Hi everyone, thanks for joining us today. I'm Mani Foroohar, I'm on the Equity Research Team at Leerink, and really happy to welcome Harmony to be with us today. We have Jeff Dayno, CEO, Kumar Budur, CMO, and Sandip Kapadia, CFO, on the stage with us today. Would you like to begin by making some opening statements?
Yeah, sure. Yeah, thank you for the invitation. Yeah, good afternoon, everyone. I think, you know, Harmony Biosciences, we are very, you know, excited about, I think, the, you know, the growth of the fundamental business in terms of WAKIX and narcolepsy, and now year six in the market and, you know, on our way to a billion dollar plus opportunity. More importantly, I think we're excited about, you know, the robust late stage, you know, catalyst-rich pipeline, you know, that we built over the past year and a half, two years. You know, with that, and, you know, the acquisitions of Zynerba Therapeutics, bringing in ZYN002 and our lead program in Fragile X syndrome, which we'll talk about, and our orexin-2 agonists, obviously a discussion, you know, next door about, you know, the potential of that class.
And then a rare epilepsy, you know, pipeline with the acquisition of Epygenix Therapeutics, really the most advanced 5-HT2 agonist, you know, program in the clinic, you know, that Kumar will share with you. Really that rolls up to, you know, in terms of the narrative has shifted from just, you know, the WAKIX commercial business to the excitement of the pipeline and those catalysts. You know, we've got three orphan rare CNS franchises, you know, each with potential peak sales opportunities of $1 billion-$2 billion each. We now have eight assets, you know, in the clinic across 13 development programs and up to six in phase three by the end of the year. We feel we have, you know, one of the most robust and deep pipelines in the industry for patients living with rare neurological disorders.
We're on track, you know, potentially, if we're successful, to deliver one or more new product or indication launches each year over the next several years. We're very excited about, you know, that opportunity and really potential for helping, you know, thousands of additional patients living with rare diseases and value creation, you know, for our investors.
Great. Maybe let's start with ZYN002 since you brought that up. I believe that's your next big catalyst that we're all looking forward to. Can you just remind us what's been shown already from the CONNECT study and what you are hoping to see in the upcoming results?
Yeah, we're actually very excited about that. I think, you know, as our pipeline comes more into focus, our next major, you know, clinical milestone, ZYN002, a very interesting, innovative product. I don't want to steal Kumar's thunder, but a purely synthetic, pharmaceutically manufactured cannabidiol gel through transdermal delivery, devoid of THC, which has, you know, certain advantages that Kumar can describe, you know, with regards to, you know, cannabidiol and that mechanism in patients with Fragile X. I think importantly, and then Kumar will expand, the phase three RECONNECT trial is really, you know, designed to replicate the key findings from a pre-specified analysis of the phase two three CONNECT study, which demonstrated in patients with full complete methylation a statistically significant and clinically relevant outcome on the primary endpoint in the social avoidance scale, subscale of the ABC checklist.
With that, Kumar can kind of give an update of where we are and why we have strong conviction in the phase three trial and on track, you know, for the data readout in third quarter.
Yeah, thanks, Jeff. Thanks for the question, Mani. Fragile X syndrome, here we really have an opportunity to bring the first and the only approved treatment in patients with Fragile X syndrome. First, a quick word about the disease state itself. Very well-known Fragile X syndrome, approximately 80,000 patients in the U.S. alone. For ZYN002, it's a global opportunity for us. Caused by mutation in FMR1 gene, which disregulates the endocannabinoid system, and ZYN002, by interacting with CB1 receptors, restores the homeostasis of the endocannabinoid system. The product itself, it's a patent-protected permeation-enhanced gel that has significant advantages because cannabidiol, if it's given orally, can cause significant nausea, vomiting, and diarrhea. Also because of the first-pass metabolism, could cause some liver function test abnormalities. We do not see that with ZYN002.
In fact, one of the features that we are really happy about ZYN002 is the long-term safety and tolerability data. Some of the patients who use ZYN002 for Fragile X syndrome are now continuing to take the drug eight years out. Thus far, the only clinically meaningful or relevant treatment emergent adverse event that is seen is application site reaction in about 7% of the patients. Finally, in terms of efficacy, as Jeff was mentioning, what we are trying to do in RECONNECT study is essentially trying to replicate the positive data that we saw in patients with complete methylation.
The target population is the same, patients with complete methylation, the primary endpoint is the same, and we are increasing the probability of success by making some enhancements, like increasing the duration of the study to 16 weeks because we saw patients continue to get better from 12 weeks to 16 weeks, and increase the dose in patients who weigh greater than 50 kilograms. Overall, a very well-designed study based on the positive data from the CONNECT study, essentially trying to replicate the positive findings from CONNECT study.
Great. Could you remind us if there's any connection between the complete methylation and the mechanism of this?
Yeah, great question, Mani. Yes. What happens is in full mutation, it's basically a triplet nucleotide repeat disorder. If the CGG triplets exceed more than 200, then there is complete methylation of the gene. What it does is it essentially silences the gene, which means that there is hardly any production of FMR protein. That results in the increased severity of symptoms. Full mutation, complete methylation, larger symptom burden, and the more likely for ZYN002 to show efficacy. What we saw from the CONNECT study is about 80% of the patients had complete methylation. In those patients, we not only saw statistically significant improvement, but also clinically meaningful difference. It doesn't mean that ZYN002 doesn't work in patients with partial methylation. It still does, but the response is a bit unpredictable, creating some heterogeneity in the signal detection.
That's why, you know, RECONNECT study, the target population is complete methylation.
Does this have any label implications, or do you think it would be used in the broader population?
Yeah, actually, you just reminded me about one thing that I forgot to mention, which is that during the discussions with the FDA, at the request of the FDA, we are enrolling a nominal number of partial methylation patients as well. If the primary endpoint is positive, and if the data in partial methylation patients is supportive, or is it trending in the same direction, there is a possibility of a much broader label.
Yeah, and I think also just if we're obviously successful with Fragile X, you know, we also have a follow-on indication of 22q that the team's also working on as well. Really an opportunity to really expand it, you know, beyond Fragile X.
Yeah. We're really excited about this program. I think, you know, sort of, you know, all those factors with regards to, you know, no approved treatments for Fragile X. And, you know, I think looking at the data and some of the skepticism, I think, you know, that, you know, that the phase two, phase two, three CONNECT study was, you know, kind of a negative study on the primary outcome, you know, we acknowledge that. If you look at the 80% of that cohort that had complete methylation, you know, it was a strong, statistically significant, clinically meaningful signal that the phase three RECONNECT trial is designed to, you know, replicate. With that, you know, sizable market opportunity, as Kumar mentioned, about 80,000 patients in the U.S., plus we have a, you know, global rights to ZYN002, we could partner that out in other territories.
You know, I think, and with positive data, Kumar and the team are ready, you know, we have another follow-on indication in 22q11.2 deletion syndrome lined up right behind that with interactions, you know, with the FDA about a pivotal phase three design. Lots of opportunity there in an area of high unmet medical need, you know, that we're excited about.
Got it. Great. Last question on this product was just in terms of physician feedback on the data that you've shown so far, like how meaningful are these endpoints to physicians and caregivers? Just curious on that.
Yeah, I mean, from a clinically meaningful perspective, a change in three points in social avoidance subscale is considered clinically meaningful. That is what we saw in the CONNECT study. From a clinician perspective, they are very excited, especially in the context that there are no approved treatments for this particular indication. If ZYN002 were to be successful, as I made the statement initially, it will be the first and only approved treatment for any symptoms in patients with Fragile X syndrome.
Yeah, I think the other is the anecdote you often share in terms of, I guess, patients on ZYN002, you know, going on eight years now. And when they started, you know, they were young children, and now some of them are still on, you know, the product seven, eight years.
Yeah, when the very first study in Fragile X syndrome was started with ZYN002, some of these kids were in middle school, and now they are in college, continuing to use ZYN002 eight years out. It's just the persistence of efficacy in a neuropsychiatric indication is pretty unprecedented. You don't see this level of persistence of efficacy and maintenance of treatment in neuropsychiatric conditions.
Great. All right. Maybe moving on to your Rexin program, I'm sure you're really excited to talk about that. Could you tell us how this may be differentiated from other products that are in the class right now?
Sure. Kumar, do you want to?
Sure. I mean, yeah, several things, Mani. I mean, to start with, look, orexin is clearly the next phase of innovation, very excited about orexin-2 receptor agonists for patients with narcolepsy. Coming to our specific orexin-2 receptor agonist, first of all, it's a novel chemical structure. It's not a me-too, pyridinone, sulfonamide, bicyclic moiety. We decided to leverage the learnings from the other orexin-2 receptor agonists, came up with this novel structure. That clearly has some implications. In terms of potency, this continues to be the most potent orexin-2 receptor agonist based on all the publicly available data, excellent selectivity, potential for once-a-day dosing, and relatively clean preclinical safety profile. The combination of all of these factors could potentially make this asset a potential best-in-class orexin-2 receptor agonist. Obviously, that has to pan out in the clinical data.
We are on track for IAPD submission in the middle of this year, first in human studies in the second half of this year.
Great. Can we expect to see any additional preclinical data this year at all?
Yes. We plan to present a comprehensive preclinical safety and efficacy data at the annual sleep meeting that's in June in Seattle this year.
Got it. Maybe moving to the EPX-100 program, that's the rare epilepsy drug that you have, maybe just some of your initial thoughts on that product and how that could be differentiated as well.
Yeah, sure. In terms of the rare epilepsy sort of pipeline that we brought in with the acquisition of Epygenix Therapeutics, I guess last April. We were busy on the BD front over the past year and a half, two years. Really EPX-100, clemizole hydrochloride, a first-generation antihistamine that was in the market for about 20 years, I think with a good safety tolerability profile, and a mechanism of action, you know, kind of proven in the zebrafish model for the rare, you know, developmental epileptic encephalopathies. Also EPX-200, a liquid formulation of lorcaserin, you know, that is in the early sort of, you know, development stage. Kumar can give an update on, you know, really the important thing is the most advanced of the 5-HT2 agonist compounds in the clinic with EPX-100 in phase three for Dravet syndrome.
We initiated a pivotal phase three trial for LGS at the end of last year. Those are advancing and excited, you know, on track for top-line data in 2026.
Right. I mean, established certain mechanism of action, reason to believe. There is a history of safety and tolerability data. Clemizole hydrochloride was in the market for almost two decades in the 1950s and 1960s. It was sunsetted with the introduction of second-generation antihistamines, no safety signal. We pursued this as a new chemical entity, did a complete battery of non-clinical tox studies, again, no safety signal. We are in Dravet syndrome for phase 3, actively recruiting in the U.S. and outside of the U.S. We initiated the study in LGS in the last quarter of 2024. We are actively recruiting for LGS as well. A simple dosing regimen, a BID dosing regimen, which is clinically meaningful for this particular patient population. At our last, the only investor meeting October last year, we shared the emerging safety and tolerability profile from the ongoing phase 3 Dravet syndrome.
The tolerability was good, and there was no need for any special monitoring like liver function tests or cardiac monitoring. The overall benefit risk profile is pretty promising for patients with developmental epileptic encephalopathies leading with Dravet syndrome and LGS. As Jeff was mentioning, we are on track for top-line in 2026 for both indications.
Yeah. We see where we are kind of as a starting point, you know, with regards to the phase three in Dravet and LGS. We also have the opportunity to go broader in terms of, you know, a broader type of basket trial approach in the, you know, developmental epileptic encephalopathies, as well as, you know, the opportunity. We have a lot of expertise in the epilepsy field where we could build, you know, off of these assets and build out a broader pipeline, you know, in epilepsy.
Got it. Could you just give us your thoughts on what the unmet need is for Dravet and LGS? There are several other agents that are approved right now for those indications. What are you hoping to fill in terms of efficacy or safety kind of need?
Yeah, I mean, if you look at both of these indications, despite several medications approved, the patients continue to suffer from intractable seizures. When we did our market research and market analytics, what was, it was not really surprising, but what was really that caught our attention is there are about 78,000 patients with Dravet syndrome in the U.S. Almost 6,000 of them continue to suffer from seizures. Very similar in LGS as well. Clearly, there is need for medications with better efficacy and also better safety and tolerability. With clemizole hydrochloride, that's exactly what we are trying to achieve. Good efficacy, known serotonergic mechanism of action, but more importantly, good safety and tolerability as well so that these patients can continue to take these medicines long term.
Great. Shall we go to WAKIX?
Sure.
Was there anything else that you wanted to mention regarding the pipeline?
No, I think we hit the highlights. You know, I think we hit the highlights of, you know, the three orphan rare sort of neurologic disorders, the next major clinical milestone in the phase three trial Fragile X. I guess I would say that with regards to, you know, if we're successful in those new indications, you know, we have a commercial model, I mean, coming to WAKIX. A proven commercial model with a single patient hub, closed pharmacy distribution system. We have the ability to sort of utilize that infrastructure. These are not sort of large sales forces. A lot of this is a centers of excellence model.
We could potentially go to market with these new indications in a very cost-effective manner, you know, utilizing our commercial model, the infrastructure, and then be able to sort of, you know, optimize, you know, those commercial opportunities. Again, both ZYN002 and EPX-100, you know, we also have global rights, you know, not just in the U.S. We also have phase three trials that have been discussed, you know, with EMA as well. We could file both in the U.S. as well as in Europe.
I mean, just to add insight, both ZYN002 and EPX-100, the clinical trial designs meet the requirement of FDA, EMA, and other parts of the world as well. That goes along with the fact that we have global rights for both of these, all of these assets.
Great. Looking forward to that data. Okay. For WAKIX, you have a couple of next-generation products in the pipeline. Maybe you could start by talking about your plans for those.
Yeah. So I think at a high level, you know, we've got obviously WAKIX and pitolisant, a first-in-class molecule, novel mechanism of action, very innovative. You know, it was the first new MOA in the narcolepsy market in over a decade, working through histamine, which has importance in terms of other some unique systems and symptoms working through, you know, histamine circuits. You know, a successful product in the market and the opportunity to enhance and improve upon, you know, you know, that product. I think the next-generation formulations we're working on represent kind of, you know, patient-focused drug development.
What are the ongoing unmet medical needs with regards to predisposition to GI symptoms and nausea and vomiting in about 80-90% of patients with narcolepsy, as well as the main sort of unmet need of residual symptoms and the need for enhanced efficacy with regards to what the pitolisant, you know, HD or high-dose program is designed to deliver. Briefly, we've got two programs. Pitolisant GR, the gastro-resistant formulation, is meant to, it's a quick-to-market strategy with a target PDUFA in 2026, which we're on track for, and designed to expand the base of patients, you know, on both WAKIX and pitolisant GR product. Really the more novel unique formulation is pitolisant HD, which with a target PDUFA in 2028, is designed to really extend the pitolisant franchise, not just beyond 2030, but into the mid-2040s with provisional patents filed to 2044.
I think with that, you know, Kumar can give an update on where we are in those programs.
Yeah. I mean, Pitolisant GR, abbreviated clinical development path, showing bioequivalence to WAKIX to address the GI symptoms that are widely prevalent in patients with narcolepsy. About 80% of the patients have some kind of upper GI symptoms. That's because of the orexin dysfunction leading to vagus nerve instability causing upper GI symptoms. Pitolisant GR formulation is designed to address some of those symptoms. The other distinguishing feature will be the ability to start at the therapeutic dose. If you look at any other narcolepsy medications, they involve some kind of titration. With Pitolisant GR, we aim to give the patients an ability to start at the therapeutic dose. Clinical development itself, we are initiating pivotal bioequivalence study this quarter. Top-line data will be available in third quarter. We are on track for PDUFA in 2026. Pitolisant HD formulation, Jeff mentioned the distinguishing features.
Very excited about Pitolisant HD because in narcolepsy with the Pitolisant HD optimized formulation, and we discussed this data last year, we are showing an increase in relative bioavailability, decrease in interindividual variability, which have significant clinical implications, and also go up to two times the dose, the maximum labeled dose of WAKIX. All of these features we anticipate, or we hope to show increased efficacy with excessive daytime sleepiness, efficacy in cataplexy, and also target fatigue in narcolepsy for which there are no approved treatments. The histaminergic mechanism of action of Pitolisant uniquely suits to treat fatigue because of the nature of the symptoms. We showed this already in a couple of our studies, one in myotonic dystrophy and some of the studies our partner Bioprojet presented in sleep apnea. That study is on target to start in the fourth quarter with PDUFA in 2028.
Similarly, idiopathic hypersomnia, we are on track to start phase three in the fourth quarter with PDUFA in 2028. With idiopathic hypersomnia, apart from excessive daytime sleepiness and idiopathic hypersomnia symptoms, we'll also be targeting sleep inertia as well.
Yeah. I think the opportunity, you know, through the sort of the mechanism of action working through histamine, the ability, in addition to sort of the usual symptoms, you know, where fatigue is a, you know, another important symptom in about 60-70% of patients, you know, with narcolepsy, we had strong data in a phase two proof of concept study in patients with myotonic dystrophy. It is really a separate construct than EDS. There were some discussions earlier, you know, with an orexin-2 agonist and, you know, whether that mechanism would actually affect fatigue or not. Clearly, different construct, you know, working kind of through histamine circuits. We feel that with Pitolisant HD, that could help further differentiate the label and really help, you know, patients also with fatigue as part of the symptom complex.
For idiopathic hypersomnia, I understand that the actual trial will not start until later this year, but curious if you are thinking about trial design and what you might do differently from the Intune study, what you might keep the same.
Right. I mean, with the study design for idiopathic hypersomnia, we had disclosed this. It will be a prospective parallel randomizable blind placebo-controlled study, different from the randomized withdrawal study that we used in the Intune study. With the randomized withdrawal study design, there's some challenges with the data interpretation and other things. The trial design that we will be employing going forward is something that we have discussed with the FDA. The trial design and the endpoints is something that we are already aligned with the FDA.
Great. Maybe moving to the base business of WAKIX, maybe you could describe some of the commercial trends and market dynamics around the continued growth of this product.
Sure. Yeah. Let me start it and Sandip can sort of also weigh in. I think that, you know, in year six on the market in an orphan rare disorder, you know, we continue to see growth. I think we continue to see growth, WAKIX and narcolepsy, really reflective of the broad clinical utility, you know, given the overall benefit risk proposition. Namely, you know, the first and only approved product for narcolepsy that's not scheduled as a controlled substance. That reflects kind of the prescriber base. You know, we call on 9,000 HCPs, which is the full market opportunity, and only 4,000 of them participate in the oxybate REMS. We continue to grow the business and the depth of prescribing in those HCPs. You know, they have bigger, larger clinics and more patients, but also the 5,000 HCPs that don't participate in oxybate REMS.
We're growing across the breadth of prescribing there, about 60% penetrated in that segment and continuing to grow. I think all this is reflective, you know, of the product profile, continued growth. I think we've guided this year to $820 million-$860 million, you know, on our way to a billion dollar plus opportunity in narcolepsy alone, you know, in year six on the market. I think that the patterns have been pretty similar kind of, you know, year over year. There's some seasonal dynamics, but, you know, steady growth in terms of patient ads and, you know, how the product has performed, you know, a lot of patient support, you know, in our patient hub in that unique commercial model. Sandip, anything to add?
No, no. I think you covered most of it. I mean, we have obviously great momentum from last year. You know, we did almost $715 million in sales, you know, great going into this year with our guidance of $820 million-$860 million. You know, we'd be, you know, close the year about fourth quarter, about 7,100 patients on therapy. You know, we'd need to get to the billion. We would need to get to about 9,000. We are not that far away from achieving blockbuster potential for the product. We are very excited about the year ahead. Good continued growth quarter over quarter in terms of net patient adds is what we expect.
Yeah. I think going forward, you know, even if the market doesn't grow, which is unique in narcolepsy as a rare disease, about 80,000 diagnosed patients. Even if the market doesn't grow, there's plenty of opportunity there. It's a polypharmacy market. I think it'll continue to be a polypharmacy market. The evolving orexin-2 agonist programs are, we're learning from them. It is the next novel target in chronic neurological disorders, you know, with a lot, you know, symptoms that are difficult to treat. It's rare that monotherapy wins the day. Oftentimes you need multiple agents. I think that's our position where, you know, we are. The other longer-term opportunity potentially is our partner Bioprojet generated some preclinical data showing synergistic mechanisms between orexin and histamine. They're both in the hypothalamus near one another, and the circuitry is very similar.
You know, as we work on an orexin-2 agonist program and we have Pitolisant HD going forward, you know, the potential opportunity to consider a combination, you know, drug development with two complementary synergistic mechanisms, you know, in the future. We are in sleep, wake, you know, to stay for the long term. We're well established both with the treating medical community, with the clinical investigative sites, because we're going to have multiple programs in the clinic. And we're excited about those opportunities.
Great. Just in the last 30 seconds or so, any additional plans for BD or anything that you think is really interesting out there that you're looking at?
Yes, yes, and yes, I would say. I think strong balance sheet. We feel like we're just getting started in terms of building the pipeline, expanding the pipeline. You know, given the current market, you know, there are interesting opportunities out there, either going deeper in one of our three franchises or possibly an adjacent orphan rare neuro opportunity. You know, we have the ability to transact. We have a dedicated business development team that kind of, you know, looks across the market. Yeah, we plan to continue to build out and grow the pipeline. I think we have the capacity and, you know, the expertise to do so.
Yeah. Just to add, obviously we're also a very profitable, positive cash flow generating company, very differentiated in that way. It really gives us the flexibility. Everything that you heard today in terms of programs, we're well funded, you know, just from our existing balance sheet and with close, you know, over $576 million as at the end of last quarter, really positions us well to execute on not only the late stage program that we have, but also with.