All right, good morning. This is David Amsellem from the Piper Sandler Biopharma team, and welcome to day two of the Piper Sandler Healthcare Conference. We're delighted to have Harmony Biosciences with us. We have Jeff Dayno, CEO, and Adam Zaeske , Chief Commercial Officer, and we're delighted to have you with us. So.
Hello, David. Thanks on behalf of the Harmony team. Thanks for the invitation, as always. Great to be here.
Oh, it's a standing invitation annually. We got a lot to talk about, so let's just dive right in. I wanted to talk about the recent performance of WAKIX. What struck me is the pace of patient adds these days, and the product's been on the market for several years. The pace of adds is almost in the same ballpark as what we saw earlier in its commercial life. With that in mind, what are you seeing regarding the continued brisk growth out of WAKIX for a product that is really not maturing?
Yeah. So let me frame that, and then Adam can sort of expand on that, provide more color. So, David, you know our story well. You follow the company, and I think we said early on that WAKIX has the potential to be a $1 billion-plus opportunity, and now we're really kind of rapidly approaching that unique and differentiated product profile, first and only non-scheduled product, calling on the entire sort of narcolepsy market. And then with that, some of the kind of recent changes in terms of execution that Adam has led, I think, is driving some of the results that we've seen, and Adam can expand on that.
Yeah, we're really pleased with the recent performance, David. I mean, you would have seen WAKIX very steady growth quarter-over-quarter for the last six years, usually adding between 100 and 400 patients in a quarter. Q2, we saw a 400-patient increase. We'd only seen that twice before, so we're very pleased. And then in Q3, whereas typically you see kind of a little bit of up and down, Q3 we saw another 500-patient increase, which was a record, actually, the highest ever since launch. And I think to your question, what's driving that? Obviously, highly differentiated product, only non-scheduled treatment option, broad payer coverage, really experienced team as well, executing effectively. And in the last, I would say, six or eight months or so, we've really been focused on the fundamentals, so really tightening up sales execution, marketing mix, and promotion.
We added a couple of payer wins, and we've also made some improvements to our process to support patients. So they're able to get access to WAKIX and obtain a dispense faster and with higher success rates.
Wanted to delve a little more deeply into where you're pulling in patients from. Is it oxybate switchers? Is it add-ons to, say, modafinil or stimulants? Are you even getting treatment-naive patients? Just help us understand where the patients are coming from.
Great question, and it's all of the above. And that's really remained steady for the last several years. In sleep-wake and with narcolepsy, what you see is a high degree of polypharmacy. So patients come to us on all different combinations of therapies, as well as naive, and that's been actually very consistent for the last several years.
I wanted to ask about the overall treated narcolepsy patient population. I mean, this is something as we think about drug development in hypersomnolence disorders, you hear a lot about expanding the pie. But you're out there with a product in the field. I mean, is the pie expanding as you think about the overall treated population? I would say it seems that way, given that we're also seeing oxybates growing. But what are your observations?
Yeah, so certainly overall market growth. We cite approximately 80,000 patients diagnosed with narcolepsy, but there's another 80,000, 90,000 or more that are undiagnosed. So it's a rare disease market, but it's a fairly large market. And in terms of WAKIX today, we've achieved 8,100 patients on therapy. In a market of 80,000 diagnosed, obviously that gives you a lot of additional room to continue to grow, and not just for WAKIX, but for all brands. As I mentioned, it's a polypharmacy market, so as we have seen brands enter, you typically see an expansion in brand utilization, not necessarily one brand taking share from another. And we'd expect that to continue.
What's the mix between NT1 and NT2 for WAKIX these days?
Yeah, I mean, claims data would show you about 50/50. I think for us, we're in that range, certainly. Maybe 45/55, 45 NT1.
Okay. And is any.
It's pretty consistent.
And that's also been consistent.
You're seeing growth in both segments.
Absolutely.
Okay. Got it.
I mean, the market, and you know this market well. It's so interesting. As an orphan rare disorder, but a sizable market, brands continue to grow. Other brands come in. Polypharmacy, patients cycling on and off, and I think we'll continue to see that trajectory, especially as the orexins come into the market and that whole dynamic that is playing out.
We'll definitely talk more about the orexins.
I'm sure we will.
Yeah. But before we do that, I wanted to ask more of a near-term question on the payer landscape. I know you talked about some payer wins, but we've got multiple Xyrem generics coming into the market next year. So with that in mind, how do you envision payer dynamics for WAKIX changing?
Yeah, no, great question. I would say payers historically, sleep-wake, narcolepsy hasn't been a huge budget impact category for them. It's not been a high priority to manage. They manage through steps and fail-firsts, which is pretty typical. And with Xyrem generics coming into the market, obviously that's going to lower the average cost of oxybate therapy, which would be a very welcome addition for payers. But as you've seen in many other categories as well, probably the impact will be restricted to within the oxybate vertical. And so we'd expect cannibalization of branded oxybates, but not really significant impact on other brands, and we wouldn't expect any payer coverage changes with other brands either.
I mean, if anything, it could open up opportunity with regards to patients on both, and then with generic oxybates coming in, because with WAKIX as the only non-scheduled product, no payer is stepping WAKIX to an oxybate. So it could provide even some upside opportunity.
We do hear that from KOLs that like the idea of a daytime wakefulness drug combined with an oxybate to address sleep fragmentation. So we do hear that a lot. Is that something that you think you could see more now that the price of at least one of the oxybate products is going to come down significantly?
Yeah, I think you could see that as a scenario.
Okay. All right, orexins. Everyone's favorite topic. We have Takeda's oveporexton. They're going to file soon. A broader question is, how are you thinking about the role of WAKIX in a world with orexin agonist? I know oveporexton is an NT1-only product, but we're going to eventually see others come in for NT2 and potentially IH. How are you thinking about the role of WAKIX in an orexin world?
Yeah, yeah. Why don't you share your thoughts?
So a lot of excitement around orexins, and we're excited as well. New treatment option for patients, which is fantastic, and certainly a promise of efficacy based on some of the study results. But as you can imagine, we've done a lot of market research on this. We've talked to payers. We've talked to healthcare providers. Also, a lot of questions. A lot of questions around what is that ultimate label going to look like, but really around safety and tolerability. In some of the studies, we're seeing pretty high incidence of insomnia, frequent urination, in some cases visual disturbances. So if you're speaking to a practicing clinician, they're interested for sure, but probably going to take a gradual approach until they can learn a little bit more about how these therapies operate in the context of that polypharmacy market.
What I mentioned before about when brands enter, we tend to see an expansion of brand utilization. It's actually about doubled in the last five, six years, but it's still only at about 20% penetration of the total narcolepsy patients in the United States. You have a lot of expansion opportunity for the entire brand set, and we would see WAKIX continuing on its trend. WAKIX, highly differentiated, only non-scheduled treatment option, it really holds a unique place in the minds of physicians, perceived as extremely well tolerated and delivering good efficacy. They feel like they can add it on to, as I said, any and all combinations of therapies in broad clinical utility across virtually all narcolepsy patients. We don't see that changing.
That's a special place that WAKIX holds in the minds of physicians, and we expect to continue to maintain that position and continue to grow.
So to be clear, you don't envision any sort of at least temporary disruption to WAKIX in NT1 when Takeda is launching oveporexton in late 2026 and into 2027?
I think the impact will be small in the short term and then gradual over time. If you speak to KOLs, as is the case in any class with a new mechanism, there tends to be a lot of excitement. So that's why when we talk to practicing clinicians, it's probably a more gradual approach. Obviously, for Takeda, they'll be limited to NT1. Also, won't have the pediatric indication. And when you talk to physicians, if patients are relatively well controlled, they're not looking necessarily to make a lot of changes in therapy until they see a need to do so.
Yeah, but I think in fairness, we are anticipating an impact, but I think that we don't think it'll be sort of disruptive to the whole class, and it'll kind of build over time. And when they come in, we'll obviously have been in the market eight or nine years, and HCPs sort of know WAKIX, and at that point, pitolisant HD coming to market. So I think we've sort of factored that into how we're seeing the business. And then in the meantime, we're excited about our orexin agonist. And we announced that we've gone into the clinic and we've dosed first patients. So we have the phase I PK/PD program started, and the plan there is we're doing a single ascending dose study in healthy volunteers.
Well, those sleep-deprived healthy?
We're doing single ascending dose in healthy volunteers, and then multiple ascending dose in sleep-deprived healthy volunteers. We're looking to generate initial PK and PD data. In the sleep-deprived healthy volunteer study, we'll get kind of an idea of sort of dosage range. The plan is with that, if we have enough information to accelerate the phase II and three program to try to sort of catch up a bit and get to market.
So I wanted to ask a bunch of questions on pitolisant GR and HD, but actually let's continue on the topic of your orexin. Wanted to pick your brain on a couple of things. I mean, there's a lot of investor chatter around, well, is split dosing, BID dosing, is that actually a bad thing? Could that be a good thing? Is dosing flexibility a good thing in the context of daytime wakefulness? And I'm not going to ask you if your drug is truly a once daily. I mean, we'll know when we know. But how are you thinking about split dosing if it came to that for your molecule?
Yeah. I mean, I think that as you've highlighted that, excuse me, I think that there is a lot that's still kind of playing out in the orexin space, these questions, and I think it remains to be seen. The initial plan was once-a-day dosing, and some of the programs that are advancing in the clinic, and now, like you said, contemplating split dosing and that flexibility. It's not dissimilar when I was at Cephalon in the modafinil program, where the original plan was once daily dosing in the morning, and then there was this sort of optionality where you can take a second dose, but if you took it, it had to be early in the afternoon to limit the risk of insomnia.
So I think that it waits to be seen how the overall clinical profile or the orexin agonist and each of these programs will play out, both on the efficacy side as well as the safety tolerability side. So we follow those. We learn from those. We will go into it thinking that we have opportunity for once daily dosing based on the preclinical PK data, but we'll go in the clinic and try to prove that out.
I know you have talked to the idea that your orexin could be best in class. We hear best in class thrown around a lot. So I don't know if you can provide more color on things like receptor affinity and selectivity, bioavailability, half-life? But what gives you confidence that you've got a potentially differentiated, or to use the term, best-in-class profile?
Yeah. So I think that the main features of that start with potency and again, as orexin-2 agonist, really exciting, the next novel target for patients with narcolepsy and other central disorders of hypersomnolence, but especially NT1, and the reason it's a direct fit. You have NT1, a disorder of orexin deficiency. You give an orexin-2 agonist, but as we know, NT2 and IH, it's sort of the other disorders in with regards to how high you have to go on the dose and how that's playing out and how that would affect safety tolerability, so potency is key, and we know that our orexin-2 agonist is the most potent of the orexin compounds that are in the clinic based on publicly available information. In the preclinical models, the lowest doses of driving sustained wakefulness.
So I think it starts with potency, the ability potentially to have lower doses to cover not just NT1, but NT2, idiopathic hypersomnia as well. Selectivity, there's been discussion about selectivity. If you look at the potency and selectivity together, then we generate about over 140-fold selectivity at the orexin-2 receptor versus orexin-1. Normally, when you're in sort of the neuro and psych arena, if you're seeing selectivity 20, 30, 40-fold, that is good. So we feel there is plenty of selectivity at the orexin-2 receptor. And then along with the potency and the plan to have lower doses to cover across the spectrum of central disorders of hypersomnolence, potentially with once daily dosing, that is what we're designing towards with regards to the development program. And we're in the clinic in the phase I program.
We'll have clinical data next year in 2026, and that's how the program is tracking.
So I did want to ask you about the development program looking beyond SAD, MAD. And given that you've got three orexins that are moving through the clinic and narcolepsy, two we know of in idiopathic hypersomnia, do you focus initially on narcolepsy with yours? Do you look at IH? There are certainly other conditions where EDS and fatigue are major issues. So there's a lot of white space here beyond just IH and narcolepsy. So probably too early to ask the question, but I'm going to ask it anyway. How are you thinking about your development program?
Yeah, so too early to answer the question, but I'll try to answer it anyway, so very fair question. I think that to be determined with regards to how the other programs play out, it is an interesting space with a lot of white space, as you said. Obviously, the most sort of direct pathway is where mechanistically the mechanism of action fits. So NT1, NT2, and IH. I think that we are looking at it closely with regards to would we divert from that and go to some of the white space based on how these other programs, where they end up, the market reception. We're open to considering another approach, but it's really too early to comment.
That's fair, so let's talk about your next-gen pitolisant program, so there's GR, wanted to get your thoughts on the value proposition of that formulation relative to WAKIX, and that's a rapid pathway to market, as you've outlined, so what's your commercial strategy for that product?
Yeah. So let me update you where we are and then add them on the commercial strategy. So I think, as you're aware, we announced the positive pivotal bioequivalent study, demonstrated that in the quick-to-market strategy. A dosing optimization study that we shared showed that you don't need the titration dose. We'll be able to remove that from the label for pitolisant GR. So we have everything we need. The team is preparing the NDA for submission early next year. Target to do for first quarter 2027. So moving ahead nicely with that. In terms of the value proposition and commercial strategy?
Yeah. So the gastro-resistant coated version of pitolisant, if you think about from a commercial strategy, this is a very intuitive play. It's housed within the existing pitolisant label, launching years ahead of LOE, and offers meaningful improvements to benefit patients. So the strategy here would be any new WAKIX patients that would have been prescribed WAKIX anyways, prescribe the new and improved formulation, tested that in market research. Healthcare providers view that as a very logical option. Also, an opportunity to recontact previous patients. So patients that would previously have been on WAKIX, maybe discontinued over the last six, by the time we launched, seven years, recontact them to see if pitolisant GR might be an option that they'd want to consider.
Let's move to HD. Just remind us where dosing for HD is relative to WAKIX and the learnings you have on the maximum tolerated dose from your early safety and PK work.
Sure. Yeah, sure. The plan is for pitolisant HD, a high-dose formulation of pitolisant, but also a unique and enhanced formulation, enhanced PK profile, so greater availability milligram for milligram, less inter-individual variability, which is something that pitolisant's current formulation has. We're looking to dose sort of 2x the highest current label dose, but with that also, in addition, the greater bioavailability milligram for milligram. We have data from all the development programs showing dose response. We think that there's more efficacy on the table to demonstrate with pitolisant HD. From a safety tolerability perspective, as we've shared, we did a phase I-B study, and we dosed up to five times the current label dose and demonstrated really no change to the safety tolerability profile compared to. We have the room and the safety margins up to 5x that we've demonstrated in the clinic.
Now we are going into the clinic and on track, actually, as we speak, initiating the two phase III trials, one for narcolepsy and in parallel another for idiopathic hypersomnia with a target PDUFA in 2028.
Yeah. And as you look beyond narcolepsy and IH, well, one of the things, at least just in hypersomnolence in general, you talk to fatigue as an outcome measure. So how do you incorporate that into both your narcolepsy and your IH studies or other studies you plan to do with HD?
Yeah. So fatigue is an interesting construct, different than excessive daytime sleepiness. The relevance there is that it's mediated through histaminergic circuits. So pitolisant as a histamine modulator, there's a good mechanistic rationale. We have proof of concept data, if you remember, from our myotonic dystrophy phase II proof of concept study that showed benefit not just in excessive daytime sleepiness, but fatigue as well in a dose response-related fashion. So what we will do is we'll design that as a secondary outcome in the narcolepsy program. Fatigue occurs in about 60% of patients with narcolepsy. So that will help differentiate the label even further post-wake acceleration. On the IH side, we're looking more at the symptom of sleep inertia, which is a kind of cardinal feature in IH, difficulty awaking from sleep or from naps.
We also have good data from the initial IH trial with the sleep inertia questionnaire that we can look to that to get data in the label in addition to improvement in EDS.
So we have a couple of minutes left. I wanted to move on to clemizole in pediatric epilepsies or DEEs. Just walk us quickly through your clinical programs here. I know you've got some deliverables in 2026. So just give us a refresher on those programs.
Yeah. So actually, deliverables coming up next week.
Yeah. Yeah. There are open label data.
Yeah. So open label data. Yeah. So very briefly. So EPX-100, clemizole hydrochloride, very interesting story, first-generation antihistamine that was in the market for about 20 years. And the relevance of that is in terms of the no major safety signals emerged. It had a lot of exposure in the market, which is important kind of in this area in terms of the overall risk-benefit proposition. So I think that with that, we are in phase III for both Dravet and Lennox-Gastaut with top-line data on track for late in 2026. And next week at AES, we'll be presenting some of the initial efficacy data from the open label extension phase. The trial is ongoing. It's still blinded. But we realized there wasn't a lot of efficacy data out there.
We wanted to share some of that initial profile from patients that went into the open label extension, had a minimum of six months exposure, and kind of what we are seeing on the efficacy side of the equation. The backdrop is what's available in the market. Good treatments, but still a lot of unmet medical need. Fintepla, good efficacy, but has a REMS, the risk of cardiac valvular disease, and you have to do echocardiograms at baseline and every six months. Epidiolex, dose-limiting GI issues, and you have to follow LFTs. So we're designing towards a profile of we see kind of comparable efficacy, but a potential for an improved safety tolerability profile in an area of major unmet medical need, both Dravet and LGS.
Just real quick on, do you see differentiation versus a very selective 5HT2C agonist like bexicaserin, the Lundbeck product?
I mean, I think with regards to the safety side of the equation where we're comfortable with, I think we see comparable efficacy. And we'll see, obviously, bexicaserin in the clinic and how that plays out. And then behind that, we have EPX-200, the liquid formulation of lorcaserin, which is a 5HT2C specific agent.
Got it. All right. Well, I wish we could talk more, but we're out of time. But thanks, Adam. Thanks, Jeff. Thanks to everyone in the audience.
Great. Thanks, David. Thank you. Thank you.