All right. Are we good to go? Yep, I hear my voice. Thank you. Welcome back, everybody. I'm Marc Goodman, one of the biopharma analysts at Leerink Partners, and welcome to our next session with Harmony Biosciences. And we have Jeff, Jeff, and Sandip, as we were talking earlier. I think everybody knows the management team here. Thank you so much for joining us here. I don't know. Thanks for the invitation. Yeah, yeah, yeah. Up to you if you want to make an opening comment or not, or we want to just jump right in. We can jump right in. Yeah. We can jump. Well, obviously, WAKIX, drug for narcolepsy, is the key here. Maybe we can just start with some of the market trends, you know, what you're seeing just broadly in narcolepsy and how that's evolved and, you know, how you see that kind of playing out over the next few years. Sure. Yeah. I think, you know, I'll kick it off, and Jeff, you know, some commentary. Yeah. So, you know, narcolepsy, really interesting market, as you're aware, you know, with regards to, you know, polypharmacy market and, a lot of opportunity in terms of, you know, 80,000 patients, you know, diagnosed in the U.S., you know, another 80,000 to 90,000, you know, not yet diagnosed. So, you know, continues to grow about a couple%, you know, per year in terms of new diagnoses. You know, and with that, I think, you know, when WAKIX was introduced, it was the first sort of novel mechanism of action in the market in over 10 years and sort of brought, you know, a product sort of profile with broad clinical utility, you know, based on its non-scheduled status and, and, you know, and I think, you know, we continue to see significant growth opportunity there, you know, with the existing therapies with regards to wake-promoting agents, traditional stimulants, and obviously, you know, sort of the, the oxybate products in that vertical. And I think, you know, Jeff, and from a commercial perspective, the dynamics that you and your team are seeing. Sure. Yeah. I, I think that the biggest key that I look at is there's a large diagnosed patient opportunity, and that continues to grow every year. And I think it's great for, you know, patients living with narcolepsy to have new treatment options coming into the market, right? That's more investment. It's more education. It helps sort of, you know, increase the diagnosis rates. But as Jeff said, this is a polypharmacy market. Sadly, most patients require two, three medicines, and doctors and patients are looking at complementary or synergistic approaches. And I think WAKIX really sets itself apart as that unique non-scheduled treatment option, the only product that works for histamine. And we've seen, you know, great success in terms of the durability of, of growth, an average number of patients and prescribers, and, you know, the four plus years of our launch. So what is kind of the progression of a patient who is diagnosed with narcolepsy? Like, how, you know, when do they get to your drug? How does it work? Yeah. So, I mean, the diagnosis path usually takes, you know, six to 10 years before someone gets diagnosed, and stereotypically. six to 10 years. Yeah. I mean, symptoms start early in, you know, the adolescent, teenage years, and it usually takes them about six to 10 years process of elimination before they get diagnosed with narcolepsy. Amazing. Yeah. Then traditionally, patients will be started on a generic treatment option driven by managed care, whether it be a generic stimulant, or a wake-promoting agent. Traditionally, after a non-response or a partial response to that, that's sort of where WAKIX fits within the paradigm as sort of the first branded treatment option. Most patients, as I said, are on two or more medicines, about 80%-90% of the patients here. So the vast majority of WAKIX use is in combination, as is oxybates, Sunosi, wake-promoting agents, and stimulants. Right. So the first thing is, they've tried, like, a modafinil. Mm-hmm. That's not doing it for them. So do they stop the modafinil and then go to WAKIX, or what do they do? What's kind of. Usually, you know, usually they add on. So in terms of. Yeah. So, and it's interesting because this market hasn't changed a lot. So, when I was, you know, practicing in neurology and taking care of patients with narcolepsy, which is sort of many moons ago now after 25 years in, you know, in the industry, but the, you know, that, you know, dynamic, wake-promoting agent, you know, plus-minus a traditional stimulant, sort of, you know, PRN. Mm-hmm. But when WAKIX is used, it's usually added on because you've got, as Jeff said, majority of patients have, you know, refractory symptoms. So you're kind of adding on, another agent and also working through a different mechanism of action. A lot of the other agents, you know, wake-promoting agents, traditional stimulants, working through sort of dopamine, norepinephrine, and that neurotransmitter system. So WAKIX working through histamine, a major wake-promoting neurotransmitter in the brain, sort of adds on, you know, an additional mechanism to sort of help those patients with residual symptoms. And then, you know, the oxybate treatment choice and those agents are very different, you know, with regards to that mechanism of action as mainly a CNS depressant working kind of through GABA and consolidating nighttime sleep. So those are, you know, the treatment options. WAKIX is often added on to any combination of those agents, to help with both excessive. Before or after oxybate, usually? I think it depends on the treatment choice, any given patient and healthcare professional making that decision. Yeah. Yeah. And relative to Sunosi, is there does it matter much? I mean, do you see your product being used before Sunosi or after Sunosi, or? Yeah. I mean, I think that the benefit of WAKIX, with regards to narcolepsy, it's, you know, indicative for both EDS and cataplexy. And I think, you know, the data from the labels, you know, show WAKIX to be a strong treatment option in terms of those. Yeah. Yeah. Yeah. What about any new strategies that you've been using? Anything different this year versus last year? What seems to be working? What things have you changed? Yeah. Marc, I think one of the things that we've learned is we continue to evolve the commercial model every year since our launch. So going back to 2021, we added field reimbursement managers to help, you know, support offices with the reimbursement that takes with prior authorizations. 2022, we expanded our field sales team to be able to reach the broad narcolepsy treating healthcare professional universe. Last year, we added in remote territory managers, like inside sales reps that will do outbound calls and video calls to reach geographically challenged doctors and maybe some of the areas in the white space. So we continue to innovate, and move forward. And I think looking into 2024, you know, the goal is to make sure that we can get out and educate the broad narcolepsy treating healthcare professional universe. You know, as we've talked about in a lot of our, you know, one-on-ones and earnings calls, there are about 9,000, you know, narcolepsy-treating healthcare professionals that see about 100% of the diagnosed patients. About 4,000 of them are enrolled in the oxybate REMS program. Another 5,000 are not. And because of the broad clinical utility of WAKIX, we have the ability to call in all those healthcare professionals, which allows us to tap into that broad diagnosed patient opportunity. So our main strategy is to make sure that we're getting out and educating all of those healthcare professionals. They all have appropriate patients in there to drive future growth. How many of the 9,000 have written a prescription? So, we basically have almost highly penetrated within the oxybate REMS program. There's 4,000 in there. The vast majority of them have prescribed. And what we shared at our last earnings call, Marc, is more than 30% of the other 5,000 have already written WAKIX at least once. So still room to grow. We have more prescribers of WAKIX than oxybate in four years on the market versus, you know, traditional oxybate being on the market for 22 years, but still ample room to grow. And we're really, really excited about the future growth. Give us a sense of the sales force change. Like, where did you start, and where are you now? Sure. So we launched with 70 representatives. We added another 10% or 7 reps in 2022. And basically, where we found is there's opportunity within some of the metropolitan areas where we, you know, basically expanded territories. But 77 representatives, they call in about 9,000 healthcare professionals. We feel that we're optimized for the narcolepsy opportunity. That's the right number. Even with the potential pending PDUFA with pediatric narcolepsy, we'll be right-sized to integrate that indication as well as successful with the approval in June. Does pediatric add to the 80, or is that within the 80 of diagnosis? It's still within the 80. It's pediatric narcolepsy is about 3%-5% of the population. So about 4,000 of that 80 are, you know, children under the age of 18. So smaller opportunity, but significantly meaningful given the fact they only have one FDA-approved treatment option, which is, you know, sodium oxybate. All right. And so as far as just tinkering with marketing messages and things like that, what seems to be working and resonating? I think that what we're learning is the non-scheduled status or the only product not being a controlled substance really resonates well, not only with healthcare professionals, but also patients. You know, the fact that WAKIX is not a stimulant. I know that, you know, patients may like the stimulating effect because it feels like the drug is working. But in market research, a lot of patients tell us they don't like that feeling. So I think a lot of that is really the foundational understanding. And then I think the broad clinical utility of treating both EDS and cataplexy and the fact that it's very well tolerated; it's really becoming one of the foundational choices for healthcare professionals once they go through generic step edits. Yeah. Yeah. And I think, you know, Jeff, this sort of evolved commercial model that Jeff was speaking to. And, you know, the, when they added the commercial analytics also, when they added the additional 7 reps, they saw an opportunity, in healthcare professionals that didn't write scheduled agents and started to, you know, to write WAKIX and, and saw sort of an additional opportunity there. And the commercial analytics sort of led us in that direction. I see. So a targeted group that you knew wanted to write a script for a non-scheduled agent. They just hadn't written yours yet, so. Correct. So, you know, as you know, sort of, you know, each year in the market, you know, learning from those things and a really strong commercial analytics. Right. A very evolved commercial model and sort of pulling those levers with a product that has the broad clinical utility. Right. Right. The only non-scheduled option. Do you feel like the idiopathic hypersomnia indication that's been added to the oxybate, has that changed the market dynamic at all? Anything else that's going on in the market today that's changed the dynamic? I mean, is it just. Yeah. It's a great question. I think we're continuing to learn about the impact of, you know, the IH indication for Xywav. And obviously, we are actively involved in that space, you know, as we shared, meeting with the FDA this month to discuss our IH development program and what the next steps may be. I mean, you know, I think it's IH is another central disorder of hypersomnolence and adjacent to narcolepsy. So I think it brings more activity to, you know, the sleep-wake field. And, you know, with Xywav as the only approved option, you know, the other agents are the traditional ones, wake-promoting agents, traditional stimulants that are written. And I think that dynamic kind of plays out with more focus there, learning the, you know, sort of the spectrum between NT1, NT2, and IH, and differentiating, you know, sort of those diagnoses. And. Yeah. I think we're still learning what the impact would, will be on the market. Yeah. Yeah. I, I think there's a lot of excitement, obviously, you know, for those that participate in the IH, the INTUNE trial for WAKIX. Obviously, we've got a meeting with the FDA later this month to, to see the path forward on that. But I think, to Jeff's point, it's bringing more investment into this community. It's helping increase diagnosis rates and getting patients in the offices. And again, for the appropriate narcolepsy patients, you know, we've seen very durable growth in our four years on the market. You know, with the guidance that we provided for 2024, you know, of over $700 million, we're well on our way to being a billion-dollar-plus opportunity just in adult narcolepsy alone. Seems like most of the investment from an R&D perspective in the industry for narcolepsy is in orexin. How do you see orexin playing into your market? So, obviously, a, you know, really interesting topic and a lot of, you know, attention there. I mean, orexin's obviously, orexin agonists represent the next sort of novel target mechanism of action, you know, for narcolepsy. As the programs and, and we follow that space very closely, as those development programs have gone forward, you know, it's also generated some additional questions, you know, both from the, you know, the safety side and the efficacy side. I mean, I think that, you know, I am hoping, those programs will go forward. I think new treatment options for patients with narcolepsy is important. It'll bring, you know, more investment, more education in, in the space. Yeah. I, I think what will remain is it'll continue. I don't think any one single agent will treat, you know, all, all symptoms in all patients with narcolepsy. So it'll continue to be a polypharmacy market. And what is interesting with regards to WAKIX and some of our next, you know, generation, you know, formulations of pitolisant is orexin neurons actually connect in what's called synapse on histamine neurons. So there's potentially a synergistic kind of mechanism there between, you know, orexin and histamine, working in the hypothalamus. Okay. What do we do about that? What do we do about that? Yeah. Meaning, why don't we start a study or something like that? So, A partnership or something. First, we go to work on our next-generation formulations, you know, with regards to managing the life cycle and optimizing that opportunity. Yeah. You know, pitolisant, very, you know, novel molecule, novel mechanism of action, very successful product in the market. So that's why we're investing there, you know, with regards to those new formulations and, generating new IP and a much longer, runway in terms of further development, you know, new indications, you know, in addition to narcolepsy, etc. Right. Right. Right. So the idea is, if we're going to do anything from that respect, it would be with the new formulation. Correct. That's what you're saying. Correct. I see. It's probably a good time to talk about the new formulations. Where, where are we on that? The timelines? Because this is a key next 12 months, I think. Yeah. Yeah. So they are in the clinic. And as we've shared, we will be generating the initial PK data to give sort of more definition to those profiles in the first half of this year. Mm-hmm. and then, you know, we'll be sharing the top, you know, top-line PK data. There are two programs actively in the clinic. The first, we call Next, you know, NextGen One, is a kind of opportunistic fast-to-market strategy. And we're designing to demonstrate bioequivalence to WAKIX and then some other aspects of the formulation to drive, some clinical differentiation. We'll do some other clinical work to try to, sort of strengthen the label. And that is designed to come to market during the WAKIX life cycle, in a more opportunistic, fast-to-market program. The NextGen Two is a truly sort of evolved, enhanced formulation of pitolisant with an optimized PK profile where we're also to, generate new IP in that formulation and then have the chance to sort of, investigate higher dosage range, of pitolisant. We feel there's an opportunity to take the dosage range up, a very safe and well-tolerated, you know, product, but, potentially driving greater efficacy. And then, you know, the plan would be to lead off and build off of the narcolepsy indication, but also to look at another indication of around fatigue. So the more we've learned about patients with narcolepsy, in addition to EDS and cataplexy, fatigue is a prominent symptom. And we know that pitolisant has shown strong positive signals in improving fatigue. So it is an opportunity to expand the development program to look at not just EDS and cataplexy, but potentially fatigue indication. Does the drug also help with attention? There is some preclinical data in terms of attentional mechanisms and the, you know, the possibility of improving that and from preclinical models with a procognitive effect. Well, I just think about modafinil, and I think about attention. I think about wakefulness. I think about fatigue, right? It kind of does all that stuff, right? Yeah. Well, I was at Cephalon back in the day. Yeah. I was involved in the modafinil and that. That's what I'm saying. That product was pretty, like, it was used a lot in a lot of different ways. I think what you're getting at is pitolisant's kind of moving in that direction. It's, it's moving in that direction with a lot of, you know, potential opportunity given the, you know, the runway, the sort of new IP and longer patent runway to investigate those opportunities. NextGen One, which is the fast-to-market strategy, the bioequivalence date is coming. So both first half this year. First half this year. And then. That's the first half of next year. Okay. So we see that. We're happy with that. Then what do we do? Right. So then there's some additional clinical work that we want to do to sort of strengthen, you know, and differentiate the label. You would run some type of pivotal study with that molecule. Right. Right. And then we would sort of provide an update from there with regards to further timing. Right. Of time to market. But basically, your idea is, okay, we're going to run a pivotal. That'll take 1-2 years or whatever for that whole program to kind of. Yeah. Well, not necessarily a pivotal trial, just some, you know, other clinical work to enhance, you know, beyond the current WAKIX label. Yeah. Okay. So, so basically, you think a launch in 2026 is reasonable for that? Yeah. So we haven't sort of disclosed a timeline on that yet. Yeah. You know, within the WAKIX life cycle. Uh-huh. And the WAKIX, just remind us of what that is, the life cycle for WAKIX. So, it's out to 2030. 2030. 2030. 2026, 2027, either one of those would be within there. That's kind of what we're thinking. Correct. And the other one, the NextGen Two, that would be a little bit behind that, you're saying? That would be behind that towards the end of the year, towards the end of the WAKIX life cycle. End of decade. You know, 2030 and around there, as the sort of opportunity to transfer that base of patients and a new treatment option. That's the one you were talking about for the fatigue. Correct. That you would go in that direction. Yeah. Got it. Got it. You did a deal for Zynerba. Mm-hmm. A while ago. Yes, we did. What did you like about that kind of company? What do you get with it? Yeah. So we're excited about that opportunity. So now, what we refer to as Zygel, ZYN002 in our pipeline now. Well, first, it was very strategic, you know, with regards to our, you know, area of expertise and, you know, orphan rare CNS neurospace. And this is sort of orphan rare neuropsych, number one. The deal terms were very favorable, you know, with regards to, you know, when we brought in the deal. And then it was also late, you know, it was late-stage in phase 3. So currently in a phase 3 trial called the RECONNECT Study for Fragile X syndrome. Sizable market opportunity, about 80,000 patients diagnosed in the U.S. 80. 80. 80. Yeah. So similar size as a diagnosed narcolepsy population, you know, high unmet medical need, no approved therapies. So very consistent with our profile in terms of what, you know, what we've been doing at Harmony. And then interesting right behind that is another neurobehavioral disorder called 22q deletion syndrome. Mm-hmm. that has positive phase 2 open-label data, but Zynerba, and now we have been engaged with the FDA about potential pivotal phase 3 trial in 22q deletion that, you know, to follow, if successful, an indication for Fragile X syndrome. So first on the Fragile X. So the phase 3 study is ongoing, and the data's coming when? phase 3 study is ongoing. The top-line data, mid-2025. Mid-'25. Yeah. So, How many patients are we talking about here? We're talking about 200-225 patients targeted for that trial. Have you talked about enrollment yet? Are we almost done or? So we basically picked up, you know, the program from Zynerba and then on our last earnings call, you know, gave an update with regards to expect to complete the trial first quarter of 2025. Okay. With top-line mid, mid-2025 for top-line data. Mm-hmm. And the endpoint there? So it's part of the Aberrant Behavior Checklist and the social avoidance scale, which is a main symptom in patients with Fragile X. Mm-hmm. Secondary outcomes around other behavioral symptoms, such as irritability and anxiety, through the ABC checklist. Right. This one pivotal could be enough to get an indication? Yes. Yeah. I mean, you know, no approved therapies, major unmet medical need, and the interactions with the agency would be. The agency would be one, one's enough. One would be, Right. And 22q is where? So 22q is basically, it was a phase 2 open-label study that had positive signals. Yep. So mainly, we've just been interacting with the FDA about an appropriate endpoint and design around a pivotal phase 3 registrational trial. And so we're sort of in preparation mode for potential phase 3. Which you hope to start this year. We haven't really talked about timing of that yet. We're, you know, right now, we're focused on bringing in the phase three Fragile X. The Fragile X. Yeah. That's called the RECONNECT Trial. Right. These are different types of physicians? Are these the same? They're the same. Site, the same so it's the same sites. So this, yeah. So similar, yeah, the same sites. And they're really along the spectrum of autism spectrum disorder. Right. These conditions. The broader opportunity with, you know, this program, you know, is ASD. Yeah. That's obviously a much loftier goal. And we're now initially focused on the, you know, the orphan rare indications. Right. And what kind of IP does that product have? The IP is out to 2038, 2039. Oh, okay. So same. Yeah. So we, we've got runway. Right. 38, 29. That's pretty, yeah. That's pretty good. Business development, obviously, that you brought this asset in. Have you been looking at others? And how do you think about that? And what else is going on internally, you know, just as you know, as far as what the company looks like in two or three years from a R&D perspective? Sure. We just talked about what might be on the market. Yeah. Absolutely. Let me start something you can check. So, the short answer is yes. We've been very active in business development. We feel like, you know, we're just getting started at Harmony. We feel that we continue to be a growth story, you know, strong core commercial business, you know, WAKIX and narcolepsy. The NextGen formulations to sort of manage the life cycle, build out new IP for longer runway. And now, you know, with the Zynerba acquisition and, you know, others that we are hoping to really expand the pipeline and diversify our portfolio, you know, within the orphan rare CNS neuropsych space where we have a lot of competency. And the other thing too, you know, these, the commercial models are so Fragile X and 22q is like a center of excellence model. These are neurobehavioral centers at pediatric, you know, centers of excellence. We don't have to build out huge infrastructure. We can leverage existing infrastructure and build off of that, you know, very evolved commercial model that we could apply to potentially new indications. Right. So very active there, strong balance sheet to transact. And maybe, Jeff, you want to. Yeah. No, absolutely. I mean, look, we're in a great financial position, north of $425 million as of the end of last quarter. We continue to generate positive cash flow. Last year, we generated over $200 million in cash flow. So we really have a unique opportunity here, with business development, look for things that can be nice and synergistic with our business that can continue to drive value for shareholders. So that's really. Right. So orphan space. Yep. Neuro. Because there's a lot of companies. There's a lot. Up until the past two or three months, I would have said there were a lot of companies that needed money. But now, the markets seem to be a little more open to fundraising. But I was just curious, like, if you've looked at a lot of these, you know, kind of fallen angel type companies that actually have, you know, assets that are interesting, they just don't have enough money. There's certainly a lot out there, very late stage even, just as Zynerba. Yeah. Yeah. There's a lot out there. We've been very active because, you know, this is the main part of our long-term growth strategy. You know, we've got a lot of internal expertise. You know, I think, you know, we've shown we can execute well. So yeah, we've been out there and looking to add to the pipeline. It's sort of the orphan rare, you know, CNS neuropsych arena. Right. Which is, you know, obviously, it's coming back in vogue, if you will. Yeah. You know? Very much so. And, But there's a lot I mean, I just find that I'm still meeting companies, you know, and they don't have that much money. And whether they got money in this last, you know, kind of good month or two, I don't know yet, you know. But they just seem like they'd be perfect for. Yeah. Yeah. You know, kind of fitting in. Our BD team, they've been very busy. Good. Good, good, good. As in, you know, the whole management team. Yeah. Yeah, yeah. So what's underappreciated, do you think, about the story? What do you think? I mean, it seems like it's going pretty well. You have a lead asset that's, you know, on, on what is it going to do this year? Yes. Seven? Seven? We have north of $700 million. $700 million. Top-line revenue. Huge product. We're well on our way to $1 billion. Yeah. We've been talking about it for quite some time. We have a very growing pipeline. Yeah. We talked about the NextGen formulations, really advancing there. That could have the potential to go into the 30s and close to 40s. So the pushback is a little bit like, "We need next generations to work because this product has a 2030 life cycle. Yeah. Correct. That's number one. Number two, we need more pipeline. We need to diversify the business. Right. Yeah. And I think that, you know, even some. I'm trying to think of, like, what things you're hearing. Yeah. Some of the modafinil like, so even the ZYN002 program's not fully valued yet, you know, because we're just starting to educate. And although it's in phase 3 and, you know, it's, you know, about a year away or so from top-line data. So that's coming into focus more in the pipeline. And yeah, I think the more definition around the NextGen formulations. Yeah. So, understanding what the value, what those opportunities could be. And we're excited about all those. And I think have the organization, you know, that can execute on those programs, commercialize, obviously, you know, proven the, you know, the strong commercial engine. So I think, yeah, that's. Well, it hasn't been an asset, really, that's been trying to go after in a pivotal study for Fragile X, right, in a while if there has been one. So that's kind of a new market, I think, for people. And 22q is also very new. Right. Yeah. Right? So it's hard to, I guess, we got to educate people on the market. One thing at Harmony, one of the really strong also in patient advocacy. So we're, you know, really out there in these rare disease patient communities and meeting them where they are, even with regards to clinical trials, you know, helping awareness and, you know, and recruiting and enrolling in, in, you know, our clinical trials. And so I think there's opportunity to, you know, educate a lot more around, you know, what these potential new indications are about and, and the value of those. 22Q is also another about 80,000 patients diagnosed in the U.S. Yeah. That's a lot of patients, sure. An area that I would bet most people don't know about because until I met Zynerba a few years ago, I didn't know what that was either, so. Yeah. Exactly. Yeah. So as far as the, you know, kind of debates, I guess number one is, can we get the life cycle extension strategies out to protect the franchise past 2030? Mm-hmm. Right? Number two is, will the new pipeline that we just acquired work? Will we have more assets to bring into the pipeline? And then will orexins change the market at all? I mean, is there anything I'm missing? Like, I think we hit on kind of the key debates. Yeah. I would agree. I think those are the key debates. I think, you know, orexins, a lot of interest there, a lot of excitement. You know, I don't think it'll take away from our opportunity, you know, going forward, as I said, polypharmacy market. Yeah. Potential synergies. You know, we keep an eye on orexin opportunities as well. You know, it'll be an interesting story as it plays out. Right. And maybe you'll be in orexin as well. There must be some orexins out there, right? There are a few. Yeah. Good. Good, good. Thank you. Thanks very much for joining us. Appreciate it. Good to see you. Thank you so much. Yeah. It's turned into a big drug.