Harmony Biosciences Holdings, Inc. Price & Performance (HRMY)

Including a reconciliation of our GAAP to non GAAP financial measures. At this stage of our lifecycle, we believe non GAAP financial results are represent the underlying business performance. Our speakers on today's call are Doctor. Jeffrey Dano, President and CEO Jeffrey Dierks, Chief Commercial Officer Doctor. Kumar Badur, 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 [indiscernible] our actual results may differ materially 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, Doctor. Jeffrey Datto. [indiscernible] 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 Sleepwake, 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 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 is successful, is poised to deliver over $3,000,000,000 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 $714,700,000 representing 23% growth year over year.

In Q4 alone, we generated $201,300,000 in net revenue.

This momentum is reflective of the continued durable growth of Wakex 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. Remain confident in Wakex being a $1,000,000,000 plus opportunity in Narcolepsy alone and we are on our way to achieving that milestone well before Wakex LOE in 02/1930.

On that topic, today we are also announcing our first generic settlement agreement with Novagen Pharma, which resolving the patent infringement litigation related to Novagen's abbreviated new drug application for a generic version of pitolacin 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 pitalizumab, which if granted would add an additional six months of regulatory exclusivity. This settlement reinforces the strength and durability of Harmony's Harmony As you can see, we remain committed to vigorously defending our intellectual property estate. [indiscernible] Commercial Engine has allowed us to finance our growing pipeline from our balance sheet. As a profitable self funding biotech company [indiscernible] 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 $1,000,000,000 to $2,000,000,000 each [indiscernible] Before turning to the opportunities ahead of us in 2025, I want to address the recent update on our supplemental new drug application for Petrolis While we recognize the challenges with this submission, Given that the Phase three INTUNE study did not meet the primary endpoint during the four week randomized withdrawal phase, we made the decision to submit the sNDA for pitalcin and IH based on the following three factors.

First, the overall benefit risk profile of cetolixin 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, Hypersomnia Foundation and more than six fifty members of the IH community signed a petition to the FDA requesting a review of the Betulson 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 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. [indiscernible] Our long term vision has always been to through the development of Pitolacin high dose or Pitolacin HD enhanced higher dose formulation of Pitolosin designed to deliver an optimized PK profile and therapeutic benefits. Kumar will share more about our development plans for our next generation petulosin formulations.

What I want you to take away is that this program is a result of patient focused drug development. These formulations are designed to build on the innovation of Pitalicin, as a first in class molecule with a novel mechanism of action addressing some of the most common unmet needs people living with narcolepsy and idiopathic hypersomnia. [indiscernible] In addition to demonstrating enhanced efficacy for excessive daytime sleepiness, the Phase three registrational trials for Betolten HD both set to initiate in Q4 twenty twenty five, 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 02/1944, Pitulacin 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 three registrational trial of ZYN002 the RECONNECT study, the third quarter, This study was designed to confirm the positive findings from the pre specified analysis of patients complete methylation, in the Phase twothree CONNECT 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-one hundred. The most advanced five HT2 agonist clinical development program in the clinic. We registrational trials in both Gervais 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 Waikix, we have been very busy over the past two years building out our pipeline.

And we are just getting started. [indiscernible] 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 SleepWake, neurobehavioral disorders for rare epilepsies and other seizure disorders.

With over $576,000,000 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 As you can see, these upcoming catalysts underscore why 2025 is shaping up to be a transformational year for Harmony Harmony. Harmony is a growth story. Built for long term success with a market leading sleep bike 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. [indiscernible] Thank you. And I will now turn the call over to Jeffrey Derks, our Chief Commercial Officer give you an update on our commercial performance. [indiscernible] Thanks, Jeff.

Q4 and full year 2024 showed continued strength in our underlying business fundamentals and durable growth as we surpassed 700,000,000 net sales, and over 7,000 average patients on Wakeex.

Net sales for the fourth quarter were $201,300,000 and full year 2024 net revenue was $714,700,000 a 23% increase from full year 2023. We continue to see strong double digit growth in net revenue for Wakex, heading into year six of our commercialization.

Demonstrating continual high interest of LACICS in the narcolepsy market, The solid net sales performance in 2024 reaffirms our confidence in Weikx representing a potential $1,000,000,000 plus opportunity in narcolepsy alone.

For the fourth quarter of twenty twenty four, we saw continued growth in the average number of patients on Wakex and in the Wakex prescriber base. Both facilitated by favorable market access as seen on Slide five. The average number of patients on Wakex increased over We're extremely pleased with the approximate 300 sequential increase in average patients on Wakex from what we reported last quarter.

We saw continued growth in pediatric narcolepsy prescriptions and prescribers Q4, but consistent with Q3, the vast majority of our growth came from the adult narcolepsy.

Which constitutes approximately ninety five percent 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 Waikix.

Fueling the growth in patient adds on Wakex was the strength of the Wakex prescriber base.

We saw solid growth in the wake us subscriber base beyond demonstrating that Wake X continues to expand the branded writer segment of the market beyond the oxibates. We're 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 OxiBeate REMS enrolled healthcare professionals, we continue to see utilization of Wakex among the approximately 4,000 oxybate REMS enrolled healthcare professionals, even with the availability of new and generic beat options.

We're highly penetrated in the subscriber audience and see Wakex being prescribed to additional narcolepsy patients each quarter in this segment. Wakex provides a meaningfully differentiated product profile.

And one that offers broad clinical utility across the Narcolepsy treating healthcare professional universe.

Allowing us to tap into 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 Wakex with net revenue guidance of $820,000,000 to $860,000,000 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 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 Wakey's on track to achieve $1,000,000,000 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 Betelesan program.

We are advancing both the Tolleson GastroResistant or GR and Pitulosan 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 Betulson 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 in strong anticipated update [indiscernible] and expected favorable market access coverage from payers. Additionally, our unique commercial model will be deployed to support the transition of the Polson franchise. In summary, Wakeus continues to deliver strong growth heading into year six of our commercialization.

The patient centric drug development approach to our Pertolosan lifecycle management program strengthens our franchise and leadership position in Sleep Wake and is poised to deliver durable patient growth I would like to now turn the call over to our Chief Medical and Scientific Officer, Kumar Vedur, to discuss the advancement in our clinical development programs. Kumar?

Thank you, Steph.

Good morning, everyone. And thank you for joining us today. In R and D, we continue to make good progress in advancing our pipeline across 13 development programs eight different assays, and three distinct funds held focused on rare neurological indication with high unmet medical needs. We currently have four Phase III registrational trials [indiscernible] in four distinct indications and we will have six Phase III registrational trials by the end of the year. This means our portfolio one of the robust next stage pipelines in the industry with the potential to deliver one or more new products or indication launches, every year in the coming years. Our full clinical development pipeline is shown on Slide number under clinical development highlights. Are on Slide nine through Slide Starting with our fleet grade front side, As we discussed recently, we received an RPO for IOH sNDA We are deeply disappointed with this outcome The rationale that the FDA provided for the RTS was based on data from the randomized withdrawal Phase III INTRO study. However, as we have discussed previously, the data from the open label Phase showed that patients experienced 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 achieve normal levels of wakefulness and sustain this response beyond one year.

This data along with real world data from the physicians treating IH, and the complexity of prokha, as well as the well established safety and tolerability profile of Matrix, and its non pivotal status made a strong benefit to for Fitralofent in IH. This is why we submitted the fNDA for spitalofentine IH Because it was the right thing to do for our patients.

Our commitment to Winglitolofen for patients with ADP hyposmia remains unchanged. We are on track to initiate the Phase III registration trial in erythropathy crichostomyumab in Q4 twenty twenty five. With Pitonofense HD an optimized and higher dose formulation which is anticipated to provide larger efficacy for EDS and other target symptoms [indiscernible] one of the core symptoms in patients with ileptic hypersomnia This double blind randomized placebo controlled parallel launch study is designed with input from the FDA and we anticipate approval date for this program in 2028.

We are also on track to initiate the pivotal Phase three registrational trial in Noculicity with filtomacent XD in Q4 twenty twenty five, [indiscernible] in 2028. It will be optimized and higher dose formulation, we don't have an HD's anticipated to deliver larger efficacy in excess data and sleepiness the greatest unmet need in patients with NorcoLF III and also target symptoms of such fatigue in Northcolepsy for which there are no approved treatments.

Moving on to the PitalofenGR program, This formulation is designed to address the GI comorbidity prevalent in almost eighty percent of patients with narcolepsy and designed to give the patients an ability to start at the therapeutic door frames with no titration We are on track initiate the pivotal bioequolates study this quarter and the top line data set with anticipated to do for date in 2026. Prostantin patents have been submitted for both Pitalif and CR and pitolofen HP.

With the potential for patent protection until 02/1944, Moving on to our Oricsin tools that are atonedees program. [indiscernible] a potential best in class RF2 receptor agonist, currently in preclinical phase The in vitro pharmacology data demonstrated greater potency compared to all the other Coricine toolsetter agonists based on publicly disclosed data. The combination of high potency excellent selectivity, potential for once a day dosing, and robust preclinical data makes our orexin two receptor agonist potentially best in class ASH site. We plan to present a comprehensive preclinical safety and efficacy the data? At the upcoming annual sleep meeting in June and we are on track towards filing an INPD in mid-twenty twenty five and initiating first in human study in the second half of this year Moving on to our Europe, Israel, France, the next major catalyst in our portfolio [indiscernible] [indiscernible] Trial of Xyngular caused by mutation in FMR1G on X chromosome resulting in decreased or lack of FMR protein production that results in the dysregulation of the endocannabinoid system manifesting itself with intellectual impairment [indiscernible] and significant neurobehavioral symptoms. In fact, Fazalex Fintro is the most common inherited cause of intellectual impairment and cortisone spectrum disorders with a prevalence of approximately eighty thousand patient each in The U. S, and EU.

ZYN002 are form critically manufactured 100% synthetic cannabinoid is a patent protected, purnishin enhanced gel that offers the unique treatment option by helping maintain the endocannabinoid by Internet with CB1 receptors, [indiscernible] The Trans Government route of administration offers significant benefit from a tolerability and safety perspective compared to oral administration of cannabidiol. That results in significant nausea, Vomiting [indiscernible] and diarrhea. In addition, oral administration of cannabilty of can result in abnormal liver function tests because of the first pass metabolism and that is not absurd. With ZYN002. The ongoing Phase three registrational trial [indiscernible] is based on the data and the learning from last Phase twothree CONNECT study In essence, we are attempting to replicate the strong efficacy signals that we observed in patients with complete methylation in the CONNECT study, Very CONNECT study If positive, it's expected to meet the registration requirements for both the FDA and the EMA.

And we have global rights for 31,002. [indiscernible] We are on track to report the top line data in Q3 twenty twenty four. [indiscernible] the mechanism of action of V1-two the clinical data from the CONNECT study, and the RECONNECT study design we have a high degree of conviction the Reconnect program [indiscernible] this would be the first and only approved treatment for any symptoms in patients with frazzledic syndrome, We are also on track to initiate the Phase three registrational trial in 22Q deletion syndrome. In 2025, twenty two Q is another rare disorders with the prevalence of approximately eighty thousand patient feet. In The U. S, and Europe, And with prominent European 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-one hundred that's chemical hydrochloride, and EPS200 liquid lucasiran, for the treatment of developmental epileptic and subloperities. EPS100 was to be a modulation of five eighty two cytokine receptors and enhances the serotonin receptor The serotonin gene form of action is a validated mechanism of action in the and EPS100 also showed efficacy in several preclinical models for various other developmental and epileptic and epilepsyopathies, For 15 a broad utility for GPX-one hundred in EPIS-one hundred is administered in a liquid formulation with BID DOPHIN a single dosing regimen.

That is especially meaningful for patients living with [indiscernible] We are currently recruiting globally for our Phase three registrational trial in Provestinto, the ARCA study, And we also initiated the global Phase three 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 and the flop [indiscernible] a liquid formulation of lucaspirin, is in the PIND 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 forthcoming years, and more importantly, we have the potential 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 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, Sandeep Kapadia, for an update on our financial performance. [indiscernible] Thank you, Kumar, and good morning, everyone. This morning, we issued our fourth quarter earnings release and filed our 10 ks.

Where you'll find the details of our fourth quarter and full year 2024, financial and operating results Our financial performance is also shown on Slide [indiscernible] We finished the year with a 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 [indiscernible] with the strength of our balance sheet, We delivered another year of double digit top line growth. As we reported $714,700,000 in annual leakage net revenue, while continuing to be profitable cash generating by a tech company. Our strong financial performance combined with a solid balance sheet including approximately $576,000,000 in cash and cash equivalents positions us well to continue advancing our industry leading pipeline along with driving continued commercialization of latex and Norcolysis For the fourth quarter of twenty twenty four, we reported net revenues of $201,300,000 as compared to 168,400,000.0 in the prior year quarter. Representing year over year growth 20% and our highest quarter to date Performance in the quarter reflects the strong sustained underlying demand for Wakefit. We also reported total operating expenses for the fourth quarter of $91,100,000 compared to $85,100,000 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 WetaX and Northwell.

Non GAAP adjusted net income for the fourth quarter twenty twenty four was 63,000,000 or $1.08 per diluted share, Believe non GAAP adjusted net income better reflects the underlying business performance Please see our press release to non GAAP results, We ended the fourth quarter cash equivalents The balance reflects robust cash generation of approximately $219,800,000 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 $820,000,000 to $860,000,000 We believe this guidance reflects [indiscernible] expectations for the year and demonstrate that we're approaching the $1,000,000,000 plus opportunity [indiscernible] As a reminder, a comment on seasonality as you think about the phasing for revenues for the first quarter of twenty twenty five, We expect to see typical seasonal dynamics that the industry as a whole experiences each year in Q1. This includes higher gross to net adoption, due to insurance plan resets and higher copay obligation. Along with potential for drawdown in trade inventory. With respect to expenses, as we continue to build our pipeline. We also dollars in R and D related milestone payments in 2025. Including milestones for the completion of enrollment and positive top line.

In our ZYN002 [indiscernible] as well as [indiscernible] in our Orectin 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 These positions us well 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. [indiscernible] Thank you, Sandeep, and thanks everyone for joining our call today. As you have heard, 2025 is set up to be a transformational year for Harmony 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. 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, Thank you, Doctor. Daniel. Ladies and gentlemen, at this time, if you would like to ask a question, please We'll go first this morning to Charles Duncan at Cantor Fitzgerald. [indiscernible] good morning, Tom, Jeff and team. Congrats on a nice fourth quarter of patient adds for Wakex. Since I'm going to answer just one question of the multi part, it's on CYN002 and the Phase three study Kumar suggested 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 the range of weight in terms of the patients being enrolled or ages and then finally how is the open label extension going? What's What's been the rollover rate into that? Yes. Good morning, Charles. And thanks for your question. On CYN002 and the ongoing 83 reconnect. [indiscernible] More color on Charles' question. 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 is the primary endpoint in patients with complete metallition 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 ACE, we are enrolling patients in the ACE group of three to thirty 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 fifty kilograms the dose is seven fifty milligram per day administered in two equally divided doses at three seventy five PIP. 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 FASAL X syndrome some of these patients are exposed to B1-zero-two for over eight years now this level of persistency is unprecedented in neuropsychiatric trials It just speaks to be durable efficacy or effectiveness of V1-zero-two in this patient population [indiscernible] that answers all of your questions. I know it was a multi part question. Did not want to miss anything. Thank you.

Super, that's helpful. Looking forward to the data. Thank you. We go next now to Francois Brisebois at Oppenheimer.

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

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

Hey, Frank. Good morning. Thanks for the question. Look, I would like to answer this question in two parts.

First and foremost, is efficacy evidence for efficacy of pitolofen in patients with idiopathic hypersonic in general. INTUNE study clearly showed the magnitude of efficacy in the open label [indiscernible] compared to what is recognized as clinically meaningful. In the long term extension study, patients continue to get a benefit one year out and they were within the normal range for Wakeferna.

Moving on to picolacin HD formulation. It's an optimized formulation of picolosan with an optimized PK profile and the higher dose and there is a body of evidence from all of our clinical trials that show a PDS dose response and exposure response. So based on all of this data, we have high confidence that Vitolacint HD will not just be efficacious in patients with idiopathic hypostalgia, but we will see a larger magnitude of efficacy in efficacy data and sleepiness.

And And also, [indiscernible] symptoms like schizophrenia which is a co symptomia for which there are no approved treatments. And finally, the tile design Frank, which we plan to initiate in the fourth quarter of twenty twenty five, be a double blind randomized [indiscernible] [indiscernible] there are some challenges with on how to interpret the data. And the traditional parallel arm design study will be much more helpful in interpretation of the data.

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

Hey, thanks. So regarding Petolacent HD, 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 Oraxane agonists. So can you talk to how you're feeling about pace of enrollment of your Betolacin HD trials? And how confident you are in your 2028 assumptions given that you're competing for patients? Thanks.

Yes. Good morning, David. Great question. I think Kumar can give you sort of our assumptions and the plan on the development program.

Hey, good morning, David. Thanks for the question. Yes, there is competition Many clinical trials are ongoing. But if you compare and contrast clinical trials in novel epilepsy, we'll pediatric hypersonia, they're relatively less number of clinical trials in pediatric hypersomnia. And the good thing is based on the data from the Intune study, we have already showed a robust signal under will definitely help with the recruitment of the Doloresent HD clinical trial compared to other clinical trials that are ongoing All set being up. And also this is our global clinical trial just completed idiopathic hyposcomia clinical trial so we have established relationship with the fight. We know these fights very well. Our long term extension study is still ongoing, so we have continued relation with these sites.

All of these things will factor into on how we will recruit for our upcoming Phase three clinical trial with pitalacin. We are confident in foreign lines. What about competition for patients with narcolepsy? Yes. Good question, David. We are also on track to commence Phase three study in narcolepsy with pitolabsorbent. Pitolofen HD in the fourth quarter. And anticipated to do for date in 2028. Once again, I would like to switch back to BNOT We have been working with these investigators for a number of years We notified also this is going to be a global clinical trial Our partner BioPlus, they 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.

Yes. David, 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 [indiscernible] being able to hit our timeline. Thanks, David. Thank you. We'll go next now to Greg Suvaanovich at Mizuho Securities.

Good morning. Congrats on the quarter and the year. Thanks for taking my questions. I just want to first congratulate you on the patent [indiscernible] 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 challengers there Harmony 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 guys remind us on timelines with the litigation and potential kind of next steps there? Thank you. Yes, sure Greg. Yes, good morning.

So I think that with regards to the ongoing process here, so obviously, this morning we announced the first 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 regards to the end of 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 obviously we can't comment on ongoing litigation [indiscernible] And we'll provide updates as appropriate. I think what is important to remember and in terms of sharing the news that the NovoGen settlement really reinforces the strength and durability of Harmony's intellectual property 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 end of litigation process. We'll go next now to Amy Fadia at Needham Hi, good morning.

Thanks for taking my question. I've got one question and a follow-up. Firstly, just on ZYNO2 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 sort of Phase twothree study, the CONNECT study as part of the filing package, with the two Phase III trials that are acquired.

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 which you study the patients etcetera to really sort of tease out the benefit of the dolosat and IH? Thank you.

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 three trial? Kumar?

Good morning, Gami. Thanks for the question.

ZYN002 is our next major catalyst top line data readout scheduled for third quarter of this year. Regarding a what a successful trial looked like a successful outcome by demonstrating a statistically significant and clinically meaningful outcome on the primary endpoint which is the social avoidance subscale inpatient with a complete metallization In essence, Ami, what we are trying to do in RECONNECT study is replicating the positive finding 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 2b connect [indiscernible] Yes, they will. Because at the end of the day, this will contribute to the [indiscernible] not just from an efficacy perspective, but also from a safety and tolerability. Thank you. And also the extensive data that we continue to generate from the long term extension study. Because Fazal Extinction 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 hypostone epiduralacent, HD and the trial design.

It's we have a good idea, Harmony, in terms of 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 pitolofenin in general and especially with pitolofenin HD, which is an [indiscernible] last thing we said actually [indiscernible] asked about the clinical meaningfulness. In the social avoidance subscale for patients with Fragile X syndrome, a change in about [indiscernible] from baseline is considered as clinically meaningful. I hope I answered all of your questions.

That was very helpful. Thank you.

Thanks, Amy.

We'll go next now to David Wong at Deutsche Bank. So I had two here. So the first one just with the TULUS and HD, could you elaborate a little bit more about the the rationale and approach to look at AT and cluve inertia in narcolepsy and IH. Respectively? And do you plan to, I guess, pursue these as co primary endpoints? Are you looking for labeled indications? And how does that sort of enhance the overall commercial opportunity? And then also on your Oraxane two receptor agonist, I was wondering about how you're thinking about the first human study there. And would you do what some of your peers have done in terms of looking at sleep deprived healthy volunteers. Thanks, David. Let me just start and then Kumar can expand. With regard to sleep and nurse as a key symptom in patients with IH. IH. In addition to EDS and also In pursuit of a differentiated label, sleep inertia somewhat pathognomonic, if you will, like [indiscernible] is for narcolepsy. So that is the rationale behind that. 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?

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. [indiscernible] that we utilized as one of the endpoints in the Intune study showed a pretty good response and the response was sustained beyond thirteen months. In vast majority of the patient, we know PDOLOSAZEK What [indiscernible] and we know we can capture that improvement [indiscernible] In terms of your question on how do you label of goal is always to get it in the label, differentiated label, which development [indiscernible] Regarding your question on Oraxindraceptre agonist, Based on the preclinical data, the potency, the selectivity, potential once a day [indiscernible] [indiscernible] to preclinical safety and efficacy data we believe this is potentially our best in class for a receptor agonist We are on track for IMPD submission in middle of twenty twenty five this year and we will pursue 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 to make sure that we have the right data sets, as we move from one phase of development to the next.

Will definitely leverage some of the lessons from other development programs, which are slightly ahead of us. Terms of details, whether healthy volunteers, keep the pride healthy volunteers, directing to patients that's something that we will disclose in two parts of time. Approach to skin contralance Thank you. We'll go next now to Ash Fermil Great. Thanks for taking my question. So I wanted to ask about the Oraxane pipeline asset There's some emerging literature that is pointing that agonizing Oraxane can accelerate Alzheimer's pathology? And this has been shown in preclinical and clinical models now. 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? Hey, Ash. Good morning and thanks for the question. Ash, there's something [indiscernible] that used to be discussed [indiscernible] Because in some of the pre KIDSAL experiments, there was some increase Carlsberg Bend, in the cerebrospinal fluid in the preclinical experiments That had more to do with the Oraxen-one. Except our agonist But really, what eventually was concluded is it's actually the insomnia and the sleep deprivation that increase the power level.

Rather than anything to do with the orexin receptor antagonist, our antagonist itself 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 those actually have long term data, for example, in the TAS nine ninety four 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 [indiscernible] increased risk of cognitive impairment with oryxin two receptor agonists Thanks Kumar. Thank you. We're going next now to Patrick Trucchio at H. C. Wainwright.

Good morning and thank you for taking my question. This is Luis Santos.

And for [indiscernible] On Pillosense GR, the gastrointestinal formulation, the biorecabulin 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? Yes. Thanks, Elyse, for your question. Kumar?

Good morning. Thanks for the question. We are on schedule to initiate the pivotal bioequivalent study this quarter and the top line data we expect to be available.

In the third quarter This is a standard pivotal bioequivalent study where we aim to show [indiscernible] 80 to 125% of the range for us within the 90% confident winter valve for CMAC and AUC. In terms of the PDUFA, we are on track for a good look for date in 2026. [indiscernible] You. We'll go next now to Jason Gerberry at Bank of America.

Hey guys. Thanks for taking my question. I wanted to hit on two topics today and this is Bhavan on for Jason.

The first is regarding the RFP letter for Pitolosan in IH Can you elaborate on the specific concerns raised by the FDA regarding the INTUNE study data? And how does this Ptolecynt HD, which is expected to start in four ks 2025. Maybe if you can provide some more details on the trial design including the planned duration of treatment I'm trying to get at how this trial addressed the limitations of the interim study and provide more robust evidence of efficacy and my second question is with regards to the next gen atolasan. Can you remind us what evidence supports the hypothesis that higher doses of atotlstan provide greater weight promoting efficacy without introducing saturation effect on H3 receptor inverse agonism. Thank you. Yes. So, yes, let me address your first first question with regards to the RTF.

I think that basically the RTF was based on the FDA 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 robustness of the signal that was seen. But I think as we shared, really the focus is on Pitulsin HD. And the longer term opportunity there With regards to the plan to pursue a Phase three pivotal trial to initiate in the fourth 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 of the total of the narcolepsy utilizing that design and demonstrating the strong efficacy on excessive daytime So that is the focus there.

As we go forward, with regards to the IH program for Pulse in HD, Yes. Hey, good morning, Pawan. Thanks for the question. Pawan, in terms of [indiscernible] as mentioned earlier, we are on track to initiate the study in Q4 of this year. And with the potential PDUFA date in 2028. In terms of the evidence itself, is a body of hair written from all of our clinical plans that showed a dose response and exposure response we split all of that.

The original charge original pivotal study that were conducted by our partner Fireplace many, many years ago, we 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 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 colorability associated with Pitolos Bank. We disclosed data did a Phase 1b study where pitolasin was administered up to one hundred and eighty milligrams in repeat dose and the safety and tolerability was consistent with established safety and tolerability profile of metallopag, [indiscernible] nice opportunity to generate efficacy and safety data [indiscernible] also targeting fatigue, in idiopathic hypersomnia, also targeting sleep inertia, and an opportunity to have a differentiated label of these indications, Thank you. Thanks, Kamal.

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

Yes.

Thank you, Bo.

And thanks everyone your interest in Harmony Biosciences and for joining our call today. And wish everyone have a great rest of your day.

Thank you very much, after Dana. Again, ladies and gentlemen, this does conclude Harmony BioScience's fourth quarter and full year twenty twenty four financial results conference Call. You may now disconnect your line and have a wonderful day.