desirable in any patient population.
The PK profile, the ability to dose once a day with the PK properties, that is, half-life, long enough but not too long, can minimize the AE profile. We will also be pursuing an accelerated development, leveraging all the lessons in this field with a potential approval in early 2030s. What is fascinating is we have the possibility or the option of potential combination with histaminergic drugs, such as pitolisant HD. I mentioned Olivier earlier. He's the head of R&D at Bioprojet, and we have generated some early clinical data to show synergistic efficacy between orexin receptor agonist and histamine antagonist. Pretty exciting. To wrap up, this is what we have in terms of catalysts. We are on track for a NDA submission in idiopathic hypersomnia by the end of this year. Potential PDUFA in the second or third quarter of next year.
We are on track for IND submission with our orexin receptor agonist in mid-2025, immediately followed by first-in-human studies. We are on track for pitolisant GR, PDUFA in 2026, and we are on track for PDUFA with pitolisant HD in 2028. Look, as a board-certified sleep specialist, for me, this is fascinating, an ability and opportunity to work with differentiated compounds that could potentially help a lot more patients, not just with central disorders of hypersomnolence, but patients beyond central disorders of hypersomnolence. All right. You heard a lot from me on sleep/wake franchise, but let's hear from a real expert who is in the audience today, Dr. Bruce Corser. Look, it is my pleasure to introduce Dr. Bruce Corser, who is... Come up, Doctor. Please have a seat. All right. So Dr. Corser is the president and medical director at Intrepid Research and Sleep Management Institute.
He is board-certified in internal medicine, pulmonary medicine, and sleep medicine, and he has participated in over one hundred clinical trials as the site principal investigator, including INTUNE study as well. Some of his patients, I believe about four or five of them, continue to participate in the long-term extension study. So Bruce, thank you for being here. I know you have a busy clinical practice and also very busy with your research, but really appreciate you being here.
Thank you, Kumar. Good to be here.
Right. So what we plan to do is, I'll ask a couple of questions on our portfolio and then open it up for the audience. So Bruce, we actually pride as a company with WAKIX. Jeffrey and Jeffrey spoke earlier about the innovation there and the ability to help so many patients with the innovative product. But we have made progress in terms of life cycle management, coming up with differentiated formulations, pitolisant HD, pitolisant GR, targeting unique patients with high unmet need. So as a clinician, where do you see this fit in your treatment making decisions? Let's start with pitolisant GR.
So, let me start by just giving you a little bit more about my background. So I've been involved in sleep medicine since nineteen eighty-nine. I have a independent sleep clinic. I have three nurse practitioners working with me. We see about twelve hundred patients per month. We see a lot of narcoleptic patients. I have a independent research site. We do many, many studies for a lot of different companies regarding any medications to help people either fall asleep or stay awake. So I've been involved in hundreds of clinical trials. The first clinical trial I was involved in was the modafinil trial for narcolepsy. This is back in about nineteen ninety-five. So I've seen the whole landscape of medications that help people with narcolepsy. And narcolepsy is a debilitating disease.
Sleepiness doesn't really adequately describe the symptoms associated with narcolepsy, as you know, Kumar. So narcolepsy really involves overwhelming sleepiness, fatigue, cognitive impairment, and there's a number of comorbidities associated with narcolepsy. For example, these people have increased mortality due to metabolic diseases such as diabetes. They have increased cardiovascular risks. They have increased depression and anxiety. So this is a disease that has a profound impact on patients' lives. So we use multiple medications to treat these people. So oftentimes, we really use something to put people to sleep, like oxybate therapy, and there's several of these oxybates on the market. We also use medications to help people stay awake.
Often, you know, these people are on relatively high doses of stimulant medications like amphetamine salts, methylphenidate, which is like Ritalin. So when WAKIX came along, this was the first non-scheduled medication that we could use to help people stay awake. You know, virtually everything else is scheduled. And that, that's a big deal because a lot of physicians, as Jeffrey pointed out, are very reluctant to prescribe medications that are scheduled. So the fact that WAKIX is non-scheduled is a really big deal. You know, and as Jeffrey eloquently pointed out in his presentation, there's probably 170-200 thousand people with narcolepsy in this country. This condition is vastly underdiagnosed and undertreated.
There's a lot of physicians that run sleep clinics that are reluctant to treat narcolepsy. They only wanna treat sleep apnea.
Mm.
So this is very underdiagnosed, you know, and it. This goes way back into the, geez, early education, you know. There's a lot of kids that develop narcolepsy. The average age of onset of narcolepsy is around 16. So these kids are falling asleep in school, you know, oftentimes teachers attribute it to just laziness or lack of sleep. But, you know, so there really needs to be better education about identifying these people that have severe excessive sleepiness. So given that context-
Mm-hmm.
As I mentioned, I think, Wakix was a welcome addition to the market when it was launched. And, geez, the fact that it's up to around sixty-five hundred patients now taking Wakix is really quite remarkable. And to give you context, about sixteen thousand people in the country are taking oxybate products. So, but, the data presented showed, and I would endorse this, that probably 75% of people with narcolepsy feel somewhat satisfied on their current therapies, and again, this may involve several different medications. But there's a significant unmet need. You know, one of the major barriers to Wakix is the fact that a significant number of folks, probably 20% or so, develop GI side effects, specifically abdominal pain, nausea-...
The GR formulation will be a welcome addition. I think that's gonna be very helpful, and that will also allow us to start at higher doses.
Right.
One of the issues with WAKIX is that we currently have to start with a relatively low dose and then build up over time and then you typically don't see the maximal benefit with WAKIX until about eight weeks. You have to encourage people to continue to take it, hoping that they'll see the maximum benefit after eight weeks. The fact that we can start with a higher dose will allow people to see benefit earlier in the therapy, which is important, you know, so people don't give up on the treatment.
Right.
I think this will be a welcome addition, and the high dose is quite exciting. The maximum dose currently of WAKIX is around 36 mg. So the opportunity to prescribe higher doses is really appealing to those people that might need some additional benefit beyond the currently available dose. So I think this is an exciting portfolio. I really welcome it. You know, and geez, it's the future is very exciting as a physician treating these people because we, you know, we're seeing a lot of medications that are coming forth that have heretofore been unavailable, especially these orexin agonists. So I think the future is very bright for the treatment of both people with narcolepsy and idiopathic hypersomnia.
Yeah. Thank you, Bruce. Thank you.
Sure.
Just shifting gears again, we talked about idiopathic hypersomnia. You participated in the study. You still have patients in the long-term extension study. Can you comment on the patients' experiences in this study?
Yes. So first off, what is idiopathic hypersomnia? So idiopathic hypersomnia means that people are very sleepy, and they don't quite fit the diagnostic criteria for narcolepsy. So we see these people in the clinic, you know, classically, they have severe, unremitting daytime sleepiness. Oftentimes, they will have sleep inertia. Probably 80% of people have sleep inertia. So what does that mean? That means profound difficulty awakening in the morning, difficulty getting out of bed. These people use multiple alarm clocks. They'll rely on spouses or family members to try to awaken them in the morning. So it's extremely difficult for them to awaken. Furthermore, somewhere around 80%-90% of these people have brain fog. They have cognitive impairment. They have difficulty concentrating. So it really has a profound impact on their lives.
The pathophysiology of type one narcolepsy is clearly defined. That means these people have a deficiency of what's called orexin in the brain. Orexin is the master neurochemical governing sleep and wakefulness. These people with type one narcolepsy have this orexin deficiency. People with type two narcolepsy and idiopathic hypersomnia have normal orexin levels in the brain. It's not quite clear what causes this excessive sleepiness. Furthermore, idiopathic hypersomnia can be divided into those that have normal sleep time and those people that sleep for 11 or more hours, not around a 24-hour day. These are the long sleepers and the normal sleepers. There may be a different pathophysiology between the long sleepers and the people that have normal sleep time.
That gives you a context of idiopathic hypersomnia. You know, the Stanford group looked at what's called the Wisconsin Sleep Cohort. This is a group of working-age adults in Wisconsin that have been followed for several decades. Based on the current diagnostic criteria set forth by the American Academy of Sleep Medicine, around 2%-3% of the U.S. population qualifies as having the diagnosis of idiopathic hypersomnia, based on overnight sleep testing and day testing called multiple sleep latency testing. There's a lot of sleepy people out there that are undiagnosed and untreated.
Right.
We see this a lot in the sleep clinic. Obviously, we have to rule out other things, sleep apnea, insufficient sleep syndrome. There's a lot of other things that can cause daytime sleepiness. When we've ruled out these other conditions and people meet the diagnostic criteria of idiopathic hypersomnia, then we treat them-
Right.
with medications. Now, currently, there's only one medication that's FDA-approved for treatment of idiopathic hypersomnia, and that's oxybate therapy. That is medicine taken at night that puts people into a very deep sleep, and this medicine is not easy to prescribe. There's a lot of physicians or providers that really don't, you know, like to prescribe or are reluctant to prescribe this oxybate therapy, so there's a huge unmet need for additional treatments for these people with idiopathic hypersomnia, so I'm hopeful that the WAKIX will get approved, so I participated in the IH trial for pitolisant for idiopathic hypersomnia. Fortunately, we were one of the highest enrollers. I think we were the highest enroller.
We were.
in the country. And what we saw was consistent with the data you presented, that is probably we had in excess of 60% of patients that actually responded well to WAKIX. And what we've seen in the people that chose to remain in the long-term extension study was maintenance of efficacy over time. In fact, there might even be a slight improvement of efficacy over time, which is consistent with the previous published data. And you know, a nine-point reduction in the Epworth Sleepiness Scale is really quite amazing.
It is.
You know, we with stimulants or with wake-promoting agents, we may see a four or five-point reduction in the Epworth Sleepiness Scale. So a nine-point reduction is truly meaningful and very impactful. So, I think that would be a very important to have this indication, and this will allow us to open up this treatment to a lot of other patients.
Yeah. Thank you, Dr. Corser. I'm wondering, in the interest of time, perhaps we can open it up. Brennan?
Yeah. Thanks. Graig Suvannavejh at Mizuho Securities. Thanks so much for doing the Investor Day. A question for Dr. Corser, please. Just, with respect to the market overall and maybe narcolepsy in particular, maybe as we think about IH as well, how do you see in terms of the new products that are coming as we think about the sustainability of WAKIX growth? Like, how do you see, like, the market in terms of what you have available for you to treat patients over the next five years in particular, with the sensitivity that WAKIX could lose its last market exclusivity in2030 ? So we're just trying to get a picture of what that looks like.
Well, as you know, the big thing now is orexin agonist. To my knowledge, there's about eight companies developing orexin agonists. I'm working with almost all of them. This is very exciting, because orexin really lights up the brain, especially for people with type one narcolepsy. What we've seen is that people with type one narcolepsy need relatively low doses of the orexin agonist, because this is analogous to giving insulin to somebody with type one diabetes. It really treats the root of the problem, and these people respond dramatically. The type one narcoleptics respond dramatically to orexin agonist. Now, there's some conflicting data regarding orexin agonist for treatment of IH and for type two narcolepsy, because that's a different pathophysiology.
But at least one company has presented data that shows that using higher doses of orexin agonist is very beneficial for these people with type two narcolepsy and idiopathic hypersomnia. This is based on a limited number of small numbers of patients. So there obviously has to be a lot more research with the larger patient sets, data sets, to really establish efficacy in the type two narcoleptics as well as IH population. But I think that this is gonna be a very important contribution. It will. Again, it will allow people to remain awake, these people with these profound excessive daytime sleepiness. But I continue to believe that the, you know, most people with narcolepsy or IH may require more than one therapy. This is what we typically see.
Oftentimes, these people end up on two or three different medications, and I think this is somewhat analogous to hypertension, so most people with hypertension need two or three different drugs to control their blood pressure, so much the same with narcolepsy. I think that a lot of these folks will continue to have disrupted nocturnal sleep that requires something to consolidate their sleep at night, but they also may need more than one wake-promoting medication to optimize their daytime functioning, so I think the market's gonna be very interesting over the next five years. I think the advent of orexin agonists are gonna be very helpful, but that's certainly not gonna be a panacea. There will be a need for other medications.
The fact that the WAKIX is non-scheduled is again a really big deal. I don't know what the orexin agonists, if they're gonna be scheduled or not. That's for the DEA to determine, but we're still early in the process with the research for the orexin agonist.
Right. Thank you, Bruce. I guess one last question before we break.
Oh, sorry. This is . Just a quick one here. Just wondering, in terms of, you know, do you think the orexin can actually help deal with disturbed nocturnal sleep at all, or is that something that you wouldn't expect to work out? And then maybe in terms of diagnosis, I think a lot of people are confused sometimes where how do you differentiate between an IH patient and a narcolepsy patient that does not have cataplexy? Is that an obvious diagnosis or is that complicated?
For the diagnosis of these central disorders of hypersomnia, people with narcolepsy type one, by definition, have low orexin. So when you do a lumbar puncture, you see a low CSF orexin level, below one hundred and ten is the sort of the cutoff. Now, that's rarely done in the U.S. because first of all, it's not reimbursed, and secondly, it's very cumbersome to do lumbar punctures. And the only commercial lab that does the analysis is Mayo Clinic. So it really is not done very frequently. So more often we use a clinical history and then a sleep study followed by a multiple sleep latency test. What that means is a series of naps that's conducted through the day.
And what we look for is the presence of excessive sleepiness, that is a rapid ability to fall asleep during these nap opportunities. So typically, there are four or five nap opportunities during the day, and the criteria for type one narcolepsy and for narcolepsy in general is a sleep latency of less than eight minutes, and then you see two or more REM onsets. That is the intrusion of REM into these nap opportunities. So that's unusual. We usually don't see REM sleep during daytime naps, so the fact that we see two or more of these is consistent with the diagnosis of narcolepsy. People with idiopathic hypersomnia have excessive sleepiness, but they do not have REM sleep during the naps.
So that's the major differentiating criteria based on the polysomnogram and multiple sleep latency testing. We also have to take the history into account, so that's a very important part of the whole diagnostic criteria. So what was your other part of the question?
Do you believe orexins can help with disturbed nocturnal sleep on their own, or is this where polypharmacy comes in?
Orexin is high. It's produced in the brain by something like around, you know, seventy to eighty thousand neurons in the brain located in the lateral hypothalamus that produce this chemical, orexin. That's a relatively handful of neurons, given the fact that there's sixty billion neurons in the average human brain. Anyway, orexin is high during the day, and then it subsides during night. There's very little orexin throughout the night. Takeda has some data regarding the effect of orexin agonists on nocturnal sleep. But I... And I, geez, I just talked with Dr. Mignot. He's one of the major figureheads in the treatment and, you know, for narcolepsy.
I was talking about him with this, and he thought, and I feel the same way, that there will probably be a need for something to consolidate sleep at night. I don't think the orexin agonists are really gonna address the disrupted nocturnal sleep. But we, you know, we'll see. We'll have to do much more research to, you know, validate Takeda's original results. But yeah, I suspect that the orexin agonists will be effective wake-promoting medications, but may not really address the fragmented sleep that we see in people with narcolepsy.
Thank you, Dr. Corser. So we are out of time. I don't know what exactly the time is, but we will reconvene in fifteen minutes from now.
Ten twenty.
We'll reconvene at 10:20? 10:20, we'll start. Thank you all for your attention. See you back soon.
Everyone, if we can take our seats, we are starting in one minute. Again, we're starting in one minute, if you can take your seats. Thank you.
... All right. Welcome back. The house is full, so I guess we are doing good. Now, thank you. Thank you for joining us again. So now we transition in this session into two other franchises, neurobehavioral and epilepsy franchise. We'll start with neurobehavioral franchise. The acquisition of Zynerba got us a very innovative product in ZYN002. Right now, we are in the midst of a phase III pivotal registration study, RECONNECT study for Fragile X syndrome, top-line data anticipated in mid-2025, and we plan to initiate phase III registration study in 22q deletion syndrome next year. Both of these opportunities, Fragile X syndrome and 22q deletion syndrome, they have approximately 80,000 patients in the U.S. alone, and this is a worldwide opportunity for us, by the way.
With Fragile X syndrome, we really have an opportunity to bring the first and only approved treatment in patients with Fragile X syndrome. There are no approved treatments for Fragile X syndrome for any symptoms. And similarly, for 22q11.2 deletion syndrome, there are no approved treatments for neurobehavioral symptoms. So with that introduction to the neurobehavioral franchise, it is my pleasure to introduce Dr. Carrie Buchanan, who is with us today. Dr. Carrie Buchanan is a developmental and behavioral pediatrician. She leads the Fragile X Syndrome Program and also leads the Autism Program at Greenwood Genetic Center in South Carolina. She's also an assistant professor at Medical University of South Carolina Children's Health. Look, when it comes to Fragile X syndrome, Dr.
Carrie Buchanan is a very well-recognized name, be it patient care, clinical research, publications, or advocacy. She... over 17 clinical trials in Fragile X syndrome, Rett syndrome, Angelman syndrome, and other disorders. It's really a pleasure to have Dr. Buchanan here, and she'll be talking about worldview of the disease state, the mutation, the methylation, endocannabinoid system, and how it all comes together. Dr. Buchanan.
Thank you. Thank you, Kumar. Perfect. Well, thank you so much for having me. I'm gonna just get situated here. Can I push this up? No one cares? Okay, I just need to set my notes down. So as Kumar said, I am Dr. Carrie Buchanan. I'm a developmental behavioral pediatrician at the Greenwood Genetic Center in Greenville, South Carolina, and I'm really excited to be here today to talk about Fragile X syndrome specifically, but I think more importantly for us today, the role of the endocannabinoid system in Fragile X. So I'm going to describe really the pathology or the pathogenesis of Fragile X syndrome, and then how the endocannabinoid system plays a role, and specifically highlight the importance in what we believe will be the efficacy of CBD in Fragile X syndrome.
We'll talk about the mechanism of action. So let me move forward. Before I get started, I do want to mention what Kumar said. At this point, there are no regulatory-approved treatments for Fragile X syndrome, so I'm just really excited for this product. I've been in this space for a long time, and I've been involved in the trials, the previous CONNECT-FX trial, where we enrolled over 200 individuals into this trial of the topical CBD, and I've seen it work. And so I'm really excited and hopeful for the success of the current trial. So let me get started with what is Fragile X syndrome?
It is an X-linked genetic condition, and I know all of you. I'm sure you all remember this, but I want to bring us back to high school biology. We remember that a gene creates or encodes for mRNA, which then creates a protein. I'm gonna use some words that you're gonna remember genetics from tenth grade. Transcription is DNA to RNA. We transcribe DNA into RNA in the nucleus of our cell, and then that is carried into the rest of the cell, where it is translated into a protein. I'm using these words because that word translation is going to become important in a minute, okay? In Fragile X syndrome, you have an abnormality in the FMR1 gene, which then causes a decrease or loss of the gene product, the FMR protein, okay?
This is an interesting mechanism on how it gets turned off, which, another word I want you to remember today is methylation, and we're gonna talk about that also in a minute. The FMR1 gene is shut off by a process called methylation. So what happens is throughout our DNA, there are things called trinucleotide repeats, right? So there are repeats of three nucleotides. Sometimes these become unstable and expand. You're familiar with Huntington's disease. You've seen, you know how it passes on through generations. You start with a normal trinucleotide repeat, it expands into a mid region, and then you get the devastating disorder. Similarly, this is what happens here. So you have a CGG repeat expansion in the promoter region of a gene. Our body really does its best to try to prevent abnormalities.
Our body, our cells, are seeing this expanded repeat of greater than 200 repeats and is saying, "Shut this off. This is abnormal. We're going to methylate it by putting methyl groups on it." The problem is you're methylating a region of a promoter, so then the gene subsequently gets shut off. You're then not making the protein that you need, okay? Again, this is caused by a repeat expansion of more than 200 repeats, and it silences or shuts off the gene. FMRP is a very important protein. It plays a really important role in brain development. You don't want to not have it. But why is this one protein so important? Remember I talked about translation before. The FMRP protein is actually a translation regulator of over 1,000 different gene products.
So you're not just dysregulating the production of FMRP, you're actually affecting the production or inhibition of a thousand different gene products. That's a thousand different proteins, okay? So it's not surprising then, the absence leads to the dysregulation of many proteins, and they're proteins within the synaptic cleft. We remember what that is, right? The connection between the neurons, which causes the firing in the brain. So then you're having this completely dysregulated neuron, abnormalities in the brain at the level of the synaptic cleft, which leads to something called a pruning defect. If you look at, I don't know if I have a way to point to this, but in that little graph at the bottom, or the picture at the bottom, there's a dendritic spine, and the one on the far right is really thick, okay?
That's in a FMR1 knockout mouse. What you see there is a pruning defect. See how thick and just it's immature, it's not working right, okay? So your signals are not flying through correctly through your brain if you have lost this protein. Interestingly, FMRP has a largely repressive effect. So actually what it's doing, it's inhibiting the production of a lot of gene products. So when you don't have it, you have this overabundance of proteins, neurotransmitters, a lot of different things. One of the most important one is glutamate, okay? In addition to translation, you can drop that out of your brain now. You're remembering methylation. I also want you to remember glutamate, okay? Glutamate is the most abundant excitatory neurotransmitter in our brain.
What is incredibly important in development and just life is the balance, homeostasis of excitatory, inhibitory neurotransmitters, okay? FMRP inhibits the release of glutamate. If you don't have FMRP, you are having excess excitation, okay? Which then leads to extreme anxiety, seizures, social avoidance, specific phobias, irritability, ADHD. What I'm describing to you is the behavioral phenotype of fragile X. Because they don't have FMRP, they're not inhibiting the release of glutamate, they have this behavioral phenotype. So it is not surprising that fragile X syndrome is a neurodevelopmental disorder. It is a development of brain, I'm sorry, a developmental disorder of the brain, okay? The brain is developing abnormally. Because of this, we get intellectual disability. These kids, individuals, have high levels of intellectual disability.
It's also the single most common monogenic or single cause, single gene cause of autism spectrum disorder. Think about autism. They are extremely overly sensitive to environmental stimuli, right? Excessive glutamate. They are extremely nervous and anxious, excessive glutamate. This is what is happening in Fragile X. So again, and I already touched on this, here's the behavioral phenotype. We can absolutely link this to excessive glutamate. They have extremely poor eye contact. They're incredibly socially avoided. If your brain was on overdrive, you would be avoiding all stimulation, right? They are hiding behind their parents. They are anxious. They are very shy. They prefer solitary activities, hand flapping, stimming, hand biting. They get. They're easily irritable. They become aggressive. Attention difficulties. Your glutamate is firing like crazy, you're not paying attention to what's going on around you.
Hyperactive, impulsive, that hyperarousal, what I talked about earlier, like the oversensitivity to sensory stimuli, and then again, autism. Looking at my time here, I got to speed up. So how does this connect? Okay, I've explained Fragile X to you, and I've explained the importance of glutamate, but okay, why? What's the importance here of the endocannabinoid system? Well, that's why we're here today, so or why I'm here today. So let me give you a quick overview of what the ECS is and then explain how it connects to Fragile X syndrome. So the endocannabinoid system is a major chemical neural pathway in our brain, okay? It facilitates synaptic homeostasis, balance of excitatory and inhibitory neurotransmitters, one of which is glutamate, and then also very important neuroplasticity.
It helps us grow, it helps us learn, it helps the neurons change and grow, right? There are two parts to the ECS. There are cannabinoid receptors, CB1, which is present throughout the brain, and then two things called endogenous or endocannabinoids that our brain actually makes. This entire room is familiar with CBD. CBD is an exogenous cannabinoid, right? It's the non-euphoric part of the cannabis plant. It is considered a cannabinoid because it interacts with this system. It is a signal for the CB1 receptor, just as our naturally produced endogenous cannabinoids are. In the normal endocannabinoid system, I want you all to look at the FMRP there in that image. When our FMR1 gene is functioning normally, when we don't have Fragile X syndrome, we have a normal amount of FMRP. What does FMRP do?
It regulates the translation of a thousand gene products. One very important one is this enzyme called DAGL. This is the primary enzyme for the synthesis of 2-AG, an endogenous cannabinoid. Are you guys following me? I know I've got a lot. I'm saying a lot here. That endogenous cannabinoid interacts with the CB1 receptor, and what does it do? Inhibits the release of glutamate, right? What is the cause of the pathogenesis, the behavioral phenotype of Fragile X? Excessive glutamate. So let's take away FMRP. I told you before, FMRP is a repressive, right? Largely repressive effect. You take FMRP away, the DAGL is excessive. It's being excessively produced, okay, which then results in what? Increased production of the 2-AG, which is that endogenous cannabinoid. We all know that our body, again, does everything it can to create homeostasis, right?
So if you excessively saturate, excuse me, a receptor, what happens? It's going to be desensitized and internalized, and that is exactly what happens. So in Fragile X syndrome, you are excessively making that DAGL enzyme, increasing the endogenous cannabinoid 2-AG, the CB1 receptor is desensitized, internalized, the inhibition of glutamate release is stopped. So you have excessive glutamate in your synapse. You have the Fragile X phenotype, behavioral phenotype. Well, where does CBD come in? I am glad you asked. So CBD works to bring the endocannabinoid system closer to normal function. What does that mean? So it actually restores the function of that internalized, desensitized CB1 receptor. We still have excessive 2-AG release, okay? FMRP is still not functioning, but we are now inhibiting the glutamate release into the synaptic cleft. So I'm going to step back for a minute, and I'm going to...
Can I go backwards? I want us all to think about. We all know what CBD does. CBD calms everybody, right? It is an anxiolytic. It decreases anxiety in the entire population. Well, why is that? Because we all have this system, right, in our brains, and but we have a normal functioning CB1, and let's say we're nervous. Well, let's increase what we're a little bit. Let's take some CBD oil or whatever. Let's trigger that CB1 receptor, and let's decrease our glutamate release. So we're calming ourselves. I mean, it makes sense, and that's what I think most people think of when they think of CBD. It's just a natural anxiolytic. But what I want to emphasize in Fragile X, it is so much more.
Of course, yes, it's calming them, it's decreasing anxiety, but it is actually. Oh, I'm going back too far. It is actually correcting the pathogenic mechanism of the behavioral phenotype of Fragile X. So this is not surprising then. So I'll say in 2023, the role of the endocannabinoid system in Fragile X specifically was published, and what is not surprising then is that consistent with these proposed mechanisms in our original trial, CONNECT-FX, which I'm going to talk about in a minute, was associated with improvements in measures of social avoidance, irritability, social interaction, because it's inhibiting glutamate, right? It is correcting that pathogenic abnormality. In 2022, the results were published, and what I'm going to emphasize here, because remember I asked you to remember the word methylation?
What we saw is an ad hoc analysis of those with complete methylation had statistically significant improvement in their, in the primary endpoint or in their behaviors. So I wanted, before I go into a detail of the results of that trial and how it informed the design of the, of this current trial, I want to talk about methylation a little bit because I think it's important. In healthy individuals, we have a normal FMR1 gene. We don't have that CGG repeat. We don't have methylation. I mean, sorry, yeah, our, our gene is not shut off. It's not methylated. So we have normal FMRP.
I've told you before that in Fragile X syndrome, if you have greater than two hundred repeats, you're going to have full methylation of the promoter region, and the gene is going to be completely shut off, and you're not going to make FMRP. In that case, you have a completely dysregulated endogenous cannabinoid system, and you're going to have better response to exogenous or external CBD. But what I didn't tell you is that that promoter region, those CGG repeats, are incredibly unstable. So in a small portion of individuals with Fragile X, even though they have greater than two hundred repeats, they actually do not have complete methylation. So they are making some of that protein, which means their endogenous cannabinoid system is not completely dysregulated, and so it's not surprising that they have an unpredictable response to exogenous CBD, okay.
Also, with lesser methylation, you have the milder, just milder presentation in general, milder cognitive effects, you know, milder behavioral, and also developmental issues. It can be anywhere. I mean, I have a patient who has full greater than 200 repeats and 0% methylation. So you can really have a significant spectrum of how much methylation you have and how much FMRP. So then it shouldn't be surprising to us that in the results of CONNECT-FX, it was the subset of greater than 90% methylation that really performed the best. These are the key learnings from the CONNECT-FX trial. I have enough time. I'm gonna quickly give you background on this trial. We enrolled across the country, 212 individuals.
They were randomized one to one to the topical CBD product and placebo, with two different doses of a weight-based of the, of the CBD. Of the 212 individuals, 179 had greater than 90% methylation. It's not like it's small, okay? So that was, what? About 30 that had less than 90% methylation. If you remove those 30, it's still a very large portion of the, of the individuals in the trial, we met statistical significance. So it was in the complete methylation and also there was a 40% median improvement in socially avoidant behavior. So the primary endpoint was this subscale of a behavioral checklist that specifically looked at social avoidance.
Those that had greater than 90% methylation, that have no FMRP, that have dysregulated endocannabinoid system, improved significantly. Clinically, anecdotally, they improved. But for regulatory approval, I guess more importantly, statistically significantly, they improved. In addition to the primary endpoint, there was also on the caregiver global impression of change, there was statistically significant more improvement. This was the caregiver's response, in social interaction and irritable and disruptive behaviors that were statistically significant. This is the complete methylation, so the 100%, which was about 65%.
But if you actually do the greater than 90% methylation, which gets you to your number of 180, I think because you're increasing the power, you actually reach statistical significance in all of those, of the caregiver impression of change, and in the CGI, clinical global impression improvement. And then if you look at a meaningful change, just a greater than 3-point improvement on the social avoidance subscale, you can see that those receiving the active drug performed or scored better, statistically so. Well, let me say this: So using this information, what Harmony has done, very importantly in this RECONNECT trial, is we've shifted the primary endpoint, right? We know we've already been successful.
We've already successfully demonstrated this medication works in 180 individuals with complete methylation. So I have full confidence in this repeat trial of over 200 individuals, that we are looking at those with a greater than 90% methylation, looking at the primary endpoint is their improvement on the social avoidance scale. And since we've, like I said, already demonstrated that subset in the previous trial, we I think we are very confident in the success of this, of the RECONNECT trial. In addition to making that alteration to this trial, if you can you see here, this is the open-label extension, right?
So after this, and I didn't go into detail, really, but that 12-week, double-blind, placebo-controlled portion, where 212 individuals were enrolled, all of them were offered, as in all clinical trials, the opportunity to roll over into the open label, where everyone received the active product, the active drug. So you can see here, well, two things. One, look at the sustained improvement. So they improve, and then they retain that improvement for up to two years. I have a patient that's been on this product for seven years. It has really been really impactful for his life. The mom's like: "We are not. We've missed a weekend here or there, and we get irritability, we get increased anxiety, we get worsening social avoidance.
We're not coming off of this." So you have sustained improvement and a decline in improvement when you come off of it. But in addition to that, you can see that the initial improvement continued up to month four to five. So because of that, in addition to changing the primary endpoint to complete methylation, the team extended the trial to eighteen weeks, because we know we see that we can see that continued improvement up to month four to five. So based on these changes, the RECONNECT trial has really been optimized, and I feel really confident in the, in its success based on those two major changes. But two other things have been changed that I'm also really excited about.
So we've increased dosing, which is really good because we currently had two doses for weight-based, but we have some really large individuals. I don't know if you are familiar with this, but a lot of individuals with Fragile X syndrome, like, really don't feel satiated, so they're kind of constantly eating, and they eat out of anxiety. And they have weight issues, and so we have this larger subset of the population. So being able to increase the dose, I think, will be very beneficial. Oh, I have 21 seconds. Perfect. In addition, they've made the trial more patient-friendly. There's a completely at-home option. So parents, these kids have intellectual disability, they have autism, they have anxiety. It's hard to get them out of the house.
So they can actually enroll at this, in this trial completely from home. And then even those that choose to come to the clinic, there's only, I think, three or four in-person visits, and the rest are done virtually. And so they've really made it a much more patient and family-friendly trial. So combined here, I really think that we have a trial that has been designed for success and really based on the learnings from the original trial. Yeah, thanks.
Thank you. Thank you. Thank you, Carrie. Thank you. And trust me, there aren't many people in the world who can speak so eloquently and bring all the complicated concepts together. So thank you.
Of course.
So we heard from one of the well-known expert in Fragile X syndrome, and now let's hear from a caregiver perspective.
... There's quite a few challenges I think that we encounter as a family and individually dealing with Fragile X. And, gosh, I would say number one is aggression. That one's been probably one of the hardest. Luckily, my son isn't as bad as he used to be, but aggression is a huge one, and it's hard to live your life regularly when you're afraid of your child or afraid that your other children are going to get hurt.
I don't think a lot of medical professionals really are aware of what Fragile X is, and it's just so sad because it's almost like, you know, Down syndrome. Everybody knows what Down syndrome is, right? They see it, they hear about it all the time. I think doctors are very well educated on Down syndrome, but other genetic disorders, I think, are just very unknown.
What makes anxiety so challenging for Elijah and for us as a family is the way it impacts every single thing we plan. What we're able to plan at all, how much extra thought it takes to plan something. Even something as simple as a trip to the grocery store requires, like, checklists and, and double-checking every single aspect, because if we forget something, then the cost of it is so high. And so we often find ourselves just not going at all.
It's hard. It's difficult. As a parent, it's so heartbreaking seeing your child not be able to regulate themselves, not... you not being able to help.
All right. It's amazing. No matter how many times you watch these videos, the emotion always seems to be the same. Probably helps us to do what we are doing here today. Just, taking from where Dr. Buchanan left, I don't think we ever had an opportunity to talk about this program in as much detail as we're talking today. ZYN002 is the result of a lot of hard work and dedication. In fact, it started all the we back in 2004 , and I'm really happy to say that Terri Sebree , who was part of this program right from day one, is here with us today. Terri, if you can wave or sign. Yeah. Thank you. Thank you for helping us get here to this stage.
The company was co-founded by a pharmacologist and a transdermal specialist all the way in 2004, and multiple studies were done. The first study in Fragile X syndrome started in 2016 as an open-label twenty fifteen, as an open-label study. Right. Then the CONNECT study was started in 2018, and the RECONNECT study was started in 2021. Patients from FAB-C study, the CONNECT study, and RECONNECT study are eligible to enroll in the open-label extension study that Dr. Buchanan was referring to. Moving on. ZYN002. At the beginning, I said this has very unique product attributes. Why is that? That's because it is the first and the only pharmaceutically manufactured cannabidiol, synthetic cannabidiol gel. It is devoid, completely devoid of THC, so it does not have any psychoactive properties.
The patent-protected, permeation-enhanced gel offers some very unique advantages that are worth mentioning. First and foremost, because it's not given orally, it avoids all the GI side effects that you see with oral administration of cannabidiol: abdominal discomfort, significant diarrhea, and vomiting. And it also avoids the hepatic first-pass metabolism and therefore does not have any impact on liver function tests. One other product that is administered orally, cannabidiol solution, does have significant GI side effects and requires routine monitoring of liver function tests, and we'll come to that again in our epilepsy franchise. In fact, this particular product, the safety profile, the database that we have for its safety profile is pretty huge for a product which is still in phase III development.
Over 700 unique patients, that's over 700 unique patients across the age group from three all the way to seventy, seventy-five years old, exposed to ZYN002, and the safety profile is pretty benign, generally safe and well-tolerated. In fact, the most common AE is application site pain, which is seen in about 7% of the patients, and application site pain pretty much captures everything like erythema, edema, irritation, itching, and other things. Some of these patients have been on this product for over seven years. It's amazing. I hear often that some of these kids were actually in middle school, having significant behavioral disturbances, wouldn't even get out of the house, and some of them now are in college, doing very well, and continuing to use ZYN002.
It just speaks to the durability and the maintenance of effect, and it also speaks to the benign side effect profile of ZYN002, and more importantly, this level of persistence is very, very unusual, especially in a neuropsychiatric disorder. This is the Reconnect study design. As Dr. Buchanan said, the lessons from the CONNECT study were implemented in Reconnect study. 16 weeks duration, enrolling patients in the age group of 3 to 29 years, double-blind, randomized, placebo-controlled study, approximately 100 patients. Excuse me. About 80 patients with full methylation in ZYN002 and 80 patients in the placebo group, and about 20 patients each in the ZYN and placebo group with partial methylation. Study duration, 16 weeks, as I mentioned earlier, weight-based dosing, and the patient who complete double-blind, randomized period are eligible for the open-label extension study.
The primary endpoint is change from baseline in ABC, specific for Fragile X syndrome, social avoidance subscale in patients who have complete methylation. Although we are enrolling a small number of patients with partial methylation, the primary endpoint is for complete methylation patients, and the study is powered as such. Key secondary endpoints, some of the important symptoms, like irritability, and one of the other key secondary endpoints is actually combining complete methylation and partial methylation, and to look at the effect of ZYN002. This study is designed to meet both the U.S. and EU regulatory requirements. As I mentioned earlier, we have worldwide rights for this particular asset. A quick word about the total addressable market. Approximately 87,000 patients with Fragile X syndrome, of whom 40,000 patients are diagnosed, and approximately 60% of them have complete methylation.
That brings us to the total addressable market of approximately 25000 patients. So what's happening to wrap up the neurobehavioral franchise? Very excited about the ongoing Reconnect study. We anticipate top-line data from the Reconnect study in mid 2025. We plan to initiate phase III registrational study in 22q11.2 deletion syndrome in 2025, second half of the year, and if everything goes well, we should have a PDUFA for Fragile X syndrome in 2026, which could potentially be the first and the only treatment for Fragile X syndrome. All right, so with that, I would like to invite Dr. Buchanan back on the stage. I think we have about three to four minutes. Perhaps we can just ask a couple of questions-
Sure.
that the audience wanted to ask.
That'd be great.
All right, so I mean, first of all, thank you for explaining it so well.
Of course.
As a neuropsychiatrist, when you were talking, I was thinking, "This is as precise as it could get in a neuropsychiatric disorder in terms of genetic mutation, abnormality in the FMRP, behavioral symptoms, dysfunction of the endocannabinoid system," and the intervention here is ZYN002, which interacts with CB1 receptors. I mean, this is like precision medicine at its best-
Perfect.
for a neuropsychiatric disorder, but what I wanted to ask you now ...
Yeah, of course.
you participated in CONNECT study and Reconnect study.
Mm-hmm.
You also mentioned about the patient for seven years.
Mm-hmm.
I wonder if you can share some experiences of your patients?
Absolutely. So I'll share experiences from the open label, 'cause of course, I don't know if my patients were on the active medication or not in the double blind. We've just had some really remarkable responses. Overall, we are seeing a decrease in social avoidance, being less anxious. These kids have real difficulty with transitions, being able to transition easier. This one mom mentioned going out of the house. Absolutely. I mean, they don't want to go anywhere, but making it easier to get out and do things just improves the quality of life for everybody. But also because I think it's really impacting that pathology. Just an N of one here, I had a patient who's 14. He has never been toilet trained in his life.
One month onto the open label, and he was using a toilet. So it was very remarkable. I have another. Actually, my patient that's been on it for seven years, I don't know if he was on placebo or not. I have a hunch, but he finished the double-blind portion in April, and then a month later in May, had his end-of-the-year IEP meeting. His teacher said, "I don't know what you've been doing for the last month, but don't stop." So the only thing that I could think in that month had been, of course, he had transitioned into the open label. Things like he had become the teacher's helper. He was volunteering to do things. He was just, you know, becoming much more involved, raising his hand, being more social.
We've seen improvement in social language, which is really, really important when it comes to daily function, and just, you know, a broad range in both males and females, we've seen improvements, well, I had one patient, very shy young lady, into the open label. The mom calls me: "You'll never believe this. She's auditioning for a play." Things that you would never have expected from this population.
Yeah. Thank you.
Yeah, of course.
Yeah. Glad to hear these experiences. So, and also the-
Can I ask one question from the audience?
Sure. Please go ahead.
All right. Hi. Just coming from the audience. In the RECONNECT phase III trial, would you expect there to be an impact on the effect size driven by any age, time since diagnosis, body composition, or BMI? Also, is there a really hard cutoff for methylation percentage, 90%, that drives efficacy, or is this a signal-to-noise issue, i.e., with lesser methylation, does the mechanism of transdermal CBD hold up?
If you look at the data, although it wasn't statistically significant, individuals with Fragile X just did better. I think the threshold of the 90% is really to get that level of statistical significance because we know they're responding better. But the others responded better than the placebo also. It just didn't come up-
Right.
Come in the data. So I think if you think of the ECS, it's still dysregulated in those that have, you know, less have partial methylation. So it absolutely does still make sense that the mechanism of action would still work. It just works better in those who have the full methylation.
Right. I mean, it's the unpredictable response if the patients do not have complete methylation. That's what the RECONNECT study design avoids and elevates the probability of success, because now we have a much more homogeneous patient population to treat. All right. Thank you.
Mm-hmm.
So the other question I wanted to ask you is the intervention itself. Look, gel is not a common intervention.
Sure.
Most often it's the oral pills. So I just wanted to ask you your experience in terms of how the patients, the family, embrace this kind of intervention, which is really rubbing the gel at the back of the arm, right?
Right. So we do both. We do arms and legs, actually, depending on if you get some dryness. It is an alcohol-based gel, so you can get some dryness, but it is incredibly safe. And you mentioned the side effects. I don't ever think I've had someone complain of site pain, but maybe some like, you know, dry skin. So absolutely. So regarding the application, a couple things. Remember, this is an intellectually disabled population. I just think of my own nine-year-old, who is neurotypical. She does not swallow a pill. It's really difficult to get them to take medication, and they have significant behavioral issues. And so this was actually a huge relief to a lot of the parents.
Like, we don't have to, you know, force our child to, you know, or crush up a pill. So that's been a real benefit. A lot of parents also feel like it's kind of a bonding.
Mm.
It takes a little while, maybe 10 or so minutes, for it to dry, and so they rub it in, and they enjoy that. The other thing is this, because of this high level of anxiety this patient population has, is they're incredibly habitual, and they love routine. And so having a twice-daily routine, sitting down with their parents, is actually been really good for them. They enjoy it. They ask for it in any way they can. They'll bring the packets to their parents, or they'll remind them. So it's – yeah, it's actually been really great. And I jokingly from the beginning asked Zynerba: Can we get, like, all medications through this application?
Sure.
Because it's really hard for these patients to take oral medications.
Yeah. Thank you.
Yeah, of course.
I think we finished right on time. So thank you for your time.
Perfect. Yeah. Thank you so much.
Yeah.
Thanks.
Thank you. All right. Moving on to our last franchise, which is epilepsy franchise. This is also a franchise where we are very optimistic of helping tens of thousands of patients in rare disorders, despite several medicines approved. Unlike some of the other disorders that we discussed today, there are medicines approved for childhood epilepsies, rare disorders, but they have their own significant limitations in terms of efficacy, safety, and tolerability, and what we plan to do is, through our development programs, we will be developing drugs, and we'll talk more in detail soon. The acquisition of Epygenix got us EPX-100 and EPX-200. That's clemizole hydrochloride and lorcaserin, respectively. The mechanism of action of these drugs is validated through a very innovative and, more importantly, highly predictive zebrafish model that Dr. Scott Baraban will be talking to us in a minute.
These products have the potential for a very favorable risk-benefit profile. We have already commenced phase III registration study in Dravet syndrome and anticipate top line in 2026. We plan to initiate a phase III registrational study in Lennox-Gastaut syndrome by the end of the year and expect top line in 2026 as well. With that high-level overview of epilepsy franchise, it is really my pleasure to welcome Dr. Scott Baraban. I need to use an index card because he has so many accolades, but I'll try to keep it brief. Dr. Scott Baraban is a professor at UCSF and an adjunct professor at the University of California, Berkeley. Dr. Baraban does pioneering research work in childhood genetic epilepsies, and his lab is the one who developed zebrafish model more than 20 years ago and published the first high-throughput drug screen for Dravet syndrome. Dr.
Scott Baraban has published more than one hundred twenty-five manuscripts in peer-reviewed journals, high-impact journals like Nature, Science, Brain, Neuron, and he's very passionate. He's very passionate about translating discoveries into meaningful interventions for patients. So with that, Dr. Scott Baraban, please.
Let's grab this. Thank you. Great to kind of give you a brief introduction to one of my life's passions, which has been to do translational research for a large unmet need in the epilepsy community, which is these families with rare diseases. And I wanna start with a video of her. You saw her a second ago. This is Kara. She's about eight or nine in this video, talking about with her mother Laurie O'Driscoll, who along with Mary Anne Meskis founded the Dravet Syndrome Foundation about fifteen years ago. And when I first met them at an epilepsy meeting, they gave my lab some pilot funds to do zebrafish research on Dravet syndrome zebrafish, a model that you'll hear about. And this is her mom explaining-
One of them, his name is, Dr. Baraban. Can you say that?
Dr. Baraban.
Do you know how he... He's trying to find a new medicine for you, and do you know what he's using to do it?
What?
Fish.
Why is he using fish?
This may sound a little strange. He has fish that have Dravet syndrome.
That is so crazy!
Of course, Kara is not the only one who thought that when we started this program about 15-20 years ago. Kara, unfortunately, succumbed to SUDEP, which is sudden unexpected death in epilepsy, about 6 or 7 years ago. I like to keep this video in her memory and to remind me why we work on this, we work so hard on this.
One of-
I want to just start with how I got here. In the epilepsy field, there are about 28 or 29 FDA-approved drugs. The first ones were developed in the 1850s, and more recently, a couple were approved, including fenfluramine for Dravet syndrome and stiripentol and cannabidiol. Unfortunately, in all of this time, the number of patients in the epilepsy community who remain medically refractory, despite one and now 28 anti-seizure medicines, has always been one-third of the patient population. This is an alarming statistic if you think about it, but it's also an opportunity as well. I kind of viewed this. The opportunity is basically that all of these drugs on this list were discovered in rodent models of epilepsy. Actually, they're not models of epilepsy, they're models of seizures, and there's a distinction.
When you have epilepsy, it's diagnosed as three or more spontaneous seizure events that occur in an unprovoked manner. A seizure, though, can be elicited by a variety of chemical or electrical means, and these drugs were discovered in healthy rodents where you induced a seizure event, and so they were all basically discovered on the same type of animal model, and none of these animals represent genetic forms of epilepsy, and none of these models were tested, or none of these drugs were discovered using a model, an animal model that had epilepsy, spontaneous seizures, and so we wanted to change that when I first started in this field.
The second part that's changed over the years is that our understanding of the genes that cause epilepsy has magnified almost one hundred fold, obviously, within the last 10 or 15 years with genetic testing. So we now know many of these genetic epilepsies, which are the ones that remain medically refractory, have a single gene basis, a single gene mutation basis. Without jumping to kind of like the pharmacology first, 'cause I think this is an important slide, we developed a zebrafish model that has the same sodium channel mutation that patients with Dravet syndrome have. There's also a mouse, several mouse models for this same mutation. But what's interesting is the pharmacology on these models, these preclinical models, differs greatly.
In our zebrafish model, which you'll hear about in a second, where we're testing drugs on spontaneous seizures, all of the standard of care drugs that are given to this patient population, including valproate, clobazam, diazepam, clonazepam, benzodiazepine classes, potassium bromide, all these are successfully identified in our assay, our assays, as well as the more recent drugs, stiripentol, fenfluramine, and cannabidiol. Cannabidiol caveat, of course, is that's an oil, so we tested synthetic cannabinoids in the fish. But you'll see on the right side, none of these drugs, including, importantly, fenfluramine, has ever been discovered to successfully induce or inhibit seizure activity in a rodent model of Dravet syndrome. And so we think there's the model that we've developed has 100% accuracy in predicting drugs that are known in the clinic to work on these patients.
And so that's one side of it. The flip side of that is there's also drugs, of course, that are contraindicated. These patients are pharmacoresistant. They don't respond to three or more anti-seizure medications. Again, testing all of those, we also had 100% predictive ability in that none of those drugs reduced the seizures in our zebrafish model, and some, of course, made seizures worse, as predicted. A few of these have been tested in rodents, again, not very many. And of course, the other big difference is, you'll hear about in a second, is throughput. Very few of these actual experiments have been done on rodents because of the difficulties with that model. So why do I use zebrafish? Well, zebrafish are vertebrates, and they've been used in basic neuroscience community for decades, for mostly developmental studies.
They share actually a very high genetic similarity with us, 70%-84% sequence identity, which is about the same as you see with rodent models. They're inexpensive to maintain. I have a colony of about 5,000 zebrafish in a room a third of this size in my laboratory. They're genetically tractable. I've actually made, using CRISPR techniques, genetic versions for over almost 40 different rare epilepsies, and I'm going to talk to you about a couple of them today, but most importantly, they're good for high-throughput drug screening, 'cause you can put the fish in a single well of a 96-well plate, and to give you some perspective, I'm not talking about the zebrafish you see in the pet store, which are about 1 or 2 inches long.
I'm talking about the larvae that they generate, which are about the size of your eyelash, and so we use those within five or six days. Larvae are transparent, they're permeable to drugs, and one pairing can produce hundreds of larvae per week, so we can actually do hundreds of experiments every single week on these models. And so a schematic of what we've done, we call it an aquarium-to-bedside approach, you'll hear why in a second, is that we take these epilepsy gene discoveries that have come out of the patient population, we look for homologous genes in the zebrafish that match up, and then we generate a CRISPR mutant using CRISPR techniques that has the same genetic mutation that the patients have.
We use two types of very sensitive assays developed in my laboratory to study epilepsy, to study spontaneously seizing fish. The first is behavior. Basically, we video track the fish in a 96-well plate to watch when they have a convulsive behavior, and that gives us a surrogate readout of them having a seizure, but more importantly, we develop electrophysiological recording techniques, 'cause even in patients, EEG is the definitive gold standard for having a seizure. A seizure is an abnormal electrical event in the brain and can be picked up using electrophysiological recordings, and we use these models then to do high-throughput drug screening. Like I said, 96-well plates. We buy initially commercially available drug libraries. All this was done in a blinded manner. We didn't know what the drugs were. This is not rational drug design.
We weren't no biased toward what we'd find. We just looked for drugs that eliminated the spontaneous seizures in these models. This is what it looks like. This is one well, one fish in one well of a 96-well plate, and the video is slowed down 'cause this fish is actually moving faster than you would pick up by your eye when it's having a seizure. On the right, in the top, you can see some of the EEG activity, as well as brain neuroimaging. This is a calcium indicator that lights up neurons in the brain when the fish is having a seizure. These zebrafish will have this event about once every minute or so, spontaneously unprovoked. They do have epilepsy, and that's our readout for looking for drugs that are basically gonna stop all these events.
But more importantly, they also model other aspects of patients with Dravet syndrome. They are pharmacoresistant, like I said. Most anti-seizure medicines don't do anything to these fish, and they have what are called comorbidities, which is common in the epilepsy community. They have metabolic deficits, they have sleep disturbances, you can actually look at sleep cycles in zebrafish larvae, and they have early fatality, SUDEP, like the patients with epilepsy, with Dravet syndrome. And so a summary of what we had done, this started about ten years ago. To give you some context, it took about five or six years to get through this library. We did phenotypic drug screening, so basically, like I said, we looked for animals and drugs that just stopped having epilepsy. We did behavior first, 'cause it's high throughput, and then electrophysiology.
The important distinction there, and this is just some of the, those data points, is that using electrophysiology, we're able to eliminate false positives. You can imagine a drug that's a sedative or a muscle relaxant is going to stop the fish from having those behaviors, but those drugs are not anticonvulsants. They're not gonna stop the electrical activity. So having a two-stage assay allowed us to have less than 1% of the drugs that came through this trial identified as hits. In fact, we screened over 3,500 drugs from a wide variety of commercially available libraries that cover almost every mechanism of action you're gonna ask me about, and the only drugs that worked were drugs that had a serotonin receptor mechanism.
So basically, they interact with serotonin signaling, which is the same kind of mechanism that fenfluramine works, though ours are receptor agonists and fenfluramine is a reuptake blocker. And this is some, just a little bit of the science, what it looks like. This was our paper in 2013, when we first described the Dravet syndrome zebrafish model, and it shows you on the left just some bar charts where you see clemizole is effective in reducing these spontaneous behaviors back to baseline, and a couple of false positives are listed, which are drugs that were muscle relaxants that reduced the behavior, but didn't show up on the subsequent physiology recordings. And you can see on the right side in red, when we give clemizole, there are no abnormal electrical events. So we weren't looking for seizure-modifying drugs, we're looking for drugs that completely eliminate this abnormal activity.
A very stringent assay. Importantly, it's not just Dravet syndrome, though that is the lead indication, and that's the first clinical trial that's being done. As I said, we have models for about forty other rare genetic epilepsies in the laboratory, and many of them have spontaneous seizures as well. One of these is shown here. We recently published a couple of years ago is STXBP1. This is a syntaxin-binding protein similar to kind of a synaptic role in synaptic transmission. These STXBP1 disorder children also have intractable epilepsies. This fish is pharmacoresistant. Most all five anti-seizure medicines we tested on this model didn't do anything. But when we gave it clemizole, we completely eliminated the seizure activity, and this is will be a subset of the LGS patients.
LGS is not a single gene mutation phenotype, but it has a number of single gene mutation families within its cohort. We'll be able to track whether clemizole is particularly effective in STXBP1 patients. In a very short time, hopefully, I gave you a sense of how this came to be. We developed, again, this zebrafish platform almost twenty years ago. We developed a wide variety of assays to study epilepsy and behaviors in these zebrafish models. We've taken advantage of CRISPR technologies to generate a large number of rare disease model zebrafish. We then use those in pharmacology and drug screening assays, and we've shown so far that the predictive effect, the predictive ability of these models and these assays is about 100% so far on drugs that we knew the answer to.
Now, of course, gives us a lot of faith in clemizole because it's a new drug, but now we have confidence that the things we pick out in our assays will also work clinically. Of course, this sends us into the clinical trials that we're teaming up with Harmony, and we're happy to see those continue in the patient population for Dravet syndrome and then soon for LGS patients. I just want to end on a quote. This is actually someone writing a review in Nature about our work, one of the Nature journals, Ellen F., who kind of came up with the idea that this is an aquarium-to-bedside approach. Of course, it's the first time largely because zebrafish have only been used for drug discovery within the last five to ten years.
So this is a very new field. Okay, thanks. Thank you. Stay. I'll come back up for discussion.
Thank you. Those videos are so cool, zebrafish. All right. Unfortunately, I don't have such cool videos, but what I have is an update on clemizole hydrochloride program. But clemizole hydrochloride, a quick word about the drug itself. It's important to note that this is not a new drug. Clemizole hydrochloride was approved as a first-generation antihistamine in the nineteen fifties, sixties, and it was in the market for almost two decades, and no safety signals were observed. The drug was sunsetted with the introduction of the next generation antihistamines. At the request of FDA, we are developing clemizole as a new chemical entity, which means we completed a full battery of non-clinical studies, including six-month rat study, nine-month dog study, the in vitro studies, the hERG studies, all of those things.
What was determined is there is no need for any additional laboratory or cardiac monitoring with clemizole. Of course, the mechanism of action is established, and Dr. Scott Baraban just mentioned about the zebrafish model as well, the serotonergic mechanism of action. The phase I study in healthy volunteers was completed, and we'll show those data soon. As I mentioned earlier, we are in phase III for Dravet syndrome, and we plan to initiate phase III registration study in LGS by the end of this year. Also important to note that clemizole has been granted both orphan drug designation and rare pediatric disease designation for both indications, Dravet syndrome and LGS. A quick look at the phase I study. It's a PK study, multiple ascending dose study, three doses, 20, 40, and 80 milligram. Quick summary, generally safe and well-tolerated. Dose proportional PK was observed.
There was no apparent effects of food on PK, which is important because many of these patients with Dravet and LGS, they tend to have feeding issues. It's not like strictly scheduled. If something has to be taken with food, it's not like you can feed the kids at 8:00 A.M., 8:00 P.M. and give the drug. So that having no apparent effect of food on PK is helpful. In terms of AE is somnolence, not unexpected, given that it was approved as an antihistamine many, many years ago, but otherwise, it was generally safe and well-tolerated. These are new data. We are showing some preliminary, preliminary safety and tolerability data compared to select approved drugs in Dravet and LGS that are more commonly used. A couple of other drugs like stiripentol and clobazam is also, are also used, but not that common.
What we wanted to emphasize is, based on this preliminary safety and tolerability data compared to other approved drugs, the risk-benefit profile, the evolving risk-benefit profile, looks pretty good. There is no need to monitor liver functions. There is no need for echocardiogram to monitor for cardiac valvular disorders or defects, excuse me, or pulmonary arterial hypertension. These are the patients and the caregivers, they already carry a huge burden, and having additional laboratory testing, additional cardiac monitoring, carries additional burden, which they don't have to. So overall, based on what we are seeing, we have a potential for a favorable risk-benefit profile. ARGUS study design, nothing unusual here. It is a pretty standard design in developmental epileptic encephalopathies: four week of dose titration, twelve week of maintenance, and then the patients are allowed to participate in the long-term extension study. The open-label extension study, though, is long.
We are going all the way to one hundred and fifty-six weeks to collect the effectiveness and safety data for a really long period of time because we want to look at the maintenance of effect, and of course, we want to support the patients who participate in our clinical trials. In terms of primary and secondary objectives, again, nothing unusual. The standard endpoints, we are looking at countable convulsive seizure frequency from baseline to the end of treatment, looking at greater than 50% responders, looking at seizure-free days. The study is designed to meet both U.S. and European regulatory authorities. This is the summary of status update for ARGUS study, ongoing phase III. We anticipate top line in 2026. Total addressable market, prevalence of approximately 8,500 patients. Almost all of them, about 7,000, are diagnosed.
What's important to note here is about five to six thousand patients, so almost all the patients who are diagnosed, are also considered as inadequately treated, because either because of the limitations with efficacy or because of the safety and tolerability issues with the drugs that are already approved. So the total addressable market for Dravet is approximately five thousand.
Prevalence of approximately-
Moving on, Lennox-Gastaut syndrome. Plan to initiate this study by the end of this year. From a study design perspective, pretty standard in developmental epileptic encephalopathy. Endpoint perspective, pretty standard. We are looking at seizures that result in drops from baseline to the end of treatment. Again, we are looking at greater than 50% reduction in seizures and also seizure-free days. A quick word about total addressable market again. LGS patient population, by the way, is much larger than Dravet syndrome, approximately 48,000 patients in U.S. alone. By the way, we also have the rights for this compound for all over the world, and as I said, we are designing our clinical trials to meet both U.S. and European regulatory authorities. Approximately 44 of the 48,000 patients are diagnosed.
About 35,000 patients are considered as not adequately treated, so the total addressable market is 35,000 patients with LGS. All right. Multiple catalysts in our epilepsy franchise. To start with, we will initiate the phase three registration study in LGS by the end of this year. We anticipate top line for both Dravet and LGS in 2026, and potentially PDUFA in 2027, 2028 for both Dravet and LGS. So that's the epilepsy franchise. Before I invite Jeffrey back up on the stage, just a couple of comments. First and foremost... No, actually, I did forget. Actually, we do have a couple of minutes here. We can actually have a quick chat with Scott Baraban before I go to my closing comments. Scott, do you mind?
Sit closer.
Uh, yes.
More intimate.
Yeah. All right, well, thank you.
Sure.
One question that often comes up is about. We often talk about bench-to-clinic research, and in this instance, aquarium to clinic.
Mm-hmm.
It's very unusual in drug development to see the discovery translate so well into the clinic.
Mm-hmm.
But in this case, this is not the first time, though. You already had experience with another compound. Can you talk about that?
Right, so after we discovered clemizole, we sought to screen other serotonin-containing libraries to see if we could find other compounds. We screened about 100 of them, and we identified two other FDA-approved drugs... lorcaserin and trazodone, which lorcaserin is EPX-200. At that time, around 2017 or so, I talked with Kelly Knupp, a colleague of mine, who's a pediatric neurologist expert and Dravet expert in Denver, and I was also in communication with a lot of the Dravet families who had been approaching me after we published the clemizole paper to see if they can get clemizole, which of course, was not on the market.
And so through those connections and kind of the leap of faith, that the community had in my science, we enrolled five patients in a compassionate use trial in Denver on lorcaserin. And in that small cohort, there was a 60%-70% seizure reduction, in those patients who were volunteers for that open label study. That actually prompted it. We published that in two thousand and seventeen in Brain. A few years later, Orrin Devinsky, here at NYU, and his group did a retrospective study of their patients in the clinic who were LGS and Dravet patients, who had also taken lorcaserin for whatever reason. And he also reported in about 20 or 30 patients, in their retrospective study, that there was a 60%-70% reduction.
It remains, to my knowledge, the first and only example of taking a drug discovery from zebrafish model. We didn't do mice, we didn't do organoids, we didn't do anything else, and we went directly to patients and got a quick readout that these drugs are potentially efficacious in the patient population. Of course, because they were repurposed drugs, and lorcaserin specifically, there was already safety data that allowed us to do that. Like I said, the faith in the Dravet community had in our science to enroll their kids in these trials with no other evidence other than our zebrafish work.
Thank you, Scott. And also, when it comes to clemizole, you worked with it extensively, characterized the receptor affinity, and you showed some data on DS and LGS, and you also briefly talked about SYNGAP, but you have done other experiments as well. So apart from LGS and DS, which we are primarily focused currently, where do you see clemizole can go potentially beyond these two disorders?
Right. So clemizole, of course, you know, we're just starting to figure out where it might work in these other rare genetic epilepsy models that we have. Interestingly, it worked on a very common rodent model for PTZ application, which is just a generalized Metrazol test that's been around since the eighteen hundreds. And so we believe it'll work more broadly, but because I'm cautious about recommending this for these patient populations, we're systematically going through these thirty-some-odd zebrafish models to find other uses of clemizole. And like I said, so far, we've seen it works in STXBP1 disorders, and we're continuing to look at it in additional single gene mutation models. But it's very possible because its mechanism of action is a serotonin acting mechanism.
It might actually rebalance excitation inhibition because these receptors might be on inhibitory interneurons, so we might actually just be boosting the inhibitory network in the brain, which is important to combat seizures. And so I think it'll be used more broadly, but of course, right now, we have to carefully find each indication in the laboratory first before we can suggest where to use it clinically. That said, if the drug gets approved by the FDA, off-label usage will give us a much quicker readout in a couple of years of other patient populations where clemizole might be effective.
Yeah. Thank you.
Sure.
I mean, just to keep us on track, probably we'll have to conclude here, but-
Yeah.
Thank you.
Sure.
All right. Just a quick comment before we have Jeffrey Dayno come up here. Look, today we had an opportunity to talk about the portfolio and highlight some of the important programs. But one thing is that we work with patients with rare neurological disorders. These patients, as I repeated a couple of times already, either have no treatment options or very limited treatment options, and we depend on their and their caregivers' altruistic nature to participate in our clinical trials to advance our programs. And we also depend on investigators like Dr. Buchanan, Dr. Corser, the sites, and the site personnel to advance our programs. Our sincere gratitude to all the patients and the caregivers, the sites, and investigators. Without you, we cannot do this. It's just we cannot do this.
And, of course, my sincere thanks to the entire R&D, medical affairs, and all the support functions at Harmony, who are working tirelessly to make a meaningful impact on many, many patients' lives. So with that, Jeffrey.
Thank you, Kumar. Wow! Where, where do I start here? So, so many thoughts in my head, you know, after this program that we walked you through. So I'm gonna share some closing remarks with all of you. First, I wanna thank, Dr. Bruce Corser, Dr. Carrie Buchanan, and Dr. Scott Baraban, great, presentation on the zebrafish model, for sharing, all of your expertise and your passion, you know, with us this morning, you know, in these rare neurological disorders and new therapeutic areas that we are moving into.... I also want to thank, members of my team, Jeffrey Dierks, for shining a light on our unique commercial model that has driven the success of the WAKIX franchise that continues to grow. Thanks, Jeffrey. And to Dr.
Kumar Budur, who obviously has done the heavy lifting here today, opening up our exciting pipeline, a robust, catalyst-rich, late-stage pipeline with, you know, all of the emerging opportunities, you know, that we shared with you today. So thank you very much, Kumar, for all that, and sharing the new data, the exciting new data that we highlighted in our pipeline. So I want to just review what we, you know, shared with you this morning. First, I introduced you to sort of neurology, the new ethos and identity of Harmony Biosciences.
My team shared, as I mentioned, compelling new data with you from the IH phase III development program and the very exciting, you know, new data emerging of our orexin agonist compound that we in-licensed with our partner, Bioprojet, demonstrating the potential to be, you know, best in class in that very exciting space. I laid out the five-year horizon with regards to what this, you know, very deep and catalyst-rich pipeline could offer, you know, with regards to one or more new product or indication launches each year over the next five years. We also shared with you the market opportunities. You know, these potential target indications in late-stage development, four programs in phase III by the end of this year, and if we look ahead to the end of next year, up to seven clinical development programs in phase III in orphan rare neurological disorders.
Again, our conviction that this represents one of the deepest and most valuable pipelines in the industry in patients living with orphan rare neurological diseases. But what I want you to take away from our program, you know, this morning is that when we deliver on our promise to patients, we deliver strong value to our shareholders. Based on the innovative approach we've taken in our commercial model, in our patient-focused drug development that we highlighted here for you this morning, this very robust, catalyst-rich, late-stage pipeline and the new data that we shared with you, and we will continue to provide updates for you as we go forward, highlighting even further the value of this rich pipeline. And also, that we have a unique profile, being a profitable, self-funding biotech company that is funding the growth of this pipeline off of our balance sheet.
I don't think you can find many other companies able to do that, especially given how full this pipeline is. And then lastly, with all this, I think the ultimate takeaway from our program this morning is that with this team and with this pipeline, today, Harmony represents a very meaningful investment opportunity, and the time is now. So thank you for your attention, and now I'm going to call up members of management team for our panel discussion and Q&A, and welcome Sandip Kapadia, our Chief Financial Officer, up to the stage as well.
Go ahead. Thank you. Dierks. Thanks for all this really helpful color. Just a couple questions. First, on WAKIX for idiopathic hypersomnia, I know you provided a little more insight into the data, but can you just talk about your overall approach with the FDA? Because it doesn't sound like there was anything that was particularly unusual about the randomized withdrawal period, other than perhaps the few patient outliers that you cited. So I'm just trying to better understand what your approach is with the agency regarding that opportunity. So that's number one. And then number two is on pitolisant HD. I'm trying to better understand what is the top priority in terms of clinical development.
You talked about narcolepsy, you talked about IH, you talked about myotonic dystrophy one, and then you also talked about fatigue. So help us better understand, you know, how you're getting from where you are now to 2028 and that approval and what that first approval is gonna look like, I guess, aspirationally. Thanks.
Yeah, sure, David. Thank you for your question. So let's take the first one first. So idiopathic hypersomnia, you know, I think that the strategy, and then I'll turn it over to Kumar to expand on that, is really, you know, building the, you know, strong overall benefit-risk, you know, proposition with regards to the totality of the data that Kumar shared with you today. So, you know, given when the FDA makes decisions on approval, a lot of it is against sort of the backdrop of risk-benefit, and where the bar is set is what's currently in the market.
So I think, you know, with that, and not only the single approval with XYWAV, you know, approved for IH, but a lot of the off-label use of Schedule II stimulants, which the FDA is very aware these days, you know, in terms of misuse and diversion and sort of having that out there in the population. So, you know, offering another treatment option with that benefit-risk profile, that the dosing scheme fits well, you know, in patients with IH. So it's building that, and as Kumar shared, bringing in the additional evidence base, from the clinic of Yves Dauvilliers to the real-world evidence in Bioprojet's compassionate use program. So that is the strategy, and then one more comment, I'll hand it over to Kumar. The other is in our interactions with the agency.
You know, we talked about in orphan rare diseases, you know, in neurology division, you know, more than a psychiatry division, the ability for regulatory flexibility. And, you know, what's interesting is I've served as the industry representative, you know, as a neurologist in practice for 12 years. I've also served as the industry rep on FDA AdCom meetings and panels and, and ones in particular where regulatory flexibility was applied. So I've seen, you know, the agency and, and how they think about when to apply that, when to employ that, and we feel in this setting, there's a good opportunity to sort of kick open the door there and looking at this in a flexible way based on the totality of the evidence. Kumar?
Yeah. Jeffrey, I think pretty much you covered everything. There is nothing much to add, apart from saying that, look, it's the totality of the data, and the FDA will look for persuasive evidence of efficacy. And this, this is where the multiple lines of evidence, the multiple datasets come into play. And the voice of the patient report that I reported on today, where actually FDA provides its input before the report is finalized, and as I said, it's not just the patients, it's not just the caregivers, it's not the providers. The agency itself said the need for more treatment options, for better treatment options, for non-stimulant treatment options in patients with idiopathic hypersomnia. So I think there was one more question from David.
pitolisant HD.
Right. Yeah.
Yeah, so pitolisant HD. Lots of opportunities to start with. So pitolisant HD, you know, innovative approach, looking in terms of the unmet medical need, you know, beginning in narcolepsy, and then the other potential indications that you mentioned. So with provisional patents filed to 2044 and the ability to extend the entire, you know, pitolisant franchise, we've sort of highlighted what those programs can be, you know, with regards to importantly, idiopathic hypersomnia. You know, indication and fatigue in patients with narcolepsy, and then picking up where we left off in the myotonic dystrophy program, you know, in terms of phase II proof of concept, Kumar alluded to strong signals in terms of improvement in both EDS and fatigue, also demonstrating a dose response.
So an opportunity there with the higher dose, you know, potentially developing and pursuing the indication in myotonic dystrophy. I think, you know, with regards to the strategy, you know, obviously, it makes sense to lead with, you know, with narcolepsy and build off of the narcolepsy franchise. And then the others, I think it's too, you know, too early for us to commit to, but I think we laid out the opportunities, whether we run some of those programs in parallel, whether we sort of pulse them or stage them out. You know, we'll see how much, Sandip, we can, you know, finance all those development programs and maintain our profitable profile. But a lot of opportunity to choose from, and if you wanna comment any further.
No, I think, yeah, as I said, the priority would be narcolepsy, lead off of narcolepsy franchise and look at the other disorders.
Yeah.
And David, what I would add just commercially is I think the biggest value driver is greater efficacy. So to your point, if you're teasing out EDS, cataplexy, fatigue, and narcolepsy, based on the research we did with healthcare professionals, driver grading efficacy is more, quote, "value than fatigue." So I think that is the main value driver of the narcolepsy trial. We all know that there's a significant unmet need, there's a ton of residual symptoms, and I think trying to, quote, "solve that," greater efficacy is probably gonna be the primary focal point within that trial, and then obviously
Yep.
If I may, and sorry, I didn't introduce myself, David Amsellem from Piper Sandler. So just if I may sneak in a quick follow-up, so let's say you don't get WAKIX approved in IH, do you then run a phase III in IH for pitolisant HD in parallel to your development in narcolepsy? You said you're leading with narcolepsy, but does that change if the FDA if you don't get FDA approval for the legacy formulation in IH?
Yeah. What I would say, David, is that, you know, we're planning to pursue IH in pitolisant HD, you know, regardless of whether we get it approved or not for WAKIX. So again, much longer opportunity in the market, you know, with provisional patents to the mid-2040s. So either way, we will pursue an IH indication with pitolisant HD. If it doesn't get approved for WAKIX, we may run them in parallel. We may move that up. We may be a little more aggressive in terms of being able to pursue the narcolepsy indication, you know, as well as IH. You know, 'cause we feel IH is an important treatment option, you know, pitolisant WAKIX is an important treatment option for patients with IH.
Next question.
Good morning. Thank you for this wonderful program today, Danielle Brill from Raymond James. I also have a question on pitolisant HD and the fatigue indication. Can you talk a little bit more about the phase three trial that you plan to run and the primary endpoint? Has this endpoint been evaluated in prior studies? Thank you.
Thank you, Danielle. Nice to see you. So yes, I think that I'll turn it over to Kumar with regards to the trial design and the primary endpoint, some of the leading work we've done around fatigue in terms of fit for purpose endpoint, you know, fatigue in patients with narcolepsy.
Yeah, sure. Hi, Danielle. Thanks for the question. So yes, I mean, we have been looking at this particular indication, particular symptom for quite some time now, and we have done a lot of work that is needed to get to that point. For example, we have completed qualitative research work to identify the right instrument to measure fatigue, particularly in patients with narcolepsy, and we are also in the midst of a study looking at the prevalence and impact of fatigue in patients with narcolepsy, and to your question about, you know, fatigue and the regulatory concept, look, there are a couple of products where fatigue is in the label, for example, RINVOQ, fatigue in rheumatoid arthritis. So it's not a new concept.
The regulatory agencies used to fatigue as an important problem from a patient perspective, and they have approved drugs with fatigue as an indication, and we want to follow something similar with our clinical trial as well. In terms of your question around the endpoints, obviously, we'll target excessive daytime sleepiness. As Jeffrey Dierks said, that's the primary value driver, and that's where the highest medical need is, and we'll also include fatigue in such a way that we will get an indication or a label claim, and then we'll discuss with the regulatory agencies in terms of what is the best way to get excessive daytime sleepiness, cataplexy, and fatigue as an indication for pitolisant HD.
Hey, Greg.
Graig Suvannavejh of Mizuho. I've got a couple of questions. The first one has to do with the orexin program, and some of the other programs we've seen have had some adverse events, tolerability issues that perhaps are not ideal. I know you've got a novel chemistry. Can you speak to the potential and what gives you the confidence that you could see a better AE profile? So that's my first question, then second is really about the breadth and depth of the pipeline, but as it relates to financing all of this, maybe Sandip, if you could address what you're currently funded for and how you expect to fund the depth of the pipeline. Thanks.
Thanks, Greg. Yeah, yeah. So Kumar, on the orexin-2 agonist, and then Sandip, you can talk about financing.
Sure. Hey, Greg. So yeah, look, today was the first opportunity where we disclosed the data on our orexin receptor agonist. Obviously, we are very excited about the potency, the selectivity, potential for once a day dosing and what it means from a clinical perspective. Based on the preclinical data, we do believe that we have one of the best-in-class orexin receptor agonist. In terms of the structure and the scaffolding, you know, one of the reasons Teijin went the way they did is actually to avoid some of the AEs that were the result of the structural issues, for example, with TAK-994, that resulted in reactive metabolites and caused some hepatic dysfunction. We had a couple of other compounds that had impact on cardiac functions like QT prolongation.
So the novel structure gives us the ability to go to a really high potency, good selectivity, good PK profile, and avoid some of the AEs that were seen with the earlier development programs. The preclinical data, we are still conducting our GLP studies to enable IND submission, but thus far, what we have seen, we actually feel very good about, the profile, the emerging profile of our orexin receptor agonist.
Yeah, and I think just regarding the financial piece, I mean, as you know, we're highly profitable company, generating significant amount of cash flow. You know, even last year, we generated over $200 million of free cash flow. Really strong margins, you know, 30+% margins overall from the business. So everything that you saw today, the good news is it's all essentially we would see that as being funded through the cash flows that we have from WAKIX. So that would be something that, you know. And then I think one of the things we didn't really necessarily cover, but we're also not stopping here, right? We're continuing to be out there, looking for programs that can help fit the profile that we have in terms of the three franchises.
And again, with over $430 million on the balance sheet, really well-positioned to continue to execute on business development as well. Andrew Serafin, who's here in the audience, you know, leads the team, and, you know, they're continuing to be out there. So not only are all the programs that we talked about here well-funded.
... while still maintaining overall the profitability of our company.
Yeah, so that's important. I think, and my team often has to remind me that, even with all this growth in our pipeline over the past year, you know, we're, we're just getting started. Yeah, and a shout-out to, yeah, Andrew Serafin, our Chief Strategy Officer, you know, and our BD team that continues to be, you know, really active, you know, with regards to, pursuing the same, you know, types of things that, that we share with you today. You know, really smart, strategic, you know, business development deals. You know, the way that, you know, the deals have been financed and, you know, really smart with low up fronts and then, you know, de-risked with, you know, milestones on the back end.
We will continue to look for those opportunities to build out our pipeline even further.
Hi, Jason Gerberry from Bank of America. My first question, just wanted to follow up on Dr. Buchanan's presentation and some of the parallels mechanistically that were drawn between Fragile X and ASD. And do you see read-across at all from some of the studies that have been done with drugs like Epidiolex for ASD, which kind of produced mixed to negative results as it pertains to reading across to Fragile X? So that's the first question. And then the second question is just, this came up a lot during GW when they were kind of advancing Epidiolex. What would be the cost of, like, a workaround synthetic or topical cannabidiol at the concentrations you're studying for Fragile X? Just as, you know, investors think about that as a workaround or a therapeutic substitution alternative. Thanks.
Any thoughts?
Yeah. I mean, look, from when it comes to ASD, we actually have generated data in ASD, and the data actually looks pretty good. I mean, right now, we are focusing on Fragile X syndrome as our initial program, 22q deletion as the follow-on indication, and after that, there are several opportunities on which we have already have proof of concept data available, and those are some of the things that we will look into. But the data that we have on ASD actually looks pretty good.
Carrie, any additional thoughts clinically on a read-through?
Yeah, absolutely. Well, actually-
Mic, mic, mic.
I got you.
That's what I was saying. Actually, there is a lot of implication in glutamate in autism spectrum disorders, and so I think the mechanism of action would absolutely be indicated in autism. Fragile X syndrome is a perfect example because it is the most common single gene cause of autism, and then autism is highly prevalent in 22q11.2 deletion syndrome as well. I was involved in that trial and the phase II, and what I saw was very impressive. So I'm excited about that. Yeah, so I think from a mechanism of action standpoint, it makes sense, and that's. Obviously, ASD is a huge market. Yeah.
Right.
You want to answer about the dose?
No, I think the...
I think the last question in terms of pricing and what would be some comps. Yeah, you want to comment in terms of the-
Pricing comps?
Yeah. I mean, pricing comps, we're looking at EPIDIOLEX, which is probably something out in the market, although it's, you know, probably used off-label, but it's probably a good parallel when you're thinking about pricing for ZYN002, you know, coming into the Fragile X market and 22q11.2, just for modeling purposes.
Right. And I don't know if this was your question, but as, like, patients going around and getting it from, like, their local-
Yeah
... CBD dispensary or whatever, it would be impossible. The dose is so. It's significantly higher in the Zygel. I mean, excuse me, the ZYN002 is now what it's called. It would just not be possible or feasible to get it, kind of on their own. Yeah.
Yeah. Thank you, Carrie. I mean, that's, I wanted to follow up with that one. The dosing that we're using is like 250, 500, and 750 mg weight-based. To get to that dose level, I mean, it has to be a lot of CBD from the CBD dispensaries that are out there. Yeah. And of course, the purity, all of those things. As I mentioned, this is the first and the only pharmaceutically produced synthetic cannabidiol preparation.
Yeah. And I think it's a combination of the, you know, the permeation-enhanced gel, the proprietary, you know, sort of formulation, and getting, you know, and dosing from the over-the-counter, you know, CBD would be... Also, the GI issues and tolerability.
Right.
So it's, yeah, very, very tough workaround.
Yeah, and I was. Exactly. I think, you know, dosing from, like, a local dispensary is, like, thirty milligrams for a month or something. I mean, dramatically lower, a few milligrams a day versus up to seven hundred and fifty in this, in this trial. The other thing is because it's, you know, a-
Mm-hmm
... a laboratory or synthetic, things like heavy metals. You know, that's actually that is a big deal in development of our brain, right? You don't want to be exposed to a heavy metal that could be potentially contaminating a product. The other thing is, again, the first pass metabolism, but also the risk of having THC, and there's none of that. And we know, you know, THC-
Right
To a developing brain is also not good.
Okay.
And so, being able to avoid that with this product is really important.
Brennan, I think,
Thank you
... time for one last question.
Thanks, guys. Corinne Jenkins from Goldman Sachs. Maybe you could spend a second kind of expanding on the potential for differentiation with EPX-100, and in particular, could you talk about how that differentiation could kind of foster clinical benefit and be borne out in the clinical trials that are currently ongoing? Thank you.
Sure. Thanks, Corinne, for your question. Kumar?
Yeah. So look, with EPX-100 clemizole hydrochloride, it's the efficacy and safety. From an efficacy perspective, it's an established serotonergic mechanism of action... and we saw the efficacy in the zebrafish model as well. What we anticipate from the clinical trials is either comparable or better efficacy compared to the serotonergic mechanism of action drugs that are out there. From a safety perspective, we will have a much better safety profile based on the fact that this was approved many, many years ago, was in the market for a couple of days. No safety signal was observed. We are developing this as a new chemical entity. We have done a battery of non-clinical tests based on which there was no need for any additional laboratory or cardiac monitoring. And you also saw the preliminary tolerability profile as well.
There was no suppression of appetite, by the way, which is extremely important in this case because many of these kids are underweight and cachectic and have feeding issues. So compared to everything that is out there, the safety profile will be a lot better and much more patient-friendly with EPX-100. Thank you, Corinne, for that question.
Thank you. Okay, a final thank you. On behalf of the team at Harmony Biosciences, I want to thank all of you in the room, those that are still following along on the webcast and hanging in there, you know, for joining us today for Harmony's inaugural Investor Day event. I think hopefully you can you know, you share our excitement and feel the passion, what we, you know, what we shared with you here today. You know, I think as a neurologist by training who practiced for 12 years and now in the industry for 26 years, you know, I'm really excited about what our pipeline can deliver in terms of the potential to deliver innovative treatments to hundreds of thousands of patients living with rare neurological diseases.
What I want you to leave here today with is an appreciation of our commitment to patients, you know, the value of our pipeline, and as we advance our pipeline and deliver, you know, on those new treatment options, the significant value it could offer to shareholders. Thank you very much. Have a great rest of your day, everyone.