Harmony Biosciences Holdings, Inc.

Good morning. My name is Madison, and I will be your conference operator today. At this time, I would like to welcome everyone to Harmony Bioscience's second quarter 2025 financial results conference call. All participants have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question at that time, please press star 1 on your telephone keypad. Please be advised that today's conference may be recorded. Lastly, if you should require operator assistance, please press star zero. I will now turn the call over to Brennan Doyle, head of investor relations. Please go ahead.

Thank you, operator. Good morning, everyone, and thank you for joining us today as we review Harmony Bioscience's second quarter 2025 financial results and provide a business update. Before we start, I encourage everyone to go to the investor section of our website to find the materials that accompany our discussion today. including a reconciliation of our gap to non-gap financial measures. At this stage of our lifecycle, we believe non-gap financial results better represent the underlying business performance. Our speakers on today's call are Dr. Jeffrey Dano, President and CEO, Adam Zeske, Chief Commercial Officer, Dr. Kumar Padur, Chief Medical and Scientific Officer, and Sandeep Kapadia, Chief Financial Officer and Chief Administrative Officer. As a reminder, we will be making forward-looking statements today, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties. Our actual results may differ materially, and we undertake no obligation to update these statements, even if circumstances change. We encourage you to consult the risk factors referenced in our SEC filings for additional details. I would now like to turn the call over to our CEO, Dr. Jeffrey Dano. Jeff?

Thank you, Brennan. Good morning, everyone, and thank you for joining our call today. I want to begin today's call by reaffirming something we believe is becoming increasingly clear. Harmony Biosciences is a growth story. We have built something rare in our industry, a profitable, self-funding biotech company with an innovative late-stage pipeline poised to deliver meaningful value for both patients and shareholders. Because of this unique profile, we continue to execute from a position of strength. Our foundational business, anchored by Wakex and Narcolepsy, has now delivered another quarter of double-digit revenue growth. We reported $200.5 million in second quarter net revenue, representing a 16% increase year over year. This performance extends our four-year streak of profitability and reinforces WCAG's strong momentum in its sixth year on the market, as reflected by the addition of 400 average patients during the second quarter. WCAG remains the first and only non-scheduled treatment for narcolepsy, leading to broad clinical utility that is meaningful to both patients and prescribers. As demonstrated by the sustained momentum, we believe WCAGX will achieve $1 billion plus blockbuster status in narcolepsy alone, well ahead of loss of exclusivity in 2030. But our story doesn't end with the success of WCAGX, because we are just getting started. What excites us most is what lies ahead. Today, Harmony is a multi-franchise company with three core areas of focus, sleep-wake, neurobehavioral, and rare epilepsies. Each of these franchises includes late-stage development programs with $1 to $2 billion in peak sales potential across multiple indications. Let me walk you through what lies ahead in our pipeline, starting with our next major clinical catalyst coming from our neurobehavioral franchise and its innovative investigational product, ZYN-002. This is a 100% synthetic, pharmaceutically manufactured cannabidiol devoid of THC, delivered through a unique, proprietary, patent-protected, permeation-enhanced, transdermal gel formulation. Our phase three registrational trial in patients with Fragile X syndrome completed enrollment in Q2, and we are on track to report top line data later this quarter. This study, the ReConnect study, was designed to confirm the positive findings of the primary outcome from the Phase 2-3 CONNECT study in the pre-specified group of patients with complete methylation of the FMR1 gene, the underlying genetic defect in patients with Fragile X syndrome. In fact, Fragile X is the most common known inherited cause of intellectual impairment and autism spectrum disorders. Stepping back a moment, in order to understand the potential significance of our Phase III ReConnect study, there are roughly 80,000 people living with Fragile X in the U.S., similar in size to the diagnosed narcolepsy market. However, unlike that market, there are currently no FDA-approved treatments for Fragile X syndrome. A positive readout from the ReConnect study could represent a major breakthrough, the potential for the first and only approved therapy for Fragile X syndrome, and a transformational moment for people living with Fragile X syndrome and their families who have waited far too long for a therapy designed to address their needs. Kumar will be sharing more detail with you on the reasons for our strong conviction in the upcoming top-line data readout. In our sleep-wake franchise, as I mentioned, WAKIT continues to grow, and our pitolicin life-cycle management programs are designed to both expand and extend this franchise well into the mid-2040s. We have major catalysts ahead for the two next-generation formulations of pitolicin, high-dose pitolicin or pitolicin HD, and a gastro-resistant formulation of Pitocin or Pitocin-GR. And we are on track to initiate phase three registrational trials in both narcolepsy and idiopathic hypersomnia with Pitocin-HD in the fourth quarter of this year. We are also advancing a novel orexin-2 agonist with a potentially best-in-class profile. and remain on track to enter the clinic and initiate first in human studies later this year with clinical data anticipated in 2026. Our third franchise in rare epilepsy is also making steady progress. EPX100, or chlamazole hydrochloride, is one of the most advanced 5-HT2 agonist compounds with a well-characterized mechanism of action and a strong safety record. It is now in phase three registrational trials for both Dravet syndrome and Lennis-Gastaut syndrome, with pivotal data expected in 2026. Our commitment to patients with serious rare neurological disorders does not end here. To that end, we recently entered into a research collaboration with CERC Biosciences. a regenerative medicine company discovering novel therapies based on cellular reprogramming and focused on developing novel regenerative cellular therapies to replace and restore function in patients with advanced neurological disorders. Our collaboration with CERC is strategically aligned with our current pipeline and focused on treatments for refractory epilepsy and treatment-resistant narcolepsy. This research could potentially result in the next generation of innovative disease-modifying therapies for these advanced chronic neurological disorders. Sandeep will be commenting further on the terms of this deal. When you look at Harmony today, it should be evident that what we are building is one of the most robust pipelines in the industry for patients with rare neurological disorders. We now have eight innovative assets across 13 development programs, including up to six phase three trials by the end of this year. This pipeline is poised to deliver one or more new product or indication launches every year for the next several years. And with more than $670 million in cash and cash equivalents on the balance sheet, and a disciplined approach to capital deployment, we have the flexibility to continue to strategically expand our pipeline through targeted business development efforts in this favorable environment. So what does all this mean? It means that in an industry where sustainable success remains elusive, Harmony has built something different and something unique, a commercially durable business with a robust late-stage pipeline and a clear path to delivering long-term value for patients, providers, and shareholders alike. And that's what makes Harmony one of the most compelling growth stories in biotech today. With that, I'll turn the call over to Adam Zeske, our Chief Commercial Officer, for an update on our commercial performance.

Adam? Thanks, Jeff. Harmony's Q2 2025 results demonstrate the enduring strength of our commercial business. Wacix delivered $200.5 million in net sales for the quarter, representing 16% year-over-year growth in its sixth year on the market. Wacix achieved 7,600 average patients in Q2, representing an increase of approximately 400 average patients for the quarter. This represents among the strongest quarterly results we've seen since launch and continues the steady, reliable growth we've seen for the past several years. This sustained performance is driven by Wayfix's unique position as the only non-scheduled treatment option with its broad clinical utility for the more than 80,000 patients with narcolepsy, as well as the strong focus and execution of our commercial teams with the support of the entire Harmony organization. We have a great deal of confidence in the continued growth, potential, and performance of WAKIX. In addition to its unique position as the only non-scheduled treatment option, WAKIX has among the highest brand awareness in the market, is perceived as efficacious and well-tolerated, and is supported by broad payer coverage that has remained consistent for years. We see continued increases in prescribing among the approximately 4,000 OxyBait REMs enrolled prescribing clinicians, as well as an increase in prescribing and addition of new prescribers with the approximately 5,000 non-Oxivate REMS-enrolled clinicians, where WAKIX is the only branded option. This dual expansion, deepening usage within our core base while broadening our prescriber footprint, demonstrate WAKIX's resilient position and reinforces our confidence in its continued growth trajectory. As we look to the second half of 2025, these strong wakex fundamentals support our competence in maintaining its growth momentum we are confirming our full year revenue guidance of 820 to 860 million and we remain on track to achieve 1 billion plus in annual revenue in narcolepsy alone looking to the future the patolis and gr and hd formulations each target significant unmet patient needs while extending our growth potential with utility patents filed through 2044. Early feedback from physicians and payers on the HD formulation has been particularly encouraging, and we'll be able to fully leverage our commercial infrastructure to drive the next phase of growth through our Petolis and Franchise formulations. We're also excited for the opportunity to expand beyond the sleep-wake franchise and are eagerly anticipating the top line data readout for ZYM002 in our neurobehavioral franchise next quarter. Kumar will provide a progress update on these programs in a moment. In summary, the fundamentals of our business remain robust. Our strong second quarter performance reflects the continued execution of our strategic priorities And we are well positioned to capitalize on the substantial opportunities before us. I'd like to now turn the call over to our Chief Medical and Scientific Officer, Kumar Badur, to discuss the advancements in our clinical development programs. Kumar?

Thank you, Adam. Good morning, everyone. And thank you for joining us today. Please refer to slide number five for our pipeline chart. And the clinical development highlights are on slide six through slide 11. In R&D, we are on track for our next major catalyst, the top-line data for ZYM002 in fragile X syndrome in Q3. We have a high degree of confidence and conviction in the success of the Phase III Registration Trial, the ReConnect Study, as it builds upon the data and insights from the large Phase II-III Connect Study. The efficacy data from the Connect Study especially in patients with complete methylation, who accounted for approximately 80% of the patients, is one of the strongest efficacy data sets generated in patients with fragile X syndrome. We saw over 50% of patients demonstrating clinically meaningful improvements in social avoidance, the primary endpoint, and irritability disruptive behaviors, other core symptoms in patients with fragile X. The RECONNECT study essentially seeks to replicate the statistically significant efficacy signals observed in patients with complete methylation in the CONNECT study with several enhancements to further bolster the probability of success. We have completed enrollment and we are on track to the top line data later this quarter. If positive, the ReConnect study is expected to support regulatory approvals in both the U.S. and EU, and Harmony holds global rights. Z1-002 has the potential to be the first and only approved treatment for any symptom domains in patients living with Frazelex. Moving on to the scientific rationale for Z1-002 in this condition, Fraselleck syndrome is a rare genetic disorder caused by the mutation of FMR1 gene on the X chromosome and it is the most common non-inherited cause of intellectual impairment and autism spectrum disorders. Fraselleck syndrome is characterized by FMR protein deficiency resulting in endocannabinoid dysfunction. ZYN002 interacts with the CB1 receptors, modulates the system, and restores the endocannabinoid homeostasis, thereby improving the neurobehavioral symptoms. With ZYN002, we also remain on schedule to initiate a Phase III registration trial in 22q deletion syndrome later this year, pending the results from the Fragile X program. This rare disorder, with significant neurobehavioral symptoms similar to Frazalax, has no approved therapies and also affects approximately 80,000 individuals each in the U.S. and Europe. Moving on to our sleep-wake franchise, we have made significant progress across our next-generation pitolosan programs. The Pitocin-HD program, a higher dose Pitocin formulation with an optimized PK profile targeting enhanced efficacy for excessive daytime sleepiness and pursuing a differentiated label with an indication for fatigue in narcolepsy is on track for the Phase III initiation in Q4 2025. The Phase III study with Pitocin HD in patients with idiopathic hypersomnia is also pursuing a differentiated label with an indication for sleep inertia and is also on track for initiation in Q4 2025. The target PDUFA dates for both programs are in 2028. Over to the Pitolacin-GR formulation, it is designed to address the potential for treatment-related GI side effects, especially since almost 90% of patients with narcolepsy experience GI symptoms. In addition, it also provides an ability to start at the therapeutic dose range, eliminating titration. This is a fast-market strategy. We are demonstrating bioequivalence to VAKIX formulation. The top-line data from the Pivotal BE study is expected in Q4 with a potential PDUFA in 2026. Utility patents have been filed for both Petrolocent GR and Petrolocent HD with potential exclusivity to 2044, securing long-term franchise value. Beyond Petrolocent, our sleep-wake portfolio continues to advance with BP 1.15205, a highly potent RXN2 receptor agonist demonstrating best-in-class potential in preclinical studies. At the recent sleep meeting, we presented a comprehensive preclinical safety and efficacy data that demonstrated efficacy at very low doses across all parameters of interest in a standard transgenic mouse model. The program remains on schedule for IMPD submission and first-in-human studies later this year, and we anticipate sharing clinical data in 2026. In our epilepsy franchise, we continue to actively enroll patients in two global Phase III registration trials with EPX100, the AURGUS study in Dravet syndrome and the Lighthouse study in Lennox-Gastaut syndrome. In conclusion, our late-stage rare neurology portfolio is advancing with exceptional momentum, positioning us to potentially introduce multiple new products or indications every year over the next several years. Beyond the clinical and regulatory milestones, what truly drives us is the opportunity to transform care for hundreds many of whom currently have either no treatment options or therapies with suboptimal efficacy and or significant safety tolerability limitations. As always, on behalf of Harmony, I would like to thank all the patients and their families who are participating in our clinical trials, as well as the clinical investigators and site personnel for all their efforts and commitment in helping us to advance our development programs. I'll now turn the call over to our CFO, Sandeep Kapadia, for an update on our financial performance. Sandeep?

Thank you, Kumar, and good morning, everyone. This morning, we issued our second quarter 2025 earnings release and filed our 10Q, where you'll find the details of our financial and operating results. We had a great first half of the year. We delivered another quarter of solid financial performance with continued double-digit top-line growth sustained profitability, and robust cash generation. Our financial performance and profile positions us well to continue advancing our growth strategy for the remainder of the year and beyond. For the second quarter of 2025, we reported net revenues of $200.5 million compared to $172.8 million in the prior year quarter, representing a growth of 16%. Performance in the quarter reflects the strong underlying demand for WCAGs offset by a reduction in trade inventories of a few days as we head into the summer months. We've recorded total operating expenses for the second quarter of $114.2 million compared to $119.3 million for the same quarter in 2024. The expenses during the second quarter of 2025 include investments in advancing our late-stage pipeline and the commercialization of wake eggs and narcolepsy. We also recognize a $15 million IPRMD charge related to the CERC research collaboration, which Jeff mentioned. We have an option to acquire an exclusive license for each program. The agreement includes customary milestones and royalties based on continued development and potential commercialization. We continue to show solid net income and margin. Non-GAAP adjusted net income for the second quarter of 2025 was $53.8 million, or $0.92 per diluted share, compared to $24.5 million, or $0.43 per diluted share, in the prior year quarter. We believe non-GAAP adjusted net income better reflects the underlying business performance. Please see our press release for a reconciliation of GAAP to non-GAAP results. Harmony ended the second quarter with $672 million in cash equivalents and investments on the balance sheet. The balance reflects strong cash generation from operation of approximately $79 million during the second quarter. Our cash position provides us the financial flexibility to execute on business development, as well as continue investments in our growing pipeline. Looking ahead to the balance of 2025, our strong first half results gives us increasing confidence in our full year outlook. We are reiterating our revenue guidance of $820 to $860 million, highlighting our progress towards a $1 billion-plus opportunity with WACICS and narcolepsy alone. We expect continued quarter-over-quarter net revenue growth the balance of the year. With respect to expenses, We expect continued investment in R&D as we advance our late-stage pipeline with multiple programs in Phase III registrational trials. As previously noted, we expect to potentially incur $29 million in R&D milestones payments in 2025, including milestones for the completion of the Phase III trial for CYN002 and Fragile X syndrome, $15 million, on track for Q3, along with a potential milestone of $10 million for positive top-line data from this trial. In addition, we expect a milestone of approximately $4 million in Q4 related to the initiation of phase one trial in our EREXN2 program. In summary, we're having a very successful first half of the year and have confidence in the continued growth of WCAGS along with the advancement of our late-stage pipeline in the second half. And with that, I'd like to turn the call back over to Jeff for his closing remarks. Jeff? Thank you, Sandeep.

My thanks to everyone for joining our call today and for your interest in Harmony Biosciences. At this juncture of our company's journey, I have never been more proud of the Harmony team or more excited about what lies ahead. The reasons for my excitement are many, but to highlight a few. WACIX is on its way to a $1 billion plus opportunity in narcolepsy alone. Our robust, catalyst-rich, late-stage pipeline is poised to deliver one or more new product or indication launches every year over the next several years with peak sales potential of $3 to $6 billion in total. And we have a high degree of conviction and are very excited about our next major clinical catalyst coming later this quarter, the top-line data readout from our Phase III trial of ZYN002 in Fragile X syndrome. If positive, this could represent a transformational moment for both the Fragile X community and for Harmony Biosciences. We have built something rare in our industry, a profitable, self-funding biotech company with an innovative late-stage pipeline poised to deliver meaningful value for both patients and shareholders alike. Because of this unique profile, we continue to execute from a position of strength. And that is what makes Harmony one of the most compelling growth stories in biotech today. Thanks, everyone. And I will now turn the call back over to the operator for Q&A. Operator?

Thank you. And at this time, if you would like to ask a question, please press star 1 on your telephone keypad. If you wish to remove yourself from the queue, you may do so by pressing star 2. We remind you to please pick up your handset and please limit yourself to one question and one follow-up question. We will take our first question from Jay Olson with Oppenheimer. Please go ahead.

Oh, hey, congrats on all the progress. I wanted to focus on the ReConnect top line data readout, which I think you mentioned is still on track for this quarter. Could you please provide any additional color on the timing of when to expect that readout? It sounds like maybe it could be after Labor Day. And then just in terms of framing the expectations, can you just describe what would be clinically meaningful and what is your target for a successful outcome in this registrational FRAGILE-X study? And finally, if you could just remind us the evidence that supports your confidence in ZYN002 achieving your target profile.

Thank you. Yeah, good morning, Jay. Thank you for your questions, and thanks for your coverage to Harmony. Welcome, you know, appreciate your initiation of coverage. I will walk and address, you know, your questions about the ReConnect study. and the opportunity in Fragile X syndrome.

Thank you, Jeff. Good morning, Jay. Thanks for the question. Yes, we are on track for top line data in Q3, and we are very excited about this opportunity, not just because it's a major milestone for Harmony, but for patients with Fragile X syndrome and their caregivers in general. Regarding the level of confidence, We have a high level of confidence and conviction in the phase 3 reconnect study because we are essentially trying to replicate the statistically significant findings that we saw in the large phase 2, 3 connect study on the primary endpoint of social avoidance in patients with complete methylation. In terms of how we will define success, Successful outcome will be defined by demonstrating a statistically significant outcome in the primary endpoint with the social avoidance in patients with complete methylation, and the study is more than adequately powered to detect that difference. positive, we have an opportunity here to bring the first and only approved treatment for any symptom domains in patients with Fraser-Lick syndrome, and that's what we're really excited about.

Super helpful. Thanks for taking the question. Thank you, Jay.

Thank you. And our next question comes from David Wong with Deutsche Bank. Please go ahead.

Hi there. Good morning. Congrats on the progress, and thanks for taking my questions. So first, I also wanted to ask on Fragile X, in terms of, I guess, the top line readout, could you just Outline for us the types of data you expect to disclose in the top line. And at that time, would we have visibility on the result in the fully methylated versus partially methylated patients? And when might we know, I guess, how you plan to approach your filing strategy with the FDA if you would be pursuing fully methylated or all comers? And then just quickly on Wakeix, as we are now in the back half of the year, I was wondering if you could just talk a little bit about the pushes and pulls that get you to the upper versus the lower end of the guidance range. Thanks a lot.

Yeah, good morning, David. Yeah, obviously I'll ask Kumar to comment further on, you know, the strategy for Fragile X and the ZYN readout, and Adam can address the question about Wakeix. Kumar? Yeah.

Hey, good morning, David. Thanks for the question. So, in terms of what we disclose at the top line data for Frasier-Lex Syndrome, it will be a standard top line data readout, which is the demographics data, safety and tolerability data, the efficacy on the primary endpoint, and the key secondary endpoints. In terms of how we will proceed next, look, if the study shows statistical significant outcome on the primary endpoint, we will move rapidly to have a pre-NDA meeting and submit an NDA. In an indication like Frazer-Lexintern, where there are no approved treatment, I think it's fair to expect a priority review. And if everything goes according to plan, hopefully we will have an approved product by the end of next year. Thanks, Kumar.

Adam?

Yes, thanks for the question on WACICS. We're really pleased with the performance that we're seeing on WACICS at this stage. We're now in our sixth year on the market. We achieved $200.5 million in net revenue for the second quarter. That's a 16% year-over-year increase in year six, which is fantastic. We also achieved 7,600 average patients in the quarter. That's an increase of 400 average patients in Q2, and that is among the highest increases we have seen in any quarter since launch, so the performance steady drumbeat continues. In terms of puts and takes, you know, I would say that WCAGS is a highly differentiated product, first and only non-scheduled treatment option for patients. We're supported by broad payer coverage with 80% of lives covered, and that's been the case for years. We don't expect any changes in payer coverage. We have a very experienced team. Many of our team members actually started at the launch of WCAGS. And we have a unique commercial model that provides really high levels of service to HCPs, office staff, as well as patients. And I would highlight that in terms of HCP prescribers, we continue to see increased preference share in the 4,000 OxyBait REMs enrolled clinicians, and we see increased preference share and the addition of new prescribers in the 5,000 non-Oxibate REMS-enrolled HCP group as well. So those are probably the key drivers of that continued performance. Sandeep, I don't know if you want to add anything.

No, I think, as you said, really a strong start to the year and really gives us increased confidence, certainly in our guidance range. Look, we're very comfortable where things are right now. It's really, at the end of the day, it's the underlying demand that really drives overall net sales. As you know, in terms of the pushes and pulls, it's the typical factors that will typically impact where we end up in the range. Everything from obviously this continued net patient ads you know, certainly have an impact, any potential growth in that impact, as well as trade inventory impacts as well. You know, as you know, we have a fairly concentrated customer base overall, so just order patterns overall. However, look, we're very confident in the guidance range. You know, consensus currently falls right within the range, and that seems a very reasonable place.

Thanks, David.

Thank you. And our next question comes from Ash Verma with UBS. Please go ahead.

Hi. Thanks for taking that question. So I just wanted to ask on Fragile X, I want to understand the implications of full methylation. So does choosing full methylation versus partial means a haircut to the patient population? Just if you can give us a sense of, like, What is the full methylation Fragile X patients in the US versus the 80,000 that you mentioned? And then secondly, can you talk about any kind of regulatory or clinical trial conduct analogs here? So has FDA accepted applications for these type of rare pediatric conditions with the data showing efficacy only in a fully turned off gene? Thanks.

OK. Good morning, Ash. Thank you for the question. So in terms of the split between complete methylation versus partial methylation, approximately 60 to 70% of patients with Fragile X syndrome have complete methylation and the rest have partial methylation. So in terms of us choosing the complete methylation as the target population, this was a data-driven approach based on the findings that we saw in the CONNECT study. And this fits into the etiology, the pathophysiology of Frazer-Lick syndrome that we know about. Basically, what happens in patients with complete methylation is they have more than 200 trinucleotide repeats of CGG, which results in almost complete silencing of the gene, which means that they are hardly able to produce any FMR protein, which causes significant dysfunction of the endocannabinoid system. And 01002 interacts with CB1 receptors, resets the endocannabinoid system, so these patients have a higher burden of symptoms. The mechanism of action fits nicely well in treating the symptoms in these patients. In terms of the FDA, yes, we actually have had extensive discussions with the FDA, and we have full alignment with the FDA on the study design. the target patient population, the primary endpoint. In fact, the study is designed not just to meet the requirements of FDA, but EMA as well. So should the study be positive, we will be pursuing an indication both in the US and in Europe.

Yeah, Ash, I would just add that I think, you know, this strategy sort of follows, you know, the science as well as the data. And the Phase 3 ReConnect trial is designed to replicate the positive findings in the Phase 2-3 ReConnect study in patients with complete methylation. And then in addition, obviously with no approved therapies with regard to where the bar would be set with a high unmet need in this patient population. Thank you. Thanks, Ash.

Thank you. And our next question comes from Greg Suvanovich with Mizuho. Please go ahead.

Thank you. Good morning. Thanks for taking my question. I was curious about your new CERC collaboration. I was just wondering, can you walk us through the thoughts, especially from a BD and corporate strategy perspective, the cell therapy approaches? interesting uh for sure but i don't think it's been a proven area and so just wanted to get your thoughts just on the collaboration but also maybe a future bd direction thank you

Yeah, sure, Greg. Good morning. Thanks for your question. Yeah, I think in terms of this CERT collaboration, you know, we see it as an exciting opportunity, obviously a very early sort of discovery phase opportunity, but one that, you know, reflects our overall commitment to patients, you know, with serious, you know, rare neurologic disorders, you know, in an advanced stage. It's strategically aligned, you know, with our pipeline of, and potential cellular therapies for refractory epilepsy in one of the discovery programs and the other treatment-resistant narcolepsy based on sort of reprogramming the cellular platform. So again, while it's still early, we see this as potentially resulting in kind of the next generation of innovative disease-modifying therapies for patients with advanced neurologic disorders. With that, Kumar can comment a little further on the platform and what we saw in the opportunity.

Hey, good morning, Greg. Thanks for the question. Look, with the CERC, what really attracted and really fascinated us was the novel cellular reprogramming platform that CERC utilizes. that offers significant competitive and manufacturing advantages compared to embryonic or induced pluripotent stem cells. It overcomes many challenges, like, say, for example, the consistency and the reliability of readily sourced GMP-grade cell lines, because these are fibroblast-derived cells that are induced to transform into progenitor cells of interest based on our small molecule epigenetic modifiers and growth factors. And also, this particular platform could potentially enable allogenic cryopreserved, ready-to-use therapies that require no manipulation at the point of care. And obviously, because we are not using the stem cells, there is less risk of tumorigenicity and manufacturing inefficiencies that are seen with the stem cells. So we are very excited about the collaboration, both in epilepsy and in narcolepsy, and look forward to data generation from CERC, and we will provide more information as we make progress.

Yeah, and Greg, I would add, I think, you know, we see this as a kind of an opportunistic play, if you will, again, you know, very early discovery phase. strategically aligned. With regards to our other BD efforts, as you asked, obviously our strategy is to continue to grow and build out our pipeline and with a very strong balance sheet. We see in terms of we're always looking for opportunities to deploy you know, our cash and drive value for shareholders. We continue to actively evaluate different opportunities across the spectrum, you know, development phase from early to late, potentially on-market opportunities. Obviously, we're in a good position to execute on our growth strategy. As always, you know, we take a disciplined approach, thoughtful, strategic to how we have built out the pipeline thus far. and some of the opportunities we see ahead. We feel that we're just getting started with regards to some of the opportunities ahead of us. Sandeep, any further comments on the capacity?

Yeah, look, I mean, this quarter was a really strong quarter in terms of cash generation. We generated from operations $79 million, closing the quarter with over $670 million in cash. So I think We're in a highly strong position to be able to transact. I mean, look, we continue to look for opportunities, as you mentioned, Jeff, across the spectrum overall. We'll continue to be disciplined in terms of how we deploy our capital, but our filters continue to be the same. So I think it's hard to predict timing at the end of the day on these types of things, but I think we're really continuing to be in a strong position. We have a very unique profile as a company, highly profitable. generating positive cash flow and the ability to deploy it in a market that is an attractive market at this point. Thanks, Sandeep.

Thank you. And our next question comes from David Amsalem with Piper Sandler. Please go ahead.

Thanks. I have some questions on the orexin. And sorry if I missed this, but With the data that you're anticipating next year, is that in healthy, sleep-deprived volunteers, or is that going to be an actual narcolepsy patient? So just help us understand what to expect for next year and to the extent you're not yet testing narcolepsy in IH patients, when do you expect to do so? That's number one. And then number two, in terms of differentiation, I know you've talked about it as potentially being best in class, but we've got a number of more advanced orexins that has shown MWT improvements well north of 20 minutes, and we've seen real validation here. So what do you need to see in order to legitimately make that claim that your orexin is indeed best in class. Thanks.

Good morning, David. Thanks for your question. Kumar, our position on the orexin programs?

Yeah. Thank you, Jeff. Good morning, David. Thank you for the question. Regarding our Oryxin program, yes, David, actually you did not miss anything because we have not talked about how we are going to approach and the first in human studies. We are on track for INPD submission and come in first in human studies later this year. The way we are approaching this is start with the single ascending dose study in healthy volunteers and in parallel also conduct Healthy Volunteer Sleep Deprivation Study because, as you know, BP1.15205 is the most potent RxN receptor agonist that is out there based on the data that is disclosed in the public domain. And we do want to get a better idea in terms of the dose range before we progress this into patients. What you can expect next year is data from healthy volunteers from single ascending dose study and healthy volunteers sleep deprivation study as well. How we are going to proceed after that is something that we are still thinking through, depending on what we are learning from others as well in this field. In terms of how do we differentiate, David, I think it's too early to comment based we showed that potency is important and potency translated to efficacy at very low doses. In fact, at 0.03 mcg per kg in narcolepsy mice model, we showed statistically significant difference in wakefulness time, the lowest dose that is ever studied in this particular model. We anticipate the high potency, and therefore low dose gives us the flexibility, the dosing flexibility to target all three central disorders of hypersomnolence, not just NT1, but also NT2 and idiopathic hypersomnia without having the safety or tolerability concerns. So this is our strategy right now.

Thank you. Thanks, David.

Thank you. And our next question comes from Danielle Brill with Truist. Please go ahead. Hi, guys. Good morning.

Thanks so much for the questions. As a follow-up to the prior question, I wanted to ask, in general, how we should think about the potential impact of Takeda's orexin-2 entering the market and how confident you are that the Wake expansion can continue to grow with orexin-2s in the market. And then just on the quarter, I wanted to clarify – It looks like the quarter-over-quarter growth was lower than what you typically observed in the past, despite the high number of new patient ads in the quarter. Was this just an inventory drawdown, or can you speak to the dynamics that were at play here, such as growth to net compliance and any other factors? Thank you.

Good morning, Danielle. Thanks for your questions. In terms of... you know, the impact of orexins, how we see, you know, as we follow these programs closely. I'll ask, you know, Adam, in regards to we still continue to see this market as a polypharmacy market, you know, with multiple mechanisms and how you're seeing that from a commercial perspective going forward.

Yeah, thanks, Jeff, and thank you for the question. You know, we're excited about orexins as a potential new treatment option for patients, and as Kumar mentioned, we're very confident in the molecule that we have in our pipeline. You know, there's still some questions to be addressed as a class, I think. Dosing, label, long-term safety and tolerability, not to mention pricing and access. You know, with WAKIX, this is the only non-scheduled treatment option. It's been on the market for now more than six years. Really steady performance quarter over quarter over that period, and that's despite new brand and generic entrants coming in. I think that's because physicians see WAKIX as highly differentiated. They perceive it to be well-tolerated and has broad clinical utility. And we expect that to continue. At the time of orexin's launch, HCPs will have more than eight years of clinical experience. It's a very familiar therapeutic option. And with the, Jeff mentioned them, with the polypharmacy approach to treatment, we expect WAKIX will continue to be added to therapy for patients broadly. Not to mention that there's evidence to suggest that orexin and histamine actually have a synergistic effect. We're very confident in the continued growth and performance of Wikix.

Thanks, Adam. With regards to the Porter's performance, Sandeep, a few comments on that?

Sure. I'm happy to comment on that. You know, I think, as I mentioned, generally, look, our results so far, you know, gives us increased confidence in the revenue guide of 820 to 860. You know, the fundamentals are strong. You know, we had strong growth even in the quarter of 16% versus prior year. And, you know, in fact, I mean, in Q2, getting to your point, it's really underlying performance is probably even stronger than I would say the net revenues would indicate. And as I mentioned in my Q1 call, you know, we did anticipate and we did see trade inventory draw down approximately a few days. As we head into the summer month, typically what happens with trade inventory, as you know, Q4, Q1 tends to be a little bit higher. Q2, Q3 tends to be a bit lower generally. But I think the more important point is really looking at the fundamentals of our business and the forward demand of one of the strongest quarters we've had in terms of net patient ads and Generally, again, it gives us really strong confidence in the balance of the year, and we expect very strong quarter-over-quarter growth for the next two quarters to finish out the year.

Yeah, so I think just to reiterate, I think underlying business fundamentals remain strong. I think some variability in inventory from quarter to quarter, as Sandeep alluded to. Obviously, as the base of patients increases, And then also, you know, with only three, you know, specialty pharmacies in terms of the ordering pattern. So I think a couple days of inventory, you know, with regards to that fluctuation. But overall, we are confident in reaffirming guidance for the year. We're comfortable with the three kind of estimates of where we are. This business continues to grow and excited, you know, as our pipeline advances and the opportunities ahead.

Very helpful. Thank you so much.

Thanks, Danielle.

Thank you. And our next question comes from Corinne Johnson with Goldman Sachs. Please go ahead.

Good morning. This is Eric on for occurring Johnson. I just wanted to ask a question elaborating on the last little bit. Specifically, how should we think about net price for wake X this quarter and specifically moving towards the back half of 2025 and beyond? And to what extent are you using price as a lever to improve volume or drive broader adoption? Thanks.

Thanks for your question.

Sundeep?

Yeah, I think in terms of net price evolution, it would be very similar to what we've seen in past years. Typically, the first quarter is the lowest, just as we have higher growths in net deductions. Typically, that happens with the insurance bonds reset and typically improves in the balance of the year. So we did see some improvement as we went into Q2, but, you know, obviously... As we go into the further quarters, we'll continue to see improvement that will help realize, you know, a good portion of the price increase that we took earlier this year.

Thanks, Wendy. Thank you. And our next question comes from Pete Stavropoulos with Cancer Fitzgerald. Please go ahead.

Thank you for taking my questions, and congrats on the quarter. I get two questions. The primary endpoint for ReConnect, the social avoidance, a domain for the ABC checklist for Fragile X, you know, it's an observer, service scale, either, you know, parents or caregivers score. Can you just talk about this outcome, potential variability, the expected placebo response, and what measures you've taken to mitigate the placebo response? And are there any other major differences between Connect and Reconnect? And the second question is for Adam. You know, you joined Harmony over 1.5 quarters ago. I'm curious to hear your views on, you know, what levers, you know, you may be able to pull to accelerate growth and build all, you know, what is already a successful franchise and also plans for lifecycle management. Thank you.

Yeah, Pete, thanks for your questions. Thanks for taking coverage on Harmony. Appreciate that. Kumar?

Yeah. Good morning, Pete. Thanks for the question. Regarding the social avoidance subscale within the broader aberrant behavior checklist, you're absolutely right. This is an observer scale. As you know, ABC has been used extensively, a very well-validated scale. We have a lot of experience with this particular scale. In terms of variability and placebo, great question. Look, in any neuropsych trial, these are some things that we carefully watch for. In this particular study, we have multiple checks and balances to manage, including rigorous inclusion-exclusion criteria. These are the patients biologically identified based on full mutation, complete methylation, with significant level of symptoms. We know the standard deviation. And we are obviously monitoring in the blinded data that we have. And thus far, where we are, we feel good about it. In terms of difference between CONNECT and RECONNECT study, the primary endpoint is still the same, which is social avoidance subscale within the broader ABC scale. The target population is patients with complete methylation only. And we made some other enhancements, like, for example, we increased the duration of treatment by four weeks. We increased the dose in patients who weigh more than 50 kilograms. This was done based on the learning from the CONNECT study to enhance the probability of success. As I mentioned earlier, a high level of confidence and conviction in this program, and really the opportunity that's in front of us. If the study is positive, we have an opportunity to bring the first and only treatment for patients with prostate syndrome.

Yeah. Thanks, Kumar. Adam, your thoughts on levers for growth in the WACUS business?

Yeah, thanks for the question, Pete. And actually, levers of opportunity is a term that we talk about quite frequently at Harmony. And it's a big focus. And I have to give credit to the team. The team here really does have a history of growth mindset, looking for continued improvement opportunities. What we've been discussing is how can we continue to improve our top-line demand, growth? So average referrals per day, and then conversion of those referrals into dispensing events. So how can we make sure that our process is efficient and effective for patients to secure a dispense? And then retention over time. How can we provide the service that supports HCPs, the office staff, and the patient to ensure that they maintain or remain on therapy over time. So we've identified levers that we're going after. The work has started, and I'm confident that the work of the team is going to continue to help drive that performance.

Great. Thanks, Adam. Thank you very much for taking my questions, and congrats again. Thanks.

Thank you. And our next question comes from Patrick Truccio. With HC Wayne White, please go ahead.

Hi, good morning. Just a couple of follow-up questions from us in the pipeline. The first is on Pitolis and HD. I'm just wondering with the expectation to initiate phase three trials in the fourth quarter, can you talk to potential trial design or differentiation goals with this program? And then separately regarding Fragile X, assuming a positive ReConnect readout, how are you thinking about the commercial build for ZYN002? Specifically, I'm wondering if you can discuss more about the engagement. with kol's advocacy groups and payers and what does this suggest about market receptivity and launch planning and you know based on that engagement would you anticipate a more gradual builder could you see you know very rapid uptake if it's approved thank you patrick um kumar on the tulsa hd

Hey, good morning, Patrick. On Pitocin-HD, we are on track to initiate two phase three studies, one in narcolepsy and one in idiopathic hyposomnia in the fourth quarter of this year. At this stage, what I can say, Patrick, is that it's going to be a standard randomized double-blind placebo-controlled parallel arm study. We are going to provide more information on the endpoint the recruitment rate, and all of the other things as we approach the study initiation.

Yeah, so I would say, you know, standard trial design and then also in addition, you know, looking at sort of novel endpoints, fatigue and narcolepsy, sleep inertia and IH to pursue a differentiated label in that regard. With regards to opportunities for ZYM002 go to market, a lot of work has started. Adam, a few thoughts on that?

Yeah, and actually, thanks for the question, and I'll just go straight to the community, and I think you mentioned receptiveness to new therapies. I mean, this is a very close-knit and tight community. You know, typically what you see in rare disease, but especially so here because these are kids that are suffering from a range of symptoms across several domains, physical manifestations, cognitive impairment, as well as behavioral symptoms. They're very well aware of any treatment that's being developed that could potentially benefit their kids. And so we would expect very high awareness and high receptivity when we come to market. In terms of go-to-market model, yes, as Jeff said, our plans are underway. We're continuing to have discussions across the community with different stakeholders and really ensure that we are prepared for a success.

Yeah, and I would just add, you know, I think, you know, this is what we do at Harmony, engaging with rare disease communities. We really have a I think, a best-in-class, a world-class patient advocacy team and a cross-functional team, you know, kind of working on, you know, our go-to-market strategy in that opportunity. So thanks.

Great.

Thanks so much.

Thank you. And we will take our next question from Jason Gerberry with Bank of America. Please go ahead.

Hey, guys. This is Bhavan Patel. I'm for Jason Gerberry. A couple questions from us focused on Zygel for Fragile X syndrome. First, based on prior Connect data, how are you modeling patient adherence to therapy if the drug replicates the subgroup data with FMR1 gene methylation? And specifically, what percent of patients do you expect to stay on drug given response rates versus what percent of patients might be expected to discontinue due to lack of response? And then my second question is, beyond achieving statistical significance on the social avoidance primary endpoint, what specific results from the key secondary endpoints like the irritability subscale or the caregiver global impression would give you the highest conviction in the data package for filing? Thank you.

Yeah. Hey, good morning. Thank you for those questions. All right, there was several questions in there. Probably I'll start with the last one in terms of beyond social avoidance, what else we anticipate or what else we are monitoring. As we have disclosed, we are looking at several other behavioral symptoms. Obviously, social avoidance is the primary endpoint, but we are also looking at irritability behaviors. Another core symptom in patients with Crosse-Leck syndrome And we saw pretty good response on this domain of symptoms from the CONNECT study. And in fact, we recently presented data on irritability at the American Association of Neurology meeting in April this year, which was a podium presentation where patients exposed to three years for Z1002 showed sustained and clinically meaningful response in irritability domain. In terms of the safety, tolerability, discontinuation, and persistence on treatment, the Z1-002 product has very unique attributes, and we have discussed this in many forums in the past. The adherence rate is very high. And in fact, over 90% of the patients who completed the randomized double-blind study in the ReConnect study and also in the Connect study elected to participate in the long-term extension study. And in those patients, we have data lasting for more than eight years still continuing to use Z1002. gaining efficacy, good benefit, with acceptable safety and tolerability profile. Yeah. I don't think I understood your very first question on the modeling between connect and reconnect.

Just asking about adherence rates and discontinuation rates. What is expected based on the prior Connect data?

Sorry, I don't think I still understood that question. Apologies.

Like what percent of patients might be expected to discontinue the drug versus remain on the drug based on response rates that you saw in the prior published Connect data?

Oh, okay, okay, got it. Sorry, I don't have that data off the top of my head, but I can certainly provide you that data. Sorry about that. Thank you. Yeah, no worries.

Yeah, and I just think overall very, you know, very well tolerated. Again, this is an innovative product, a little different than, you know, the oral cannabidiol that's, you know, that's sort of in the market for other indications as a transdermal gel in terms of the GI side effects and others. I think, you know, overall well tolerated. And Kumar will get back, you know, with that information. Next question.

Thank you. And our next question comes from Amy Fadia with Needham. Please go ahead.

Hi, good morning. Thanks for taking my question. Maybe two follow-ups on prior comments. Firstly, with regards to the ReConnect study, if, Kumar, you could sort of remind us what was the placebo response in the Connect study and what assumption you've made for the ReConnect study. And you mentioned that there's a standard deviation that you're sort of watching for within which, as long as the response stays, you feel good about it, if you could sort of elaborate what that range is. And then with regards to the orexin space and the potential implication on WAKIX, we've heard from physicians that with the orexins bringing patients to normalized levels, it might actually allow patients to move from polypharmacy to monotherapy in that context and maybe increasing peer scrutiny on just cost of medicines. Have you thought about potentially looking at some sort of a prospective study evaluating the complementary mechanisms between erections and vacuums? Thank you.

Yes. Ami, good morning. Thanks for your questions. Kumar, in terms of the CONNECT study and the findings,

Yeah, Ami, great questions. Good morning. Thank you. So in terms of the placebo response for the CONNECT study, the data is published by Barry Kravitz et al. in the Journal of Neurodevelopmental Disorders. Happy to share that paper. What we saw, the placebo response in the overall patient population was around 2.29 points. on the placebo arm. And in patients with greater than 90% methylation, we saw a lower placebo response, around 1.99. And similarly, we saw also an increase in the magnitude of efficacy in patients with complete methylation. This again goes to the earlier point that I was making. In patients with complete methylation, they have a higher burden of symptoms. The mechanism of action of Z1-002 fits very well interaction with the endocannabinoid system and the greater magnitude of response. In terms of your question about the orexin and wake eggs prospective study, there is some early preclinical data to show synergistic effect between orexin and orexin receptor agonist and H3 inverse agonist. We haven't shared that information. And just one final point I wanted to make is the study is over 90% powered. to detect a one-point placebo-adjusted difference between the active and the placebo arms.

So, Ami, I think in terms of your question about the orexin landscape, obviously we're following the programs closely. and, you know, looking at, you know, ultimately its overall kind of risk-benefit and, you know, I think durability of response and understanding, obviously, orexins working through, you know, kind of wakefulness and, you know, and how the mechanism of action of wakex, you know, working through histamine. We have contemplated, you know, the opportunity of a synergistic mechanism and the opportunity of of concomitant, even a combination type of approach further down in our pipeline. And that is something that we have contemplated to possibly address the opportunity of lower doses of orexin agonist supported by the tolicent working through a synergistic mechanism. In the meantime, you know, we focus on advancing the next-gen, you know, Ptolemy products and, you know, continuing to grow the WCAG space business.

Thank you.

Thanks, Ami.

Thank you. And I'm showing no further questions. I would now like to turn the call back for any closing remarks.

Thank you, Madison. And thanks, everyone, for joining our call this morning and for your interest in Harmony Biosciences. Have a great rest of your day.

This does conclude today's Harmony Biosciences second quarter 2025 financial results conference call. You may now disconnect.