Harmony Biosciences (HRMY 4.62%)Q4 2024 Earnings CallFeb 25, 2025, 8:30 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Please stand by. We're about to begin. Good morning, everyone. My name is Bo, and I will be your conference operator today.

At this time, I would like to welcome everyone to Harmony Biosciences fourth quarter and full-year 2024 financial results conference call. All participant lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. [Operator instructions] Please be advised that today's conference is being recorded.

[Operator instructions] I will now turn turn the call over to Mr. Brennan Doyle, head of investor relations. Please go ahead, sir.

Brennan Doyle -- Head of Investor Relations

Thank you, operator. Good morning, everyone, and thank you for joining us today as we review Harmony Biosciences' fourth quarter and full-year 2024 financial results and provide a business update. Before we start, I encourage everyone to go to the Investors section of our website to find the materials that accompany our discussion today, including a reconciliation of our GAAP to non-GAAP financial measures. At this stage of our lifecycle, we believe non GAAP financial results better represent the underlying business performance.

Our speakers on today's call are Dr. Jeffrey Dayno, president and CEO; Jeffrey Dierks, chief commercial officer; Dr. Kumar Budur, chief medical and scientific officer; and Sandip 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 Dayno. Jeff?

Jeff Dayno -- President and Chief Executive Officer

Thank you, Brennan. Good morning, everyone, and thank you for joining our call today. 2024 was a year of strong execution and meaningful progress for Harmony Biosciences. We continue to strengthen our leadership position in Sleep/Wake, while advancing and expanding one of the most robust late-stage CNS pipelines in the industry.

Beginning at our Investor Day last October, we outlined a clear path toward becoming the leading CNS company focused on developing and delivering innovative treatments for patients with unmet medical needs. That path includes advancing our late-stage pipeline to deliver one or more new product or indication launches each year over the coming years. We remain committed to delivering on our promise to patients while generating long-term durable value creation for shareholders. In fact, our current pipeline, if successful, is poised to deliver over $3 billion in net revenue going forward.

2024 was also a year of exceptional growth in both our commercial business and in our pipeline through strategic acquisitions. Our net product revenues in 2024 were $714.7 million, representing 23% growth year over year. In Q4 alone, we generated $201.3 million in net revenue. This momentum is reflective of the continued durable growth of Wakix in narcolepsy based on its broad clinical utility and differentiated profile as the first and only FDA approved once daily non-scheduled treatment for narcolepsy and our proven commercial execution.

We remain confident in Wakix being $1 billion-plus opportunity in narcolepsy alone, and we are on our way to achieving that milestone well before Wakix LOE in 2030. On that topic, today we are also announcing our first generic settlement agreement with Novogen Pharma, resolving the patent infringement litigation related to Novogen's abbreviated new drug application for a generic version of pitolisant hydrochloride. As part of the agreement, Novogen will have a license to sell its generic product beginning January 2030 or earlier under certain circumstances. In addition, we are on track in pursuit of obtaining pediatric exclusivity for pitolisant, which if granted, would add an additional six months of regulatory exclusivity.

This settlement reinforces the strength and durability of Harmony's intellectual property portfolio. As you can see, we remain committed to vigorously defending our intellectual property estate. Commercial engine has allowed us to finance our growing pipeline from our balance sheet as a profitable self-funding biotech company. Harmony was founded on our leadership in Sleep/Wake, and our pipeline is now made up of three orphan rare neurology franchises, each with potential peak sales opportunities of $1 billion to $2 billion each.

Before turning to the opportunities ahead of us in 2025, I want to address the recent update on our supplemental new drug application for pitolisant in idiopathic hypersomnia or IH. While we recognized the challenges with this submission, given that the phase 3 INTUNE study did not meet the primary endpoint during the four-week randomized withdrawal phase, we made the decision to submit the sNDA for pitolisant in IH based on the following three factors. First, the overall benefit risk profile of pitolisant in IH based on the totality of the data, second, the unmet medical need in IH based on limited treatment options, and third, our deep commitment to the IH patient community. In fact, the Hypersomnia Foundation and more than 650 members of the IH community signed a petition to the FDA requesting a review of the pitolisant sNDA file for IH, citing the burden of disease and significant lack of treatment options, especially ones that are non-scheduled.

While this outcome is not what we had hoped for, it is only a short term setback that in no way affects the progress we are making toward our strategic priorities. In fact, 2025 is shaping up to be a transformational year for Harmony. This is a pivotal moment in our growth story, one where we are advancing important late-stage programs, poised to deliver key clinical milestones, and reinforce our leadership in Sleep/Wake and rare CNS disorders. Our long-term vision has always been to extend our leadership in sleep wake through the development of pitolisant high dose or pitolisant HD and enhanced higher dose formulation of pitolisant designed to deliver an optimized PK profile and therapeutic benefits.

Kumar will share more about our development plans for our next-generation pitolisant formulations. But what I want you to take away is that this program is the result of patient-focused drug development. These formulations are designed to build on the innovation of pitolisant as a first-in-class molecule with a novel mechanism of action while addressing some of the most common unmet needs in people living with narcolepsy and idiopathic hypersomnia. In addition to demonstrating enhanced efficacy for excessive daytime sleepiness, the phase 3 registrational trials for pitolisant HD, both set to initiate in Q4 2025, will also evaluate the common symptom of fatigue in the narcolepsy trial and the very common and burdensome symptom of sleep inertia in the IH trial.

With top-line data anticipated in 2027 toward PDUFA dates for both narcolepsy and IH in 2028, along with a provisional patent extending to 2044, pitolisant HD is the foundation of our long-term growth strategy and path toward durable long-term value creation. Beyond Sleep/Wake, 2025 will bring another major milestone with the top-line data readout from our phase 3 registrational trial of ZYN002 in Fragile X syndrome, the RECONNECT study in the third quarter. This study was designed to confirm the positive findings from the pre specified analysis of patients with complete methylation in the Phase 2 RECONNECT study, and if positive, could put us on a path toward bringing the first approved treatment for Fragile X syndrome to patients and their families. Importantly, we possess global rights to ZYN002, which provides us an opportunity to expand access worldwide if successful.

And that is just the beginning. Kumar will share more details with you on our Fragile X program as well as the exciting work we are doing in 2025 to advance our innovative rare epilepsy franchise with EPX-100, the most advanced 5-HT2 agonist clinical development program in the clinic. With registrational trials in both Dravet syndrome and Lennox-Gastaut syndrome, we are building a rare epilepsy franchise with potential to have a meaningful impact on the lives of these patients with plans to go broader in the developmental and epileptic encephalopathy space. Based on our strong foundation of commercial success with Wakix, we have been very busy over the past two years building out our pipeline, and we are just getting started.

The acquisitions we did were thoughtful and strategic, leading to our three orphan rare CNS franchises. And we remain actively engaged in identifying and evaluating additional opportunities that could expand our leadership in Sleep/Wake, neurobehavioral disorders for rare epilepsies and other seizure disorders. With over $576 million in cash and cash equivalents in the balance sheet, we are in a solid position to deploy our resources to expand our pipeline and create meaningful value for patients and shareholders alike. As you can see, these upcoming catalysts underscore why 2025 is shaping up to be a transformational year for Harmony.

Harmony is a growth story built for long-term success with a market leading Sleep/Wake franchise, a robust late-stage pipeline, and the experience and strategic ability to navigate short-term challenges that make us stronger and even more committed to our long-term mission to develop and deliver innovative therapies for patients living with rare neurological diseases. When we deliver on our promise to patients, we generate long-term durable value creation for our shareholders. Thank you, and I will now turn the call over to Jeffrey Dierks, our chief commercial officer, to give you an update on our commercial performance. Jeff?

Jeff Dierks -- Chief Commercial Officer

Thanks, Jeff. Q4 and full-year 2024 showed continued strength in our underlying business fundamentals and durable growth as we surpassed $700 million in net sales and over 7,000 average patients on Wakix. Net sales for the fourth quarter were $201.3 million, and full-year 2024 net revenue was $714.7 million, a 23% increase from full-year 2023. We continue to see strong double-digit growth in net revenue for Wakix, heading into year six of our commercialization, demonstrating continual high interest of Wakix in the narcolepsy market.

The solid net sales performance in 2024 reaffirms our confidence in Wakix representing a potential $1 billion-plus opportunity in narcolepsy alone. For the fourth quarter of 2024, we saw continued growth in the average number of patients on Wakix and in the Wakix prescriber base, both facilitated by favorable market access as seen on Slide 5. The average number of patients on Wakix increased to approximately 7,100 in the fourth quarter. We are extremely pleased with the approximate 300 sequential increase in average patients on Wakix from what we reported last quarter.

We saw continued growth in pediatric narcolepsy prescriptions and prescribers in Q4, but consistent with Q3, the vast majority of our growth came from the adult narcolepsy, which constitutes approximately 95% of the diagnosed narcolepsy opportunity. The growth in average patients in the fourth quarter was in line with our expectation and reaffirms our confidence in future growth with Wakix. Fueling the growth in patient adds on Wakix was the strength of the Wakix prescriber base. We saw solid growth in the Wakix prescriber base beyond Oxybate REMS enrolled healthcare professionals, demonstrating that Wakix continues to expand the branded writer segment of the market beyond the Oxybate.

We are now more than 50% penetrated in this segment of approximately 5,000 healthcare professionals at the end of the fourth quarter. Coupled with the growth we're seeing beyond the Oxybate REMS enrolled healthcare professionals, we continue to see utilization of Wakix among the approximately 4,000 Oxybate REMS enrolled healthcare professionals, even with the availability of new and generic Oxybate options. We are highly penetrated in the prescriber audience and see Wakix being prescribed to additional narcolepsy patients each quarter in this segment. Wakix provides a meaningfully differentiated product profile and one that offers broad clinical utility across the entire narcolepsy trading healthcare professional universe, allowing us to tap in to the full diagnosed narcolepsy patient opportunity of approximately 80,000 patients.

Looking ahead for full-year 2025, we expect continued growth in the underlying business fundamentals for Wakix with net revenue guidance of $820 million to $860 million. We anticipate a similar rhythm to our business as we've seen in traditional seasonal payer dynamic headwinds that impact the industry as a whole in the first quarter. Tailwinds coming out of Q1 into Q2 with stronger prescription demand. Typical seasonal headwinds in the third quarter was lower patient visits that are common for all products and diseases that are chronically managed and tailwinds in the fourth quarter with strong patient refill behavior as we close out the year.

With Wakix on track to achieve $1 billion plus in narcolepsy alone and with a robust scalable commercial infrastructure we have built, we have the strong foundation to drive growth and value in our next-generation pitolisant program. We are advancing both pitolisant gastro resistant or GR and pitolisant high dose or HD through the lens of patient-centric drug development. With the goal of improving patient care with meaningful features and benefits and extending durable patient growth and revenues of the pitolisant franchise into the mid-2040s. Kumar will share more details on the HD and GR development programs.

Preliminary market research that we conducted with healthcare professionals and payers with the HD target product profile showed early excitement and strong anticipated update by healthcare professionals and expected favorable market access coverage from payers. Additionally, our unique commercial model will be deployed to support the transition of the pitolisant franchise. In summary, Wakix continues to deliver strong growth heading into year six of our commercialization. The patient-centric drug development approach to our pitolisant lifecycle management program strengthens our franchise and leadership position in Sleep/Wake and is poised to deliver durable patient growth and significant revenues to the mid-2040s.

I would like to now turn the call over to our chief medical and scientific officer, Kumar Budur, to discuss the advancement in our clinical development programs. Kumar?

Kumar Budur -- Chief Medical Officer

Thank you, Jeff. Good morning, everyone, and thank you for joining us today. In R&D, we continue to make good progress in advancing our pipeline across 13 development programs, eight different assets, and three distinct franchises focused on rare neurological indication with high unmet medical needs. We currently have four phase 3 registrational trials ongoing in four distinct indications, and we will have six phase 3 registrational trials by the end of the year.

This makes our portfolio one of the robust late-stage pipelines in the industry with the potential to deliver one or more new product or indication launches every year in the coming years. Our full clinical development pipeline is shown on Slide 8, and the clinical development highlights are on Slide 9 through Slide 13. Starting with our Sleep-wake franchise, as we discussed recently, we received an RTF for IH sNDA. We are deeply disappointed with this outcome.

The rationale that the FDA provided for the RTF was based on data from the randomized withdrawal phase of the INTUNE study. However, as we have discussed previously, the data from the open label phase showed the patients experience improvements on the Epworth Sleepiness Scale that were about five times greater than what is recognized as clinically meaningful. And the majority of the patients in the long-term extension study achieved normal levels of wakefulness and sustained this response beyond one year. These data along with real world data from the physicians treating IH and a some positive use program, as well as the well established safety and tolerability profile of Wakix and its noncurative status made a strong benefit risk proposition for pitolisant in IH.

This is why we submitted the SNDA for pitolisant in IH because it was the right thing to do for our patients. Our commitment to bring pitolisant for patients with idiopathic hypersomnia remains unchanged. We are on track to initiate the phase 3 registrational trial in idiopathic hypersomnia in Q4 2025 with pitolisant HD, an optimized and higher dose formulation, which is anticipated to provide larger efficacy for EDS and also target symptoms such as sleep inertia, one of the core symptoms in patients with idiopathic hypersomnia. This double-blind randomized placebo controlled parallel study is designed with input from the FDA and the anticipated PDUFA date for this program is 2028.

We are also on track to initiate the pivotal phase 3 registrational trial in narcolepsy with pitolisant HD in Q4 2025 with target PDUFA in 2028. With the optimized and higher dose formulation, pitolisant HD is anticipated to deliver larger efficacy in excessive daytime sleepiness, the greatest unmet need in patients with narcolepsy, and also target symptoms such as fatigue in narcolepsy for which there are no approved treatments. Moving on to our pitolisant GR program, this formulation is designed to address the GI comorbidities prevalent in almost 80% of patients with narcolepsy and designed to give the patients an ability to start at the therapeutic dose range with no titration. We are on track to initiate the pivotal bioequivalence study this quarter, and the top-line data is expected in Q3 25 with anticipated PDUFA date in 2026.

Prominent patents have been submitted for both pitolisant GR and pitolisant HD with the potential for patent protection until 2044. Moving on to our orexin-2 receptor agonist program, BP1.15205, a potential best-in-class orexin-2 receptor agonist currently in preclinical phase. The in vitro pharmacology data demonstrated greater potency compared to all the other orexin-2 receptor agonists based on publicly disclosed data. The combination of high potency, excellent selectivity essential for once a day dosing, and robust preclinical data makes our orexin-2 receptor agonist a potentially best-in-class asset.

We plan to present a comprehensive preclinical safety and efficacy data at the upcoming annual sleep meeting in June this year, and we are on track toward filing an IMPD in mid-2025 and initiating first-in-human studies in the second half of this year. Moving on to our Neurobehavioral Franchise, the next major catalyst in our portfolio is the top-line data from the phase 3 registrational trial of ZYN002 in Fragile X syndrome, the RECONNECT study. Fragile X syndrome is a rare genetic disorder caused by mutation in FMR1 gene on X chromosome, resulting in decreased or lack of protein production that results in the dysregulation of the endocannabinoid system, manifesting itself with intellectual impairment, developmental delays, and significant neurobehavioral symptoms. In fact, Fragile X syndrome is the most common inherited cause of intellectual impairment and autism spectrum disorder with a prevalence of approximately 80,000 patients each in the US and EU.

ZYN002, a pharmaceutically manufactured 100% synthetic cannabidiol, is a patent protected permeation enhanced gel that offers a unique treatment option by helping maintain the endocannabinoid homeostasis by interacting with CB1 receptors and treats the neurobehavioral symptoms. The transdermal route of administration offers significant benefits from a tolerability and safety perspective compared to oral administration of cannabidiol that results in significant nausea, vomiting, abdominal cramps, and diarrhea. In addition, oral administration of cannabidiol can result in abnormal liver function tests because of the first-pass metabolism and that is not observed with the ZYN002. The ongoing phase 3 registrational trial, the RECONNECT study is based on the data and the learnings from last phase 2 RECONNECT study.

In essence, we are attempting to replicate the strong efficacy signals that we observed in patients with complete methylation in the CONNECT study. The RECONNECT study, if positive, is expected to meet the registration requirements for both the FDA and the EMA, and we have global rights for ZYN002. We are on track to report the top-line data in Q3 2025. Based on the pathophysiology of Fragile X syndrome, the mechanism of action of ZYN002, the clinical data from the CONNECT study and the RECONNECT study design, we have a high degree of conviction in the RECONNECT program, and, if approved, this will be the first and only approved treatment for any symptoms in patients with Fragile X syndrome.

We are also on track to initiate the phase 3 registrational trial in 22q deletion syndrome in 2025. 22q is another rare disorder with a prevalence of approximately 80,000 patients each in the US and Europe and with prominent neurobehavioral symptoms for which there are no approved treatments. Moving on to our epilepsy franchise, we have the most advanced development program in developmental and epileptic encephalopathies. We have two investigational candidates, EPX-100, that's clemizole hydrochloride and EPX-200, liquid lorcaserin, for the treatment of developmental and epileptic encephalopathies.

EPX-100 works via modulation of 5HT serotonin receptors and enhances the serotonergic tone. The serotonergic mechanism of action is a validated mechanism of action in DE, and EPX-100 also showed efficacy in several preclinical models for various other developmental and epileptic encephalopathies, suggesting a broad utility for EPX-100 in DE. EPX-100 is administered in a liquid formulation with bid dosing, a single dosing regimen that is especially meaningful for patients living with DE. We are currently recruiting globally for our phase 3 registrational trial in Dravet syndrome, the ARGUS study, and we also initiated the global phase 3 registrational trial in LGS, the LIGHTHOUSE study, in the fourth quarter of last year.

The top-line data for both programs are anticipated in 2026. Our other investigational product in developmental and epileptic encephalopathies EPX-200, a liquid formulation of lorcaserin is in the pre-IMD phase. Overall, we are progressing our late-stage pipeline across our three distinct franchises. If successful, these programs could result in one or more new product or indication launches every year for the coming years.

And more importantly, we have the potential to help hundreds of thousands of patients with rare neurological disorders for whom there are either no approved treatments or limited treatments that come with significant limitations in efficacy and or safety and tolerability. 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 their efforts and commitment in helping us to advance our development program. I will now turn the call over to our CFO, Sandip Kapadia for an update on our financial performance. Sandip?

Sandip Kapadia -- Chief Financial Officer

Thank you, Kumar, and good morning, everyone. This morning, we issued our fourth-quarter earnings release and filed our 10-K while we will find the details of our fourth quarter and full-year 2024 financial and operating results. Our financial performance is also shown on Slides 14 through 16. We finished the year with great momentum across the business, delivering strong growth across several of our key metrics, setting us up for another successful year in 2025.

We continue to be a profitable, cash-generating company, able to fund the growth and advancement of our pipeline fully with the strength of our balance sheet. We delivered another year of double-digit top-line growth as we reported $714.7 million in annual Wakix net revenue, while continuing to be profitable, cash-generating biotech company. Our strong financial performance combined with a solid balance sheet, including approximately $576 million in cash and cash equivalents, positions us well to continue advancing our industry-leading pipeline along with driving continued commercialization of Wakix and narcolepsy. For the fourth quarter of 2024, we reported net revenues of $201.3 million as compared to $168.4 million in the prior-year quarter, representing year-over-year growth of 20% and our highest quarter to date.

Performance in the quarter reflects the strong sustained underlying demand for Wakix. We also reported total operating expenses for the fourth quarter of $91.1 million compared to $85.1 million in the same quarter in 2023, representing a 7% increase. The growth was primarily driven by our expanding late-stage pipeline, along with investments for the commercialization of Wakix and narcolepsy. Non-GAAP adjusted net income for the fourth quarter of 2024 was $63 million or $1.08 per diluted share, compared to $42.8 million or $0.73 per diluted share in the prior-year quarter.

We believe non-GAAP adjusted net income better reflect the underlying business performance. Please see our press release for a reconciliation of GAAP to non-GAAP results. We ended the fourth quarter with $576.1 million of cash, cash equivalents, and investments. The balance reflects robust cash generation of approximately $219.8 million from operations in 2024, providing us with the financial flexibility to execute our growth strategy.

Looking ahead to 2025, as we previously disclosed, our guidance for net revenues for 2025 is $820 million to $860 million. We believe this guidance reflects the strong expectations for the year and demonstrates that we're approaching the $1 billion-plus opportunity in Wakix and narcolepsy alone. As a reminder, a comment on seasonality as we think about the phasing for revenues for the first quarter of 2025, we expect to see typical seasonal dynamics that the industry as a whole experiences each year in Q1. This includes higher gross domestic options due to insurance plan free sets and higher co-pay obligation, along with potential for drawdown in trade inventory.

With respect to expenses, we expect increased R&D investment as we continue to build our pipeline. We also expect to potentially incur $29 million in R&D-related milestone payments in 2025, including milestones for the completion of enrollment and positive top-line in our ZYN002 phase 3 program as well as started study in our orexin program. In summary, I'm pleased with our strong financial performance in 2024. We once again delivered another year of strong top-line growth, maintained healthy operating margin, while continuing to generate cash.

This positions us well as we enter 2025 with the potential for significant value creation through our catalyst risk pipeline. And with that, I'd like to turn the call back over to Jeff for his closing remarks. Jeff?

Jeff Dayno -- President and Chief Executive Officer

Thank you, Sandip, and thanks everyone for joining our call today. As you have heard, 2025 is set up to be a transformational year for Harmony. With a market-leading Sleep/Wake franchise, a catalyst rich pipeline, and a clear path for continued growth, we are in a strong position to execute on our vision of becoming the leading CNS company focused on delivering innovative treatments to patients with unmet needs. 2025 will be a pivotal moment in our long-term growth strategy.

I am proud of the progress that the Harmony team has made, and we are well positioned to deliver on our promise to patients while also generating durable long-term value creation for our shareholders. Thank you again. And I will now turn the call back over to the operator. Operator?

Questions & Answers:

Operator

Thank you, Jeff. [Operator instructions] We'll go first this morning to Charles Duncan at Cantor Fitzgerald.

Charles Duncan -- Analyst

Hey, good morning, Jeff and team. Congrats on a nice fourth quarter patient adds for Wakix. Since I'm going to answer just one question, multi-part. It's on ZYN002 and the phase 3 study.

Kumar suggested that you're pleased with how it's going. I'm wondering if you can provide any color on, I guess, beyond the methylation rates, how do you feel about the range of weights in terms of the patients being enrolled or ages? And then finally, how is the open-label extension going? What's been the rollover rate into that?

Jeff Dayno -- President and Chief Executive Officer

Yes. Good morning, Charles. And thanks to your question on ZYN002 and the ongoing phase three RECONNECT trial. Kumar, more color on Charles' question?

Kumar Budur -- Chief Medical Officer

Yes. Hey, good morning, Charles. Thanks for the question. We are very pleased with the way the trial is ongoing, Charles.

We are on track for top-line data in the third quarter of this year. The primary endpoint is in patients with complete methylation, but we are also enrolling a nominal number of patients who also have partial methylation. If the primary endpoint in patients with complete methylation is positive and if we see a strong signal in patients with partial methylation, there is an opportunity for a broader label. In terms of your question in terms of age, we are enrolling patients in the age group of three to 30 years.

And in terms of weight, the weight is variable, obviously, depending on many factors, including the age. And one of the things that we did in RECONNECT study is went higher on the dose in patients who weigh more than 50 kilogram. The dose is 750 milligrams per day administered in two equally divided doses at 375 bid. In the open-label or rather long-term extension study, a good proportion of patients are rolling over into long-term extension study, and we have discussed this in the past.

Currently, if you look at all the way back to the patients who enrolled in the very first Factor X syndrome study, some of these patients are exposed to ZYN002 for over eight years now. This level of persistency is unprecedented in neuropsychiatric trials. It just speaks to the durable efficacy or effectiveness of ZYN002 in this patient population. Hope that answers all of your questions.

I know it was a multi-part question. We did not want to miss anything. Thank you.

Charles Duncan -- Analyst

Super, that's helpful. Looking forward to the data.

Brennan Doyle -- Head of Investor Relations

Thank you, Charles.

Operator

Thank you. We go next now to Francois Brisebois at Oppenheimer.

John Gregory Dean -- Oppenheimer and Company -- Analyst

Hi. This is John Gregory Dean on for Francois Brisebois at Oppenheimer. Thank you for taking our questions. I was wondering, why should we feel comfortable that pitolisant HD has a higher likelihood of success in IH patients?

Brennan Doyle -- Head of Investor Relations

John, thanks for your question. I think we have data with regards to it, and Kumar can expand showing dose response and exposure response with pitolisant over the years in the clinical trials that have been done.

Kumar Budur -- Chief Medical Officer

Hey, Frank, good morning. Thanks for the question. Look, I would like to answer this question in two parts. First and foremost, efficacy evidence for efficacy of pitolisant in patients with idiopathic hypersomnia in general, the INTUNE study, clearly showed the magnitude of efficacy.

The open label was quite gracious compared to what is recognized as clinically meaningful. In the long-term extension study, patients continue to derive benefit one year out, and they were within the normal range for wakefulness. And moving on to pitolisant HD formulation, it's an optimized formulation of pitolisant with an optimized PK profile and the higher dose, and there is a body of evidence from all of our clinical trials that show clear dose response and exposure response. So based on all of this data, we have high confidence that pitolisant will not just be efficacious in patients with idiopathic hypersomnia, but we will see a larger magnitude of efficacy in excessive daytime sleepiness and also impact symptoms like sleep inertia, which is a core symptom In patients with idiopathic hypersomnia for which there are no approved treatments.

And finally, the trial design, Frank, the upcoming study which we plan to initiate in the fourth quarter of 2025 will be a double-blind placebo controlled, randomized parallel arm study, and with randomized withdrawal study design, there are some challenges on how to interpret the data and the traditional parallel arm design study will be much more helpful in interpretation of the data.

John Gregory Dean -- Oppenheimer and Company -- Analyst

Thank you.

Operator

Thank you. We go next now to David Amsellem at Piper Sandler.

David Amsellem -- Analyst

Hey, thanks. So regarding pitolisant HD, I want to drill down in your assumption for 2028 PDUFA. There's obviously a number of trials in NT1 and NT2 and eventually IH for various orexin agonists. So can you talk to how you're feeling about pace of enrollment of your pitolisant HD trials and how confident you are in your 2028 assumptions given that you're competing for patients? Thanks.

Jeff Dayno -- President and Chief Executive Officer

Yes. Good morning, David. No, great question. I think Kumar can give you sort of our assumptions and the plan on the development program.

Kumar Budur -- Chief Medical Officer

Hey, good morning, David. Thanks for the question. Yes, there is competition. Many clinical trials are ongoing.

But if you look and compare and contrast to clinical trials in narcolepsy with idiopathic hypersomnia, there are relatively less number of clinical trials in idiopathic hypersomnia. And the good thing is based on the data from the INTUNE study, we have already showed a robust signal and that will definitely help with the recruitment of pitolisant HD clinical trial compared to other clinical trials that are ongoing or that are coming up. And also, this is a global clinical trial. We just completed idiopathic hypersomnia clinical trial, so we have established relationship with the site.

We know these sites very well. Our long-term extension study is still ongoing, so we have continued relationship with these sites. All of these things will factor into on how we will recruit for our upcoming phase 3 clinical trial with pitolisant. We are confident in the timeline.

David Amsellem -- Analyst

What about competition for patients with narcolepsy?

Kumar Budur -- Chief Medical Officer

Yes. Good question, David. We are also on track to commence phase 3 study in narcolepsy with pitolisant HD in the fourth quarter and anticipated PDUFA date in 2028. Once again, I would like to switch back to we know this space.

We have been working with these investigators for a number of years. We know the sites, and also this is going to be a global clinical trial. Our partner, Bioprojet, are very active in Europe. So based on everything that we know about the disease condition, the clinical trial sites, the investigators, we feel confident with our timelines.

Jeff Dayno -- President and Chief Executive Officer

Yes. Stephen, I would also add, I think we have plans with regard to other regions globally where we're able to sort of access in terms of accelerating that trial, having access to patients and being able to hit our timelines.

David Amsellem -- Analyst

All right. Thank you.

Jeff Dayno -- President and Chief Executive Officer

Thanks, David.

Operator

Thank you. We'll go next now to Graig Suvannavejh at Mizuho Securities.

Graig Suvannavejh -- Mizuho Securities -- Analyst

Good morning. Congrats on the quarter and the year. And thanks for taking my questions. I just want to first congratulate you on the patent settlement that you announced this morning.

I was wondering if you can comment what the status is of the remaining patent challenges, if you could remind us how many other patent challenges there are? And also I believe on in your third quarter Q, there were some upcoming dates potentially even starting next month in terms of litigation. So if you could just remind us on timelines with the litigation and potential kind of next steps there? Thank you.

Jeff Dayno -- President and Chief Executive Officer

Yes, sure, Greg. Yes, good morning. So I think with regards to the ongoing process here, so obviously this morning we announced the first generic settlement agreement with Novagen Pharma, and it's one of the seven ANDA filers. With regards to the next steps, I think it's important to remember that both the regulatory and legal processes continue forward in parallel with regard to the ANDA process.

So while we'll see the ongoing process, I think the Markman hearing, as we mentioned, is scheduled for March and that sets up the claims construct followed by the trial which will take place in 2026. I think we are beyond the first settlement. We're actively engaged with the other ANDA filers, but obviously we can't comment on ongoing litigation matters, and we'll provide updates as appropriate. But I think what is important to remember and in terms of sharing the news that the Novagen settlement really reinforces the strength and durability of Harmony's intellectual property.

And I think it also shows how we're committed to vigorously defend the intellectual property on the state. And we'll provide updates as appropriate going forward on the rest of the -- at the end of the litigation process.

Graig Suvannavejh -- Mizuho Securities -- Analyst

OK. Thank you.

Operator

We'll go next now to Ami Fadia at Needham.

Ami Fadia -- Analyst

Hi, good morning. Thanks for taking my question. I've got one question and a follow-up. Firstly, just on ZYN002 with the data coming up later this year, it's certainly a focus for investors.

Could you sort of frame what would be success for the trial in terms of the endpoints and how much of a clinically meaningful change you would like to see? And can you remind us if the FDA would accept the first phase 2, 3 study, the CONNECT study, as part of the filing package with the two phase 3 trials that are required? And then just separately on the idiopathic hypersomnia study for the high dose, maybe aside from the change in the trial design, what else do you think you need to do in terms of perhaps the duration for which you study the patients etc. to really tease out the benefit of pitolisant in IH? Thank you.

Jeff Dayno -- President and Chief Executive Officer

Yes. Good morning, Ami. Thanks for your questions. Thanks for your interest in ZYN002.

And I think Kumar can address that, so you understand what success would look like on that phase 3 trial. Kumar?

Kumar Budur -- Chief Medical Officer

Hey, good morning, Ami. Thanks for the question. ZYN002 is our next major catalyst top-line data readout scheduled for third quarter of this year. Regarding your question about what a successful trial would look like, a successful outcome for this trial will be defined by demonstrating a statistically significant and clinically meaningful outcome on the primary endpoint, which is the social avoidance subscale in patients with complete methylation.

In essence, Ami, what we are trying to do in RECONNECT study is replicating the positive findings that we saw in the CONNECT study in patients with complete methylation on social avoidance subscale in this particular patient population. In terms of your question about will the FDA accept the phase 2, 3 CONNECT study data, yes, they will because at the end of the day, this will contribute to the totality of evidence, not just from an efficacy perspective but also from a safety and tolerability perspective, and also the extensive data that we continue to generate from the long term extension study. Because Fragile X syndrome is a rare condition, what we need is only one adequately and well controlled study that shows statistical significance. The data from the CONNECT study will be supportive data in our NDA package if the study is positive.

Finally, in terms of your question about idiopathic hypersomnia pitolisant HD and the trial design, it's -- we have a good idea, Ami, in terms of the duration of the study and the endpoints. Again, based on the INTUNE study, the data from the INTUNE study granted that the primary endpoint was not statistically significant in the randomized withdrawal period of the study. The data from the open label long-term extension study gave us a pretty good idea in terms of what to expect with pitolisant in general and especially with pitolisant HD, which is an optimized and a higher dose formulation. One last thing which I actually wish to say is you asked about the clinical meaningfulness.

In the social avoidance subscale for patients with Fragile X syndrome, a change in about three points from baseline is considered as clinically meaningful. Hope I answered all of your questions. Thanks, Ami.

Ami Fadia -- Analyst

That was very helpful. Thank you.

Jeff Dayno -- President and Chief Executive Officer

Thanks, Ami.

Operator

We'll go next now to David Wong at Deutsche Bank.

David Wong -- Deutsche Bank -- Analyst

Hi there. Congrats on the quarter and taking my questions. So I had two here. So the first one just with the pitolisant HD, could you elaborate a little bit more about the rationale and approach to look at AT and sleep inertia in narcolepsy and IH respectively? And do you plan to, I guess, pursue these as coprimary endpoints? Are you looking for labeled indications? And how does that sort of enhance the overall commercial opportunity? And then also on your orexin-2 receptor agonist, I was wondering about how you're thinking about the first-in-human study there and would you do what some of your peers have done in terms of looking at sleep-deprived healthy volunteers? Thanks a lot.

Jeff Dayno -- President and Chief Executive Officer

Thanks, David. Let me just start, and then Kumar can expand. With regards to sleep inertia as a key symptom in patients with IH, in addition to EDS and also in pursuit of a differentiated label, sleep inertia, somewhat pathognomonic, if you will, like cataplexy is for narcolepsy. So that is the rationale behind that.

And it's also there are scales that are fit for purpose that can address that. In terms of the other thinking around how we'll capture that in the development program, Kumar?

Kumar Budur -- Chief Medical Officer

Hey. Good morning, David. Thanks for the question. So in terms of sleep inertia, David, again, we generated a lot of data from the INTUNE study, and most of it was discussed at our investors' meeting last year.

The sleep inertia questionnaire that we utilized as one of the endpoints in the INTUNE study showed a pretty good response, and the response was sustained beyond 13 months in vast majority of the patients. So we know pitolisant works in sleep inertia, and we know we can capture that improvement via sleep inertia questionnaires. In terms of your question on how do we want the label of [Inaudible] the goal is always to get it in the label, initiated label with the goal of getting patients with idiopathic hypersomnia. Regarding your question on orexin receptor agonist, based on the preclinical data, the potency, the selectivity, potential for once-a-day dosing, novel chemical structures, good preclinical safety and efficacy data, we believe this is potentially a best-in-class orexin receptor agonist.

We are on track for IMPD submission in middle of 2025 this year, and we will also first-in-human studies in the second half of this year. In terms of how we do that, the goal is to have a nimble and an accelerated clinical development program to make sure that we have the right data sets as we move from one phase of development to the next. We will definitely leverage some of the lessons from other development programs, which are slightly ahead of us. In terms of details, whether healthy volunteers, sleep deprived, healthy volunteers directly into patients, that's something that we will disclose in due course of time as we approach those clinical trials.

David Wong -- Deutsche Bank -- Analyst

Thanks, Kumar.

Operator

Thank you. We'll go next now to Ash Verma at UBS.

Ash Verma -- Analyst

Great. Thanks for taking my question. So I wanted to ask about the orexin pipeline asset. There's some emerging literature that is pointing that agonizing orexin can accelerate Alzheimer's pathology and this has been shown in preclinical and clinical models now.

So I wanted to understand how do you think about this as an effect on your program, and would that be higher at higher doses? And lastly, is that something that would be on the radar of the FDA? Thanks.

Kumar Budur -- Chief Medical Officer

Hey, Ash. Good morning, and thanks for the question. Ash, this was something that used to be discussed many years ago because in some of the preclinical experiments, there was some increase in TAL proteins in the cerebrospinal fluid in the preclinical experiments. That had more to do with the orexin-1 receptor agonist.

But really, what eventually was concluded is it's actually the insomnia and the sleep deprivation that increase the TAL levels rather than anything to do with the orexin receptor antagonist or antagonist itself. So this is not something that we have seen in any of our preclinical models. And also, this is not something that has been seen in some of the ongoing clinical trials and some of who actually have long-term data, for example, in the TAK-994 study that was discontinued because of safety issues. So for now, that is not a concern.

I don't think there is any level of evidence to suggest any increased risk of cognitive impairment with orexin-2 receptor agonists.

Ash Verma -- Analyst

Thanks, Kumar.

Operator

Thank you. We'll go next now to Patrick Trucchio at H.C. Wainwright.

Luis Santos -- H.C. Wainwright and Company -- Analyst

Good morning, and thank you for taking my question. This is Luis Santos in for Patrick. On the pitolistant GR, the gastro-resistant formulation, the bioequivalence study is expected to read out this third quarter. What key data points do you expect would support the regulatory submission? And is that regulatory submission still on track for later this year, beginning of next year for PDUFA date next year? Thank you.

Jeff Dayno -- President and Chief Executive Officer

Thanks, Elyse, for your question. Kumar?

Kumar Budur -- Chief Medical Officer

Good morning. Thanks for the question. We are on schedule to initiate the pivotal bioequivalence study this quarter, and the top-line data we expect to be available in the third quarter. This is the standard pivotal bioequivalence study where we aim to show bioequivalence, which is 80% to 125% of the range for within the 90% confidence interval for Cmax and AUC.

In terms of the PDUFA, we are on track for a PDUFA date in 2026.

Luis Santos -- H.C. Wainwright and Company -- Analyst

Thanks, Kumar.

Operator

Thank you. We go next now to Jason Gerberry at Bank of America.

Unknown speaker -- -- Analyst

Hey guys, thanks for taking my questions. I wanted to hit on two topics today. This is [Inaudible] on for Jason. The first is regarding the RFP letter for pitolisant in IH.

Can you elaborate on the specific concerns raised by the FDA regarding the INTUNE study data? And how does this inform the phase 3 trial for pitolisant HD, which is expected to start in 4Q 2025. Maybe if you can provide some more details on the planned trial design, including the planned duration of treatment, trying to get at how this trial addressed the limitations of the INTUNE study and provide more robust evidence of efficacy? And then my second question is with regards to the next-gen pitolisant. Can you remind us what evidence supports the hypothesis that higher doses of pitolisant provide greater wake-promoting efficacy without introducing a saturation effect on H3 receptor inverse agonism? Thank you.

Jeff Dayno -- President and Chief Executive Officer

Yes. So, yes, let me address your first question with regards to the RTF. So I think that basically the RTF was based on the FDA's review was on the primary endpoint that was not statistically significant when they were looking at the sNDA submission, a very traditional sort of conservative approach to the totality of the evidence and the robustness of the signal that was seen. But I think as we shared, really the focus is on pitolisant HD and the longer-term opportunity there with regards to the plan to pursue a phase 3 trial that we initiate in the quarter.

With a randomized prospective parallel group design, which was in concurrence with the agency in terms of the trial design and then then all of the clinical trials with pitolisant and narcolepsy utilizing that design and demonstrating the strong efficacy on excessive daytime sleepiness. So that is the focus there as we go forward with regards to the IH program for pitolisant HD.

Kumar Budur -- Chief Medical Officer

Yes. Hey, good morning, [Inaudible]. Thanks for the question. In terms of pitolisant HD program, as mentioned earlier, we are on track to initiate the study in Q4 of this year and with a potential PDUFA date in 2028.

In terms of the evidence itself, there is a body of evidence from all of our clinical trials that show a dose response and exposure response with pitolisant. The original trial, original pivotal narcolepsy trials that were conducted by our partner Bioprojet many, many years ago employed a dose to effect dosing strategy. Therefore, some of the higher doses were never really interrogated. So here, we have an opportunity to do that with an optimized formulation at a higher dose and capture the largest efficacy that we anticipate with the higher dose based on the data that we have.

We will be doing this without compromising on the safety or tolerability of the tolerability associated with pitolisant. We disclosed data where we did a phase 1b study where pitolisant was administered up to one hundred and eighty milligrams in repeat dose study, and the safety and tolerability was consistent with the established safety and tolerability profile of pitolisant. So a really nice opportunity to generate efficacy and safety data in narcolepsy, also targeting fatigue in idiopathic hypersomnia, also targeting sleep inertia, and an opportunity to have a differentiated label in both of these indications. Thank you.

Unknown speaker -- -- Analyst

Thanks, Kumar.

Operator

Thank you. And there are no further questions today. Dr. Dayno, I'd like to turn things back to you, sir, for any closing comments.

Jeff Dayno -- President and Chief Executive Officer

Yes. Thank you, Bo. And thanks, everyone, for your interest in Harmony Biosciences and for joining our call today. And I wish everyone have a great rest of your day.

Thank you.

Operator

[Operator signoff]

Duration: 0 minutes

Call participants:

Brennan Doyle -- Head of Investor Relations

Jeff Dayno -- President and Chief Executive Officer

Jeff Dierks -- Chief Commercial Officer

Kumar Budur -- Chief Medical Officer

Sandip Kapadia -- Chief Financial Officer

Charles Duncan -- Analyst

John Gregory Dean -- Oppenheimer and Company -- Analyst

David Amsellem -- Analyst

Graig Suvannavejh -- Mizuho Securities -- Analyst

Ami Fadia -- Analyst

David Wong -- Deutsche Bank -- Analyst

Ash Verma -- Analyst

Luis Santos -- H.C. Wainwright and Company -- Analyst

Unknown speaker -- -- Analyst

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