Harmony Biosciences Holdings, Inc. (HRMY) Earnings Call Transcript & Summary

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 going to 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, Jeff.

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 want to thank you very much for your time this morning and your interest in Harmony Biosciences. We are here today because 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 we'll 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. 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; two, 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. leading patients with rare diseases where they are and the communities that they -- 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 Newrology. 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 Newrology. [Presentation]

So you just heard the themes of Newrology, growth, innovation, delivering meaningful treatments to patients living with rare diseases and driving strong value creation for our shareholders. And that all starts with a strong pipeline, a catalyst-rich pipeline. So 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. 3 CNS franchises in orphan rare diseases each with potential peak sales opportunities of $1 billion to $2 billion, 8 assets across 13 development programs 4 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 2025, we will have up to 7 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. So let me share some highlights with you and some exciting new information, new data that we'll be sharing with you today from each of the 3 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 2028, out ahead of the WAKIX LOE out at 2030, 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 ZYN-002, 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 can 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 the Phase III pivotal trial Lennox-Gastaut syndrome that we're on track to initiate before the end of the year. And this is what the team has been working on and is focused and driven to deliver on over the next 5 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 III 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 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 III 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 of 2017, I went down to the NIH with the patient community -- they saw a potential utility after WAKIX was approved in Europe 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. And then from our other 2 franchises, target PDUFA dates for Dravet syndrome, and Lennox-Gastaut Syndrome, the Phase III pivotal trial that we're on track to initiate later this quarter. In addition, the follow-on opportunity in our neurobehavioral franchise with ZYN-002 in 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. So this adds up to one or more new product or indication launches each year over the next 5 years, a deep catalyst-rich near-term and long-term pipeline that we are very excited to advance and share with you this morning. So 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 2030. 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 growth going forward. And now with a robust catalyst rich late-stage pipeline with the potential to deliver multibillion dollar revenue going forward. And I also want to 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 5 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 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. Jeff?

Good morning, everyone, and thank you for all those who came out as well as those participating on the webcast. And 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 up here in the next couple of minutes. But the key takeaway is that the sleep wake franchise at Harmony Biosciences is far more and so much more than just WAKIX and narcolepsy. WAKIX is our potential $1 billion-plus foundational opportunity in narcolepsy. But we have an exciting opportunity with WAKIX in idiopathic hypersomnia. We have 2 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 Jeff shared, WAKIX has been one of the most successful rare orphan launches in the industry. Generated durable double-digit revenue growth for the first 5 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 million to $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. And at the end of the second quarter, we reported approximately 6,550 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 favorable 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 5 respective years of their launch and the first 5 years of our respective launch, we have more average patients on WAKIX every single year in the first 5 years than oxybate did. Oxybate good drug. It's helped thousands of patients and achieved over $1.5 billion in net sales that is a peak. So it gives us a lot of confidence in our ability to achieve that $1 billion 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 has been growing in 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 health care professionals. There's about 9,000 health care 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 rate all the scheduled medicines and nonscheduled medicines. The 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 2nd, their 5th, their 10th, their 25th patient for WAKIX. And they were seeing durable growth in the depth of prescribing in this audience. Now there's another 5,000 health care professionals who've chosen not to prescribe oxybate and not enroll in the oxybate REMS program. And these are physicians and health care 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. As you've got introduction of once-nightly low sodium, generic, full sodium. These 5,000 health care 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 health care 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. And we did research back in 2018 prior to WAKIX approval to get an understanding of what the key unmet needs were in this marketplace. And even with the availability of numerous treatment options, there are a number of key unmet needs in the marketplace. So if you look at the left-hand side of the slide, the top unmet needs that were cited from both health care 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 product 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 proof 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 2018. 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. And many of you in the audience are probably looking at the slide and saying, Jeff, this looks like every other model I've seen for specialty pharmacy. And you know what on the surface that's probably true. But 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. So when 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 because we want to make sure we can communicate to them when their prescription is approved. And we also get their consent to conduct reimbursement on their behalf. Once that prescription is approved from the hub, it's sent securely and safely to 1 of our 3 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 is going to be until we ran into a global pandemic in March of 2020. We launched this drug in November of '19 within 3 to 4 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 in 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 into 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 '17 by our Head of Commercial Operations, almost immediately after the founding of Harmony. And it's because of his experience and expertise and data management aggregation and deployment, we've turned what's kind of a traditional cloud-based data warehouse into a proprietary business-intelligence engine. So as I said, we've got data that's coming in from our hub. Patient information, health care 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 e-mail 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 in prescriptions that are written today, the sales calls that are written today will be in my dashboard tomorrow morning at 5:00 a.m. And 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 in 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 2 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. And we've been extremely successful in capturing more than 50% of the patients who lapse in therapy through this closed-loop catch. And it may not sound like a lot, but let's fast forward about a month or 2 when we get into the election. How many people in here getting robo calls 800 numbers, patients don't pick phone calls up. I may not actually have the 800 number of my specialty pharmacy on 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 [ Rare Med or Hub ]. And so that way, when Susan hasn't received your call from the SP and gets a call from Rare Med. Susan, we noticed you've lapse in therapy. I know I'm getting a lot of robo calls on not answering my phone. Well, good news, Susan, I won't transfer you right now over to our speciality 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 weight-promoting agent and stimulants are written. And we can then flag physicians in our sales force database and have them call about 28 days later after that generic is written to call on a health care 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. So if you've been to the wakix.com website, we have a link for our prescription referral form. And that forum form 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 e-mail to a representative alerting them that a physician in their geography has downloaded that referral form, deploying them to that office within 24 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. And lastly, some of the things that we're using with the opt-in. So 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 have met in their 60s 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 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 6 months after DC, a year after DC, 2 years. And it probably doesn't surprise anybody. We've had a high level of interest raising their hand to say, you know what, I'm going to actually be ready to go back and talk to my doctor. And even more important than that, we've been able to connect a lot of these individuals with their doctor and getting them started back on WAKIX therapy. Now this model is really important as you think and fast forward to our next-generation pitolisant life cycle management franchise. Because we're going to have the ability to access this entire database to recontact every single patient who's opted in on WAKIX to see if they actually 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 1. 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 going to be able to do this with every future WAKIX indication, our next-generation pitolisant assets or neurobehavioral or 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. So we obviously have a potential $1 billion blockbuster product in the making. We have a very unique and scalable commercial model. We have all the recipes for success for life cycle management with pitolisant. We brought WAKIX to market to meet an unmet need that we saw back in 2018 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 [indiscernible] 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 as proof for both EDS and cataplexy and a pretty well-tolerated product. And so this is a foundation from which we build and we were thinking about our pitolisant life cycle management programs. WAKIX is a great product. But even with the introduction of WAKIX, there's 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 life cycle management for everybody in this room, you're like, Jeff, everybody does it. But again, traditionally, what happens in life cycle management is everybody focuses on function. I'm going to take a TID, make a BID, take a BID make it once a day. I'm going to look at the delivery method. I'll take 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 going to take it out to make it better but very few companies look in the marketplace a patient unmet need and build life cycle management around unmet need. The WAKIX pitolisant life cycle management program is predicated on patient-centric drug development and looking at unmet needs. So the first product that we looked at is pitolisant gastro resistant or GR. Because 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. So 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, 9 out of 10 of them. And this is just the 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 1 in 5 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 coding, not because WAKIX has a high incidence of nausea, because 90% of these patients are predisposed to having GI disturbances. And we're also going to 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're 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 a 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 Chicago Rush Memorial back at a Sleep meeting. And nearly 6 out of 10 patients report untreated fatigue, which is different than excessive daytime sleepiness. So introduce pitolisant HD, high dose. Looking to push the dose to drive greater efficacy in EDS and cataplexy, we're going to be looking at a very unique indication for fatigue and narcolepsy. In addition to keeping the gastro-resistant coding starting in a therapeutic level, non-scheduled treatment option indicated for both EDS and cataplexy in a well-tolerated treatment option. Target PDUFA, as Jeff 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 to have at least 25 patients under their care, and they prescribe WAKIX to at least 5 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 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 to 24 months before WAKIX, which allows full time for these physicians who express interest to want a transition to WAKIX patients over to HD prior to WAKIX LOE. So to try to understand whether the physicians were going to 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 going to 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 was 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 going to 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 the 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-step and if a physician doesn't have the electronic look back in the last 12 months, guess who has all the data. We have every single prescriptions written since August of 2019. That physician asked us, we can provide that data to be able to get to the insurance to pre-step that patient. So 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. So to summarize, I want you to see the pitolisant franchise as 3 distinct meaningfully products. First is WAKIX, a potential $1 billion plus opportunity in adult narcolepsy alone. First and only non-scheduled treatment option. Then you have 2 meaningfully differentiated life cycle management pitolisant based products. The first pitolisant GR are gastro-resistant target PDUFA in 2026. Provisional patent filed until 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 of thousand patients to the pitolisant base. We see this as a $300 million to $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 2 meaningfully differentiated pitolisant life cycle management assets with Target PDUFAs in 2026 and 2028. And 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 a 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 to stage to share data on these exciting programs. Kumar?

Good morning. Good morning, everyone. All right. Look, it is with great pleasure and indeed great pride I'll be walking you through the Harmony Biosciences R&D portfolio. Jeff 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. 4 Phase III studies in 4 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 over the next 5 years. And this is important and help hundreds of thousands of patients living with rare neurological disorders for who, 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. So 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 Jeff has mentioned earlier, 7 to 8 out of 10 patients with narcolepsy despite the available treatments have residual excessive data and sleepiness. And here, we have an opportunity with pitolisant because pitolisant has clearly shown our 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, 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 dose 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-milligram cohort and went all the way up to 180-milligram and 180-milligram equates to approximately 5x 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. So through this study, we noticed that the safety and tolerability profile of pitolisant up to 180 milligrams, approximately 5x the highest label dose of WAKIX is very similar to the established safety profile of WAKIX. So 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 and excessive data and sleepiness and cataplexy, target indications like fatigue as Jeff just mentioned, 60% of patients with narcolepsy have fatigue. And for that, there are no approved treatments. We talked about optimized PK profile, gastro-resistant coating inherently is designed to address some of the common GI issues seen in patients with narcolepsy. Differentiated indications will be going after a differentiated label for taking narcolepsy. Sleep inertia in idiopathic hypersomnia. Fatigue and excessive data and 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 data and sleepiness. And 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. And 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 will 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 was scheduled control substance Class III 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, 8 weeks of open-label period where all patients get pitolisant. This is followed by 4 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 one point more than what AASM considers as clinically meaningful. By day 22, the main 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 5x 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 who are randomized either to placebo or 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 the 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 1 or 2 weeks, for 4 complete weeks, we anticipated worsening by about 6 to 8 points, but what we saw was only a modest decline of about 4 points. 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 are assigned to pitolisant, there were a 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 was part of the schedule of assessment. And the relatively benign side effect profile of pitolisant, 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 assume they were assigned to placebo and they responded accordingly. But primarily, it's the persistence of efficacy in the placebo arm and the decline of only about 4 points in the placebo arm resulted in lack of statistical significance. So what happened in the long-term extension study? 9 out of 10 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 9 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 1 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, 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 a benefit from pitolisant. Another set of data. These come to us from Bioprojet Compassionate Use with just over 300 patients accessed pitolisant for narcolepsy and for idiopathic hypersomnia amongst these 300 patients, just over 100 patients to pitolisant for idiopathic hypersomnia. Obviously, it's the Compassionate Use study. The data are not collected in any systematic fashion. That's why it's real-world evidence. What we saw here in a subset of 61 patients on who we have good data. We again saw about approximately 4 points drop in the ESS score, which is 2x what is considered as clinically meaningful. So what do this data say? In a clinical trial setting, highly structured, or clinical practice, a semi structured setting, a 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 Externally 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 the 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, nonscheduled track, 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. Shifting gears. Onto our new asset, BP1.15205, a potentially best-in-class orexin-2 receptor agonist. B stands for Bioprojet because we in-licensed this asset from Bioprojet. And I do want to acknowledge Olivier Finance, if you could raise your hand or stand up, is the Head of R&D from Bioprojet. Thank you, Olivier, for joining us today. Great collaboration the past 7 years, and the collaboration continues. Speaking of innovation, with WAKIX, we often say we work with a 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 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 99 days and went on to describe the impact of orexin on sleep-wake cycle. This has a unique structure and chemical scaffolding. Based on the lessons -- 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. We often mention that it has novel chemical scaffolding, it has a differentiated structure compared to the usual pyrrolidine sulfonamide bicyclic moiet, 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 nanomolar range. This potency was consistent across species. Similar potency in mouse, similar potency in nonhuman primates. And greater than 600 fold selectivity over human orexin-1 receptor. And more importantly, more than 1,000 for selectivity or 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. And also, we will be pursuing an accelerated development leveraging all the lessons in this field with a potential approval in early 2030s. And 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, is 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 catalyst. We are on track for sNDA 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 the board-certified sleep specialist, for me, this is fascinating, and 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. 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 -- 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 100 clinical trials as a site principal investigator, including INTUNE study as well. Some of his patients, I believe, about 4 or 5 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. Jeff and Jeff 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 within 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 1989. I have an independent sleep clinic. I have 3 nurse practitioners working with me. We see about 1,200 patients per month. We see a lot of narcoleptic patients. I have an 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 1995. 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 are several of these oxybates on the market. We also use medications to help people stay awake. And often, these people are on relatively high doses of stimulant medications like amphetamine salts, methylphenidate, which is like Ritalin so the -- when WAKIX came along, this is the first nonscheduled medication that we could use to help people stay awake. Virtually everything else is scheduled. And that's a big deal because a lot of physicians, as Jeff pointed out, are very reluctant to prescribe medications that are scheduled so the fact that WAKIX is nonscheduled is a really big deal. And as Jeff eloquently pointed out in his presentation, there's probably 170,000 to 200,000 people in 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 want to treat sleep apnea. So this is very underdiagnosed. And this goes way back into the early education. 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, oftentimes teachers attribute it to just laziness or lack of sleep. So there really needs to be better education about identifying these people that have superior excessive sleepiness. So given that context, as I mentioned, I think WAKIX was a welcome addition to the market when it was launched. And is the fact that it's up to around 6,500 patients now taking WAKIX is really quite remarkable. And to give you context about 16,000 people in the country are taking oxybate products. But the data percentage of -- and I would endorse this and 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. 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. So the GR formulation will be a welcome addition. I think that's going to be very helpful. And that will also allow us to start at higher doses. 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 8 weeks. You have to encourage people to continue to take it hoping that they'll see the maximum benefit after 8 weeks. The fact that we can start with a higher dose will allow people to see benefit earlier in the therapy, which is important. So people don't give up on the treatment. So I think this will be a welcome addition. And the high dose is quite exciting. The maximum dose currently of WAKIX is around 36 milligrams 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 and the future is very exciting as a physician treating these people because we're seeing a lot of medications that are coming forth that have heretofore have been unavailable especially these orexin agonist. So I think the future is very bright for the treatment of both people with narcolepsy and idiopathic hypersomnia.

And 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 patient's experience 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 do -- we see these people in the clinic. And 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% to 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. And the pathophysiology of type 1 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. So these people with type 1 narcolepsy have this orexin deficiency. People with type 2 narcolepsy and idiopathic hypersomnia have normal orexin levels in the brain. So it's not quite clear what causes the success of sleepiness. And furthermore, idiopathic hypersomnia can be divided into those that have normal sleep time and those people that sleep for 11 or more hours around a 24-hour day, so these are the long sleepers and the normal sleepers. And there may be a different pathophysiology between the long sleepers and the people that have normal sleep time. So anyway, that gives you a context of idiopathic hypersomnia. 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. And based on the current diagnostic criteria set forth by the American Academy of Sleep Medicine, around 2% to 3% of the U.S. population qualifies as having the diagnose idiopathic hypersomnia based on overnight sleep testing and day testing called multiple sleep latency testing. So there's a lot of sleepy people out there that are undiagnosed and untreated. And we see this a lot in the sleep clinic. Obviously, we have to rule out other things, sleep apnea, insufficient sleep syndrome. So there's a lot of other things that can cause daytime sleepiness. But when we've ruled out these other conditions, and people meet the diagnostic criteria of idiopathic hypersomnia, then we treat them 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 like to prescribe or reluctant to prescribe this oxybate therapy. There is 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've participated in the IH trial for pitolisant for idiopathic hypersomnia. Fortunately, we were one of the highest enrollers. So I think we were the highest enroller 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 and the people that chose to remain in the long-term extension study as a 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 a 9-point reduction in the Epworth Sleepiness Scale is really quite amazing. With stimulants or with wake-promoting agents, we may see a 4, 5-point reduction in the Epworth Sleepiness Scale. So a 9-point reduction is truly meaningful and very impactful. So yes, I think yes, that would be very important to have this indication and this will allow us to open up this treatment to a lot of other patients.

I'm wondering in the interest of time, perhaps we can open it up, Brennan?

Yes.

Graig Suvannavejh, Mizuho Securities. Thanks much for doing the Investor Day. Question for Dr. Corser please. 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 5 years in particular with the sensitivity that WAKIX could lose its lost market exclusivity in 2030. So we're just trying to get a picture of what that looks like.

Well, as you know, so the big thing now is orexin agonist. So is, to my knowledge, there's about 8 companies developing orexin agonist. I'm working with almost all of them. And this is very exciting because orexin really lights up the brain, especially for people with type 1 narcolepsy. So what we've seen is that people with type 1 narcolepsy need relatively low doses of the orexin agonist because this is analogous to giving insulin to somebody with type 1 diabetes. It really treats the root of the problem. And these people respond dramatically, the type 1 narcoleptics respond dramatically to orexin agonist. Now there's some conflicting data regarding orexin agonist for treatment of IH and for type 2 narcolepsy because that's a different pathophysiology. But at least one company has presented data that shows that using higher doses of orexin agonists is very beneficial for these people with type 2 narcolepsy and idiopathic hypersomnia. This is based on 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 2 narcoleptics as well as IH population. But I think that this is going to 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 most people with narcolepsy or IH may require more than one therapy. This is what we typically see. Oftentimes, these people end up on 2 or 3 different medications. And I think this is somewhat analogous to hypertension. So most people with hypertension need 2 or 3 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 1 wake-promoting medication to optimize their daytime functioning. So I think the market is going to be very interesting over the next 5 years. I think the advent of orexin agonists are going to be very helpful, but that's certainly not going to be a panacea. There will be a need for other medications. And the fact that the WAKIX is nonscheduled, is, again, a really big deal. I don't know what the orexin agonist if they're going to be scheduled or not that's for the DEA to determine. So -- 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.

This is Frank Brisebois with Oppenheimer. Just a quick one here. Just wondering, in terms of, 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 if you -- 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?

So for the diagnosis of these central disorders of hypersomnia, people with narcolepsy type 1 by definition, have lower orexin, so when you do a lumbar puncture, you see a low CSF orexin level below 110 is 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's -- 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 4 or 5 nap opportunities during the day and the criteria for type 1 narcolepsy and for narcolepsy in general is sleep latency of less than 8 minutes and then you see 2 or more REM onsets that is 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 2 or more of these is consistent with the diagnosis 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 -- the other part of the question?

Do you believe orexin's can help with the [indiscernible] nocturnal sleep on their own? Or is this with polypharmacy?

So orexin is a high -- is produced in the brain by something like around 70,000 to 80,000 neurons in the brain located in the lateral hypothalamus produces this chemical orexin so -- that's relatively handful of neurons given the fact that there's 60 billion neurons in the average human brain. So certain way, orexin is high during the day and that it subsides during night. So there's very little orexin throughout the night. So Takeda has some data regarding the effective orexin agonist on nocturnal sleep. And I just talked with Dr. [ Emmanuel ]. He's one of the major figure heads in the treatment and discovery of 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 going to address the disrupted nocturnal sleep. But we'll see. We'll have to do the more research to validate Takeda's original results. But yes, I suspect that the orexin agonist will be effective wake-promoting medications but may not really address the fragmented sleep that we've seen 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 15 minutes from now. Will we reconvene at 10:20. 10:20, we start. Thank you all for your attention. See you back soon. [Break]

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. Thank you. Thanks for joining us again. So now we transition in this session into 2 other franchises, neurobehavioral and epilepsy franchise. We'll start with neurobehavioral franchise. The acquisition of Zynerba got us a very innovative product in ZYN-002. 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 a 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 22q 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 -- just a brief intro. Dr. Carrie Buchanan is a developmental and behavioral pediatrician. She leads the Fragile X syndrome program and also leads the autism program at Greenwood Medical Center in South Carolina. She is 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 -- has 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 overview of the disease state, the mutation, the methylation, endocannabinoid system and how it all comes together. Dr. Buchanan?

Perfect. Well, thank you so much for having me. I'm going to just get situated here. Can I push this up. No one cares. Okay. I just need to set mic. So as Kumar said, I'm Dr. Carrie Buchanan. I'm a developmental behavioral pediatrician at the Greenwood Genetics Center in Greenville, South Carolina, and I'm really excited to be here today talk about Fragile X syndrome specifically, but I think more importantly for us today, the role of the Endo or endogenous cannabinoid 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. There are no -- or highlight. 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 to -- in this trial of the topical CBD. And I've seen it work. And so I'm really excited and hopeful for the success of this -- of the current trial. So let me get started with what is Fragile X syndrome. So 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. And I'm going to use some words that you're going to remember genetics from tenth grade. Transcription is DNA to RNA. So we transcribe DNA into RNA and 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? So 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 -- it's an interesting mechanism on how it gets turned off, which another word I want you to remember today is methylation, and we're going to 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 3 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 tried nucleotide 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. So our body, ourselves 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? So again, this is caused by repeat expansion of more than 200 repeats and its silences or shuts off the gene. Well, FMRP is a very important protein. It plays a really important role in brain development. So 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 1,000 different gene products. It's a 1,000 different proteins, okay? So it's not surprising then the absence leads to the dysregulation of many proteins and their 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 a little graph at -- or the picture at the bottom, there's a dendritic spine and the one on the far right is really thickened and thick, okay? That's in 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 neurotransmitters in our brain. What is incredibly important in development and just life is the balanced homeostasis of excitatory inhibitory neurotransmitters, okay? FMRP inhibits the release of glutamate. If you don't have FMRP, you were 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, the Fragile X syndrome is a neurodevelopmental disorder. It is a development of brain -- I'm sorry, neurodevelopmental disorder of the brain, okay? The brain is developing abnormally. Because of this, we have -- 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 simulation, right? They are hiding behind their parents. They're 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 -- well 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 neuro pathway in our brain. Okay. It facilitates synaptic homeostasis, balance of excitatory inhibitory neurotransmitters, one of which is glutamate. And then also very important neuroplasticity. So it helps us grow. It helps us learn. It helps the neurons change and grow, right? There are 2 parts to the ECS. There are endocannabinoid receptor, 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 a translation of 1,000 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'm -- 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 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, increased of 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 comes 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 -- 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 detail of the results of that trial and how it informed the design 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, I'm sorry, yes, our gene is not shut off. It's not methylated, we have normal FMRP. I've told you before that in Fragile X syndrome, if you have greater than 200 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 200 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 a milder presentation in general, milder cognitive effects, 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 subsets of greater than 90% methylation that really performed the best. This here are the key learnings from the CONNECT-FX trial. I have enough time. I'm going to quickly give you background on this trial. So we enrolled across the country 212 individuals, they were randomized 1:1 to the topical CBD product and placebo with 2 different doses of weight based 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 -- 30 that had less than 90% methylation. If you remove those 30, it's still a very large portion of the individuals in the trial, we met statistical significance. So it was in the complete methylation and also -- there we go. There was a 40% median improvement in socially avoidant behavior. So the primary endpoint was the subscale of a behavioral checklist that specifically looked at social avoidance. And 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 -- no back -- 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 caregivers response in social interaction and irritable and disruptive behaviors that were statistically significant. This is the complete methylation of the 100%, which was about 65%. But if you actually -- 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 in the Clinical Global Impression improvement. And then if you look at a meaningful change, just a greater than -- more than 3-point improvement on the social avoidance subscale, you can see that those in the -- receiving the active drug performed or scored better, statistically so. So let me say this. So using this information, what Harmony has done very importantly in this RECONNECT trials, 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 the greater than 90% methylation, looking at the primary improvement is their improvement on the social avoidance scale. And since we've, like I said, already demonstrated that subset in the previous trial, 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 -- 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 work, 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, 2 things. One, look at the sustained improvement. So they improve and then they retain that improvement for up to 2 years. I have a patient that's been on this product for 7 years. It is really been -- really impactful for his life. The mom is 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 a month 4 to 5. So because of that, in addition to changing the primary endpoint to complete methylation, the team extended the trial to 18 weeks. Because we know we see that -- we can see that continued improvement up to month 4 to 5. So based on these changes, the RECONNECT trial has really been optimized. And I feel really confident in its success based on those 2 major changes. But 2 other things have been changed that are I'm also really about. So we've increased dosing, which is really good because we currently had 2 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 in 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. In addition -- I have 21 seconds, perfect. In addition, we have -- 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, 3 or 4 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. Okay. Thanks.

Thank you, Carrie. 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. So we heard from one of the well known expert in Fragile X syndrome, and now let's hear from a caregiver perspective. [Presentation]

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 are talking today. ZYN-002 is the result of a lot of hard work and dedication. In fact, it started all the way back in 2004, and I'm really happy to say that Terri Sebree, who was part of this program right from day 1 is here with us today, Terry if you can wave or stand. Yes. Thank you. Thank you for helping us get here to this stage. So the company was cofounded by pharmacologist and a transdermal specialist, all the way in 2004, and multiple studies were done. And the first study in Fragile X syndrome started in 2016 as an open-label -- 2015 as an open-label study. And 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. ZYN-002. 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 3 all the way to 70, 75 years old exposed to ZYN-002 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 past. And application site pain pretty much captures everything like erythema, edema, irritation, itching and other things. And some of these patients have been on this product for over 7 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 continue to use ZYN-002. It just speaks to the durability and the maintenance of effect, and it also speaks to the benign side effect profile of ZYN-002. 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 -- about 80 patients with full methylation in ZYN-002 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 patients 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 studies forward as such. Key secondary endpoints, some of the important symptoms like irritability. And one of the other key secondary end points is actually combining complete methylation and partial methylation and to look at the effect of ZYN-002. 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 25,000 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 a Phase III registrational study in 22q 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 3 to 4 minutes. Perhaps we can just ask a couple of questions that the audience wanted to ask. All right. So I mean, first of all, thank you for explaining it so well. And as neuropsychiatrist, when you're talking I was thinking, this is as precise as it could get in a neuropsychiatric disorder in terms of genetic mutation, abnormality in the FMR protein, behavioral symptoms, dysfunction of the endocannabinoid system and the intervention here is ZYN-002, which interacts with CB1 receptors. I mean this is like precision medicine at its best for a neuropsychiatric disorder. But what I wanted to ask you now you is you participated in CONNECT study and RECONNECT study. You also mentioned about the patient for 7 years. I wonder if you can share some experiences of your patients.

Absolutely. So I'll share experiences from the open label because, 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 end of one here. I have a patient who's 14. He has never been told or trained in his life, 1 month on to the open label, and he was using a toilet. So it's -- that was very remarkable. I have another -- actually, my patient that's been on it for 7 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. And 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 became the teacher's helper. He was volunteering to do things. He was just 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 a broad range in both males and females, we've seen improvement. 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.

Thank you. Glad to hear these experiences. So -- and also...

Can I ask one question from the audience?

Please go ahead.

All right. 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?

So if you look at the data, although it wasn't statistically significant, individuals with Fragile X just did better. So I think the threshold of the 90% is really to get that level of that statistical significance because we know they're responding better. But the others responded better than the placebo also. It just didn't -- it didn't come in the data. So I do -- I think if you think of the ECS, it's still dysregulated in those that have less -- that have partial methylation. So it absolutely does still make sense. The mechanism of action would still work. It just works better in those who have the full methylation.

Right. When you see 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 trade. All right. So the other question I wanted to ask you is the intervention itself. Look, gel is not a common intervention. Most often, it's the oral of both. So I just wanted to ask 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, 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 dry skin. So -- absolutely. So regarding the application, a couple of things. Remember, this is an intellectually disabled population. I just think of my own 9-year-old who is neurotypical. He does not swallow a pill. It's really difficult to get them to take medication. 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 force our child -- 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. 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 has 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 -- yes, it's actually been really great. And I jokingly from the beginning, I asked Synera, can we keep like all medications through this application because it's really hard to -- for these patients to take oral medications.

Thank you. We finished right on time. So thank you for your time. Yes.

Thank you so much.

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 liquid 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. So 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 in 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 125 manuscripts in peer-reviewed journals, high-impact journals like nature, science, brain, neurons, and he's very passionate -- he's very passionate about translating discoveries into meaningful interventions for patients. So with that, Dr. Scott Baraban, please.

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 epilepsy community, which is these families with rare diseases. And I want to start with the video of a -- you saw her a second ago. This is Kara. She's about 8 or 9 in this video, talking about -- with her mother, Lori O'Driscoll, who along with Marianne Mescas founded the Dravet syndrome Foundation about 15 years ago. And when I first met them in 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. [Presentation]

And 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 unexplained death in epilepsy about 6 or 7 years ago. And I'd like to keep this video in her memory and to remind me why we work on this -- we work so hard on this. So I wanted to 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 1 in now 28 antiseizure medicines has always been 1/3 in patient population. This is alarming statistic, if you think about it. But it's also an opportunity as the way I kind of viewed this. And the opportunity is basically that all of these drugs on this list were discovered in rodent models of epilepsy. Now actually, they are not models of epilepsy, they are models of seizures. There's a distinction. When you have epilepsy, it's diagnosed as 3 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 induce the 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 an animal model that had epilepsy, spontaneous seizures, and so we wanted to change that when I first started in this field. And the second part that's changed over the years is that the -- our understanding of the genes that cause epilepsy has magnified almost hundredfold, obviously, within the last 10 or 15 years with genetic testing. And 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. And so without -- to jumping kind of like the pharmacology first because 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. And 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 -- sorry, clonazepam, benzodiazepine classes, potassium bromate, all of these are successfully identified in our assay -- our assays as well as the more recent drug, 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 counter indicated. These patients are pharmacoresistant. They don't respond to 3 or more antiseizure medications. Again, testing all of those. We also had 100% predictive ability in that. None of those drugs reduce 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 it 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 vertebrate 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% to 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 and a room 1/3 of this size in my laboratory. They're genetically tractable. I've actually made using CRISPR techniques, genetic versions for almost 40 different rare epilepsies, and I'm only going to talk to you about a couple of them today. But most importantly, they're good for high throughput drug screening. Because 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 were about the size of your eyelash. And so we use those within 5 or 6 days. Larvae are transparent, they're permeable to drugs, and they can produce hundreds of -- 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 using CRISPR techniques, a mutant that has the same genetic mutation that the patients have. And then we use 2 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, because even in patients, EEG is a 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 do -- 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 look for drugs that eliminated the spontaneous seizures in these models. And this is what it looks like. This is 1 well -- 1 fish in 1 well of a 96-well plate and the video slows down. This fish is actually moving faster than you would pick up by your eye when it's having a seizure. And on the right, on the top, you can see some of the AG activity as well as brain neuroimaging. This is a calcium indicator that lights up neuron to the brain when the fish is having a seizure. And so these -- zebrafish will have this event about once every minute or so spontaneously unprovoked, so they do have epilepsy. And that's our readout for looking for drugs that are basically going to stop all these events. But more importantly, they also model other aspects of patients with Dravet syndrome. They're 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 have done. This started about 10 years ago. To give you some context, it took about 5 or 6 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 because it's high throughput and then electrophysiology. And the important distinction there -- and this is just some of 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 going to stop the electrical activity. So having a 2-stage assay allowed us to have less than 1% of the drugs that came through this trial and 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 going to 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 RS are receptor agonist and fenfluramine is a reuptake blocker. And this is just a little bit of a science. Well 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 the 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 can completely eliminate this abnormal activity. So a very stringent assay. Importantly, it's not just Dravet syndrome. That is the lead indication and that's the first clinical trial that's being done. As I said, we have models for about 40 other rare genetic epilepsies in 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 SCXBP1. This is a syntaxin binding protein, similar to kind of a synaptic -- role in synaptic transmission. These SCXBP1 disorder children also have intractable epilepsies. This fish is pharmacoresistant, most -- all 5 antiseizure medicines we tested on this model, didn't do anything. But when we gave the clemizole, we completely eliminated the seizure activity. And this is -- will be a subset of the LGS patients. So LGS is not a single gene mutation phenotype, but it has a number of single-gene mutation families with it as cohort. And so we'll be able to track whether clemizole is particularly effective in SCXBP1 patients. And so in a very short time, hopefully, I gave you a sense of how this came to be. We developed again the zebrafish platform almost 20 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 predictability 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 their assays will also work clinically. And 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. And then 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, LNF, who kind of came up with the idea that this is an aquarium to bedside approach. And of course, it's the first time and it's the first time largely because zebrafish has only been used for drug discovery within the last 5 to 10 years. So this is a very new field.