Harmony Biosciences Holdings, Inc. (HRMY) Earnings Call Transcript & Summary

Good morning. My name is Britney, and I will be your conference operator today. At this time, I would like to welcome everyone to the Harmony Biosciences Fourth Quarter and Full Year 2023 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to turn the call over to Luis Sanay, Head of Investor Relations. Please go ahead.

Thank you, operator. Good morning, everyone, and thank you for joining us today as we review Harmony Biosciences' fourth quarter and full year 2023 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 life cycle, 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 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 Dr. Jeffrey Dayno. Jeff?

Thank you, Luis, and thanks, everyone, for joining our conference call today. Harmony continues to be a growth story as demonstrated by our team's accomplishments throughout 2023. We delivered another strong year of performance across the organization, growing revenue and average number of patients on WAKIX. We advanced all our clinical development programs for pitolisant, moved to the next generation or next-gen formulations of pitolisant into the clinic, and expanded our pipeline and diversified our portfolio with the acquisition of Zynerba, and the ongoing Phase III clinical trial in patients with Fragile X syndrome. Yesterday, we announced that FDA granted priority review for our supplemental NDA or sNDA for WAKIX in pediatric narcolepsy with a PDUFA date of June 21. Earlier this week, we also shared that FDA granted orphan drug designation for pitolisant for the treatment of Prader-Willi Syndrome, or PWS, as we are preparing to initiate our pivotal Phase III TEMPO study in patients with PWS down to age 6. All of this reflects momentum across our organization, from our commercial business with WAKIX in narcolepsy to our clinical development programs, as well as positive interactions with FDA related to these programs. These outcomes also reflect excellence in execution and the dedication of our team to deliver on the strategy we have laid out and are executing on. In addition, we returned capital to shareholders via our share repurchase program and we'll continue to take an opportunistic approach to this program throughout this year. I am very excited for the year ahead, and believe that Harmony is poised to accelerate our growth in 2024. For the fourth quarter, we reported WAKIX net revenue of $168.4 million and full year net revenue was $582 million, representing growth of 31% and 33%, respectively. This result demonstrates the significant underlying demand for WAKIX and the durability of the brand going into year 5 in the market. Other factors that drive our confidence in our ability to grow WAKIX include its meaningfully differentiated product profile, which results in its broad clinical utility. Couple that with our ability to reach the broad prescriber universe of approximately 9,000 HCPs who see and treat almost a 100% of the diagnosed narcolepsy patient opportunity. We have seen growth in patients on WAKIX and prescribers every quarter since launch, even with the entrance of new branded and generic oxybate treatment options coming into the market over the past few years. Finally, while there are several investigational agents in the clinic for narcolepsy, we do not see any new or novel mechanisms of action coming to the market that will impact the growth of WAKIX until late during its life cycle in this polypharmacy market. Based on these reasons, along with the vast market opportunity that remains in narcolepsy, we believe that we can continue to grow the franchise for years to come and remain confident that WAKIX represents a $1 billion plus opportunity in adult narcolepsy alone, and we are well on our way. This is evidenced by our net revenue guidance for 2024, ranging from $700 million to $720 million. In addition to our strong commercial performance, we also advanced and expanded our clinical development enterprise on several fronts. Kumar will provide more details on our clinical development programs later in the call. But first, let me highlight some of our progress. Starting with pediatric narcolepsy. We are pleased that FDA granted priority review for our sNDA for WAKIX. This expedites the review process and FDA has set a PDUFA date of June 21. We look forward to collaborating with the agency to potentially introduce a new non-scheduled treatment option for pediatric patients living with narcolepsy. Turning to Idiopathic Hypersomnia or IH. After completing our review of the full data set, we continue to believe that based on the totality of the data, along with pitolisant receiving orphan drug designation for IH, and against the backdrop of only 1 currently approved product that there is a strong case to be made regarding the overall benefit risk proposition of pitolisant for patients with IH. We will be engaging with the agency with this goal in mind, have a meeting scheduled with them next month, and look forward to working with the agency on bringing a potential new non-scheduled treatment option to patients living with IH. Our current life cycle management programs for pitolisant, which include IH, Prader-Willi Syndrome and Type 1 Myotonic Dystrophy, represent about 100,000 diagnosed patients in the U.S. So, if successful, these new indications could contribute up to an additional $1 billion of revenue to the WAKIX franchise. Given pitolisant's novel mechanism of action and the success of WAKIX in the market, we have been working on next-gen formulations of pitolisant with the goal to generate new IP and extend the pitolisant franchise out beyond 2040. These programs entered the clinic last quarter and we are on track to report PK data in the first half of this year. Another key component of our growth strategy is business development to expand our pipeline beyond WAKIX and diversify our portfolio beyond sleep-wake. The Zynerba acquisition, which closed last October, represented an important step in that direction and was an excellent strategic fit for Harmony, bringing in 2 late-stage development programs focused on orphan rare neuropsychiatric disorders with significant unmet medical needs. And we are not stopping with the Zynerba acquisition and remain very active in business development, continually assessing the BD landscape with a focus on rare neurological disease assets and other rare disease assets with unmet medical needs where we can leverage our existing infrastructure and synergies across our organization. We are looking for assets across a range of development stages with a preference for late-stage assets, but open to early-stage assets where there is a strategic fit. With approximately $426 million in cash, cash equivalents and investments at year-end, we are in a solid financial position to execute on BD opportunities, which is a strategic priority for us. In conclusion, I am proud of our team's accomplishments in 2023 and what we were able to do to help patients living with narcolepsy while advancing our development programs in other rare disease patient populations. We experienced solid and durable growth in our core commercial business, strong momentum in our clinical development programs and expansion and diversification of our pipeline assets. Based on the dedication and commitment across our organization, I am very excited for our opportunities in 2024 as we remain focused on developing and commercializing innovative treatments for patients living with rare neurological diseases who have unmet medical needs. I will now turn the call over to Jeffrey Dierks, our Chief Commercial Officer, to provide more details on our commercial performance. Jeff?

Thank you, Jeff. 2023 was a strong year of growth for WAKIX in year 4 of our commercialization in adult narcolepsy. The fourth quarter represented the strongest revenue quarter in our history, with continued growth and momentum in our underlying business fundamentals and top line performance metrics. Net revenue for the fourth quarter was $168.4 million, representing 31% growth from the same quarter prior year and our second consecutive quarter of over $150 million in net revenue. Full year 2023 net revenue was $582 million, a 33% increase from full year 2022. We continue to see strong double-digit growth in net revenue for WAKIX heading into year 5 of our commercialization, reflecting continued high interest of WAKIX in the narcolepsy market. The solid performance and continued growth reinforces our long-term belief that WAKIX represents a potential $1-billion-plus opportunity in adult narcolepsy alone. I'd like to share a few key highlights from our performance in the fourth quarter on Slide 5. The average number of patients on WAKIX in the fourth quarter increased to approximately 6,150, an increase of approximately 350 average patients sequentially from what we reported last quarter. The impressive growth in average patients in the fourth quarter was driven by strong top line demand and new patient starts and speaks to continued product adoption. And more importantly, it highlights the remaining large diagnosed patient opportunity that we continue to tap into each quarter as the market allows. In addition to the strong growth in average number of patients on WAKIX, we also saw continued product adoption of WAKIX by the narcolepsy health care community, both in new and existing prescribers. The number of unique prescribers of WAKIX increased again in the fourth quarter. And importantly, we continue to see growth in product adoption of WAKIX in the prescriber base beyond oxybate REMS enrolled health care professionals. Of the approximately 5,000 health care professionals not enrolled in the oxybate REMS program, more than 30% of them have prescribed WAKIX to date, up from 25% reported in our last earnings call. In addition to the continued growth of our prescriber base, we also saw strong growth in the depth of prescribing within the approximately 4,000 oxybate REMS enrolled health care professionals. Our ability to reach and educate the broad narcolepsy treating health care professional universe allows us to access the full diagnosed adult narcolepsy patient opportunity and gives us confidence in continued growth for WAKIX. The availability of new and generic oxybate hasn't impacted patient or prescriber growth or existing strong payer coverage for WAKIX, given its meaningfully differentiated product profile. WAKIX remains the first and only FDA approved treatment for EDS and cataplexy in narcolepsy that is not scheduled as a controlled substance, an attribute that continues to appeal to our broader narcolepsy health care professional audience and patient population and is a driver of brand growth. In summary, 2023 was another year of strong commercial performance for WAKIX. Full year net revenue of $582 million, 33% growth versus the full year 2022. The fourth quarter represented the strongest revenue quarter for Harmony to-date, with over $168 million in net revenue. The average number of patients on WAKIX increased to approximately 6,150. The WAKIX prescriber base within and beyond the oxybate REMS enrolled health care professional audience continued to grow. And lastly, payer coverage remained strong even with the availability of new and generic oxybate options. WAKIX continues to demonstrate durable growth in the narcolepsy market. We've seen growth in patients and prescribers every quarter since launch, even with branded and generic treatment availability and new launches during its first 4 years on the market. Looking ahead to 2024, we expect continued growth in the underlying business fundamentals for WAKIX, with net revenues expected to be between $700 million and $720 million. We anticipate a similar quarterly rhythm to our business in 2024 with what we've experienced in previous years; traditional seasonal payer dynamic headwinds that impact the entire industry as a whole in Q1, tailwinds coming out of Q1 and Q2 with stronger prescription demand, typical seasonal headwinds in Q3 with lower patient visits that are common for all products and diseases that are chronically managed, and tailwinds in the fourth quarter as we close out the year. With no new competition expected in 2024 and limited differentiation in generic and branded products in the near-term pipeline, coupled with the large remaining diagnosed patient opportunity, unmet need and the polypharmacy nature of the narcolepsy market, WAKIX is well positioned for continued growth. Our ability to educate the broad REMS and non-REMS narcolepsy treating health care professional audience, and ability to tap into the full diagnosed patient opportunity gives us confidence in the long-term potential for the brand to represent a $1 billion plus opportunity in adult narcolepsy alone. Our commercial business has been resilient and I appreciate the dedication and impact of the entire commercial team and the passion that they have for the narcolepsy patient community. I would like to now turn the presentation over to Kumar Budur, our Chief Medical Officer, to provide an update on our clinical development pipeline. Kumar?

Thank you, Jeff. Last year was a defining year for Harmony R&D. We made great progress in advancing, expanding and diversifying our portfolio, working on 9 different development programs across 5 different assets, several of which are in late-stage development. It is not just the number, but also the complexity of the program as we target a broad set of indications in rare disease patient populations with significant unmet medical needs. As we grew our portfolio, we also built a strong, experienced and dedicated R&D organization ready to take on new opportunities as we continue to build our existing portfolio with new assets via business development. I'm proud of the work that our team does every day, as we look forward to delivering potential new treatment options for patients with rare diseases with high unmet needs. Our full clinical development pipeline is shown on Slide 7. Starting with pediatric narcolepsy, we submitted a supplemental NDA to the FDA for an indication in pediatric narcolepsy in the fourth quarter, and we are pleased with the FDA's decision to grant a priority review. This decision highlights the need for new treatment options for the approximately 4,000 pediatric patients living with narcolepsy. The FDA has set a PDUFA date of June 21. We look forward to working with the FDA to potentially bring a non-scheduled treatment option administered once a day in the morning for pediatric patients with narcolepsy. Moving on to our development program in Idiopathic Hypersomnia. We completed our review of the full data set and submitted an FDA meeting request in the fourth quarter to discuss the path forward and the meeting is scheduled for March. We are optimistic that we will be able to find an efficient path forward to bring pitolisant to patients with Idiopathic Hypersomnia. Our optimism is based on the totality of the data, which strongly supports pitolisant's efficacy in patients with Idiopathic Hypersomnia, especially in the context of high unmet need with only 1 drug approved, which is a scheduled Class III control substance with a REMS program and the off-label use of Class II control stimulants with significant safety issue. The data from the open-label part of the study, double-blind randomized withdrawal part of the study, and the ongoing long-term extension study in conjunction with the benign safety profile offer a strong benefit risk proposition in favor of pitolisant for patients with Idiopathic Hypersomnia. We look forward to engaging with the FDA in the meeting scheduled next month and making a strong case for a positive benefit/risk profile for pitolisant in Idiopathic Hypersomnia. We will provide further updates on the IH program at our next earnings call. For Prader-Willi Syndrome, we are on track to initiate the Phase III TEMPO study in the first quarter of this year. This will be a global, double-blind, randomized, placebo-controlled study that will randomize approximately 134 patients to either pitolisant or placebo in a 1:1 ratio. The duration of the double blind treatment period is 11 weeks. The age range is 6 years and older and the primary endpoint is change in severity of excessive daytime sleepiness as measured by PROMIS-SRI T-score from baseline to the end of double-blind treatment period compared to placebo. Based on the promising data from the Phase II proof-of-concept study, we are also evaluating the irritable and disruptive behaviors which are common in PWS. This Phase III registration study is designed not just to meet the requirements for an indication in PWS, but also fulfill 1 of the 2 requirements to gain pediatric exclusivity. We remain confident and committed to gaining pediatric exclusivity for WAKIX, which will offer an additional 6-month regulatory exclusivity on the back end of the longest patent for pitolisant. Based on the discussions with the FDA, we have a clear line of sight on the requirements for our PWR, which include data in pediatric narcolepsy patients and data from the Phase III study in PWS. We are making steady progress to meet these requirements. The pediatric narcolepsy sNDA submission in the fourth quarter and the initiation of Phase III PWS study this quarter are designed to support our efforts to gain pediatric exclusivity for WAKIX. In Myotonic Dystrophy Type 1 or DM1, we were pleased to report positive top line results from the Phase II proof-of-concept study, where we saw clinically meaningful improvements in not just excessive daytime sleepiness as measured by the daytime sleepiness scale, but also in fatigue, which was assessed using fatigue severity scale, and these data are summarized on Slide 9. It's important to note that these 2 symptoms, excessive daytime sleepiness and fatigue are present in approximately 80% to 90% of patients with DM1, and these symptoms are as impactful as the core symptoms of myotonia and progressive muscle weakness. A clear and consistent dose response was also demonstrated with the higher dose showing a greater response than the lower dose across the study endpoint. In addition, the safety profile in this patient population is consistent with the established safety profile of pitolisant. We are currently reviewing the complete data set to assess the opportunity and inform our next steps. As we have noted in the past, this is an indication, which could be pivoted to the Next-Gen pitolisant-based formulation, which will have a much longer patent runway. We continue to make good progress on the Next-Gen pitolisant-based formulations NG1 and NG2 with our partner Bioprojet with the goal of generating new IP, extending the pitolisant franchise beyond 2040, and bringing new treatment options for people living with rare diseases. Please note, we have updated the naming conventions for these 2 formulations according to their respective market entry timing. Next Gen 1 or NG1 is a modified formulation of pitolisant with the potential for clinical differentiation and a fast-to-market strategy, based on the demonstration of bioequivalent. We expect to launch NG1 within the WAKIX lifecycle. Next Gen 1 or NG2, is an enhanced formulation of pitolisant, designed to deliver an optimized PK profile and a higher dosage strength. This formulation will have a new IP, a full clinical development program and is expected to be launched towards the end of WAKIX lifecycle. Both formulations, NG1 and NG2, entered in the clinic in the fourth quarter, and we expect PK data on both of them in the first half of this year. We were also pleased to expand and diversify our pipeline last quarter with the acquisition of Zynerba. This brought in ZYN002, a pharmaceutically produced synthetic cannabidiol devoid of THC for transdermal delivery, which, like WAKIX, represents another portfolio and a product opportunity. We are currently enrolling patients in pivotal Phase III RECONNECT trial in Fragile X syndrome and are very excited about this opportunity. There are approximately 80,000 patients diagnosed with Fragile X syndrome in the U.S. with no approved treatments and significant unmet medical need. We had an opportunity to assess the time line of the RECONNECT trial and expect to complete patient enrollment in the first quarter of 2025 with top line data in mid-2025. ZYN002 was also studied in an open-label Phase II proof-of-concept study in patients with 22q Deletion Syndrome, known as the INSPIRE trial, which generated promising data. This represents another market opportunity of approximately 80,000 patients in U.S. and we have been interacting with FDA about Phase III program in 22q. It is worth noting that ZYN002 is a global opportunity for Harmony, and we look forward to exploring ex-U.S. opportunities to bring this novel treatment to people living with Fragile X syndrome and 22q around the world. To conclude, we have made great progress at Harmony in advancing, expanding and diversifying our portfolio, resulting in a pipeline with multiple late-stage programs. I look forward to sharing additional updates as we continue to make progress on our clinical development programs. 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 programs. I'll now turn the call over to our CFO, Sandip Kapadia, for an update on our financial performance. Sandip?

Thank you, Kumar, and good morning, everyone. This morning, we issued our fourth quarter earnings release and filed our 10-K where you'll find the details of our fourth quarter and full year 2023 financial and operating results. Our financial performance is also shown on Slides 10 through 13. We finished the year with strong momentum across the business, helping us deliver solid growth across several key metrics. We reported $582 million in annual WAKIX net revenue, achieved our third year of profitability, along with robust cash generation. In addition, we advanced our pitolisant life cycle management program and executed on business development with the acquisition of Zynerba. We also deployed capital towards our share repurchase program. Overall, we remain well positioned to execute on our growth strategy moving forward. So let me take a moment to review our financial results in more detail. For the fourth quarter of 2023, we reported our strongest revenue quarter in company history, with net revenues of $168.4 million compared to $128.3 million in the prior year quarter, representing a growth of 31%. Performance in the quarter reflects the strong continued underlying demand for WAKIX. In the fourth quarter of 2023, operating expenses were $85.1 million compared to $53.8 million in the prior year quarter. The higher operating expenses were primarily driven by our advancement of our clinical development programs, including ZYN002, expenses related to the commercialization of WAKIX and one-time Zynerba transaction-related cost of $9.8 million. Operating income for the fourth quarter of 2023 was $40.2 million compared to $47.6 million in the prior year quarter. Non-GAAP adjusted net income for the fourth quarter of 2023 was $42.8 million or $0.73 per diluted share compared to $61.9 million or $1.01 per diluted share in the prior year quarter. We believe non-GAAP adjusted net income better reflects the underlying business performance. Please refer to our press release for a reconciliation of GAAP to non-GAAP results. We ended the year with $425.6 million of cash, cash equivalents and investment securities on the balance sheet. The balance reflects continued strong cash generation with approximately $77 million in cash from operations in the fourth quarter, offset by the Zynerba acquisition cost and share repurchase activities in the quarter. For the full year of 2023, we generated $219 million in cash from operations. During the fourth quarter, we returned capital to shareholders and repurchased approximately 1.8 million shares of common stock for $50 million, bringing the full year total of repurchase activities to 3.2 million shares of common stock for $100 million. Moving forward, we expect to continue to opportunistically repurchase shares under the remaining share repurchase program authorization of $150 million. Our strong balance sheet allows us not only to execute on return of capital, but also maintain financial flexibility to execute on business development. In the fourth quarter, we closed the acquisition of Zynerba, which was treated as an asset acquisition for accounting purposes. As previously disclosed, we paid approximately $60 million in cash for the closing of the transaction. We received approximately $26 million of cash and $45 million in deferred tax assets from the acquisition and assumed approximately $14 million in liabilities. Thus, we recorded $2.3 million in IP R&D charge related to the acquisition, along with $7.5 million in one-time restructuring cost. As a result, we were able to acquire 2 late-stage programs at very attractive deal terms. Going forward, we will recognize considerable operating synergies and expect ongoing incremental costs from the Zynerba development program of approximately $30 million for 2024. Turning to 2024 guidance. For the full year, we expect net revenues of $700 million to $720 million. This range reflects our thoughtful and balanced approach to providing guidance for the first time in company history. It also highlights that we are well on our way towards the $1 billion plus opportunity in adult narcolepsy alone, that we have consistently communicated and remain confident in. And finally, a comment on seasonality as you think about the phasing of revenue for the first quarter of 2024. We expect to see the typical seasonal dynamics that the industry as a whole experiences each year in Q1; higher gross to net deductions due to insurance plans reset and higher co-pay obligations, along with the drawdown in trade inventories. In conclusion, we're very pleased with our strong financial performance in 2023 and remain well positioned to continue growth in 2024 and beyond. We look forward to leveraging our financial strength as we continue to expand and diversify the portfolio while also returning capital to shareholders via our share repurchase program. And with that, I'd like to turn the call back to Jeff for his closing remarks. Jeff?

Thank you, Sandip. In summary, Harmony continues to be a growth story as evidenced by the significant progress our team made in 2023. Looking ahead, we see durability in our core business, strong momentum in our development programs and remain focused on continuing to grow our WAKIX business and helping even more adult patients living with narcolepsy; advancing our pipeline across both our pitolisant and ZYN002 clinical development programs; working with our partner Bioprojet on next-gen formulations to extend the pitolisant franchise to help even more patients living with rare neurological diseases; continuing to build out our pipeline through business development to create a robust portfolio of rare disease assets covering all stages of development; and deploying capital to maximize shareholder value through our share repurchase program and business development opportunities. I am excited for what is to come this year and believe that we are poised to accelerate Harmony's growth in 2024. This concludes our planned remarks for today. Thank you for joining our call. And I will now turn the call back over to the operator to facilitate the Q&A session. Operator, can you please open the call to questions?

[Operator Instructions] We'll take our first question from Ami Fadia with Needham & Company.

Thank you for giving all the updates on the pipeline. Firstly -- I had 2 questions. First, can you talk about the 2 new pitolisant formulations on which you're going to be sharing data in the first half? What should we expect to see from the data? And just to set up expectations for investors, will we be able to get visibility into how these formulations may be differentiated from WAKIX based on that data? And then the second question is regarding Idiopathic Hypersomnia. If you could shed any additional color on the analysis that you've put together for your meeting with the FDA? And if you could comment on whether there's any possibility of generating any additional data from the open-label portion of the study to support an approval?

Yes. Ami, thank you for your questions, and I'll ask Kumar to comment on the Next-Gen formulations and some visibility there, and -- as well as our preparation for the FDA meeting on IH. Kumar?

Yes. In terms of next-gen formulation, as we mentioned, we made significant progress on next-gen formulations last year, and we were really pleased to bring both of those 2 formulations into the clinic in the fourth quarter. And as we previously said, we will provide data from the Next-Gen formulation in the first half of this year. In terms of Next Gen 1 or NG1, it's a modified pitolisant formulation with the potential for clinical differentiation fast-to-market strategy by demonstrating bioequivalence, alongside a clinical study that will offer a meaningful clinical differentiation for patients. The nature of the clinical study and the potential differentiation that will be offered will be discussed at the next earnings call along with the PK data. With the Next Gen 2 or NG2 formulation, it's an enhanced formulation of pitolisant designed to deliver optimized PK and also an ability to go to a higher dose strength. This is the formulation that will have a full development program, a new IP, and it will extend the pitolisant franchise well beyond 2040. And we plan to provide the PK data from these formulations at our next earnings call. Regarding your question about the Idiopathic Hypersomnia, Ami, the totality of the data from the open-label study, from the randomized withdrawal period of the study and the long-term extension study supports pitolisant's efficacy in patients with Idiopathic Hypersomnia. And in terms of the arguments or the discussions that we will be having with the FDA, it's the totality of the data, the non-scheduled status of pitolisant, the ease of administration, a relatively benign safety profile, especially in the context of only 1 drug that is a -- it happens to be scheduled III controlled substance and the off-label use of Class II controlled substance drugs that have their own safety profile. So, all these factors offer a strong benefit/risk proposition to bring pitolisant for patients with Idiopathic Hypersomnia, and we hope to have good discussions with the FDA and find an efficient path forward to bring pitolisant in patients with Idiopathic Hypersomnia as soon as possible.

We'll take our next question from Charles Duncan with Cantor Fitzgerald.

Congratulations on a good year in '23. I have one commercial question and then a pipeline question to follow. So, regarding the commercial question, absolutely appreciate the '25 revs guide. Looks good to me. I note that you've added about 350 patients on WAKIX per quarter for the last 3 quarters. And that seems to be just a really consistent number. And I guess I'm wondering if you could speak to anything in the market dynamics or prescriber access that results in that 350 or is that just serendipity?

Yes, I think Jeff Dierks can provide some color on the patient adds and the continued market opportunity for WAKIX.

Sure. Yes, we've been extremely pleased with the durable growth that we've seen in the average number of patients on WAKIX, and I think some of the things that we're seeing, Charles, is given the unique and meaningfully differentiated product profile, WAKIX has the ability and our sales team has the ability to engage with the broad 9,000 approximate health care professionals that see and treat the narcolepsy patients. And what that does is, that affords us the opportunity to tap into the full diagnosed patient opportunity, both those individuals and health care professionals outside the oxybate REMS program, which we continue to see meaningful growth in the number of unique writers every quarter. But even within the oxybate REMS enrolled health care professionals, even with the availability of generic and once-nightly oxybate launches this year, we're seeing meaningful growth, in terms of depth of prescribing in that audience. So, I think really what we're seeing is the unique nature of the meaningfully differentiated product profile, the non-scheduled status, the broad clinical utility that Jeff Dayno spoke about, that really affords us the ability to continue to tap into that broad diagnosed patient opportunity, as the market allows around the traditional quarterly dynamics that we speak about each earnings call. But Charles, we're extremely pleased with what we're seeing, as I'm hearing from you as well, and we're confident in continued growth in the average number of patients as we move into '24.

Okay, that's helpful added color, Jeff. Quick question on the pipeline. Actually, a multi-part question, sorry about that. And that is, appreciate the Phase III TEMPO study data or not data, excuse me, details. I'm wondering when you would anticipate data? How rapidly do you think that study can enroll, given some competing programs? And then, is the NDA -- sNDA timing, I assume it would be gated by the open-label extension or would you file perhaps before that's completed? And then the second part of the question is, regarding the pediatric narcolepsy and priority review, it seems to say something about the agency's perspective on the safety of the product. So, I'm wondering if you could provide any thoughts on that and recent priority review being granted.

Yes. Charles, first let me say, I think that we're excited to be initiating the Phase III TEMPO study in patients with Prader-Willi. I'll have Kumar comment on that, and then I'll circle back on some thoughts about the priority review for the pediatric narcolepsy sNDA. Kumar?

Yes. Charles, thanks for the question. Regarding the PWS study, first of all, we are very pleased to have the orphan drug designation from the FDA for PWS program. In terms of recruitment, we anticipate to complete enrollment in about 2 years. It is true, Charles, that there are multiple programs in this space. But then we are the only ones who are looking at excessive daytime sleepiness and the behavioral symptoms in PWS. The other programs are targeting more towards hyperphagia in PWS. And as I mentioned previously, more than half of the patients with PWS have excessive daytime sleepiness, and almost all of these patients have behavioral disturbances. And from our proof-of-concept study, we showed strong data supporting pitolisant's efficacy both in excessive daytime sleepiness [indiscernible].

Yes. And Charles, can you repeat that second question about the pediatric narcolepsy sNDA?

Yes. I mean, the pediatric narcolepsy PDUFA and rapid time to respond, just seems to say something about the safety of the product or the agency's perspective on that, and not speaking for the agency of course, but that combined with the priority review, I guess, do you have any thoughts about the perspectives on that.

Yes, Charles, I mean, what I would say, I think that as we've shared this week, we're very pleased with the interactions we've had with FDA with regards to the orphan drug designation for pitolisant for Prader-Willi and then followed by the decision priority review for the pediatric narcolepsy sNDA. I think that it reflects, with regards to the overall benefit/risk profile of pitolisant and what we have said all along and advancing the development programs, we don't have any concern with regards to -- the safety profile has been consistent from the original pivotal development program in narcolepsy and on through the life cycle management programs that we've been conducting with no real change in the overall safety profile and the favorable benefit/risk profile. I think that reflects the positive interaction we've had with the agency, the decisions that we've received. And we remain focused on the execution and advancement of those development programs to bring potential new treatment options to those patient populations.

Very good. Congrats on a good year.

We'll take our next question from Francois Brisebois with Oppenheimer.

Hi, can you hear me, okay?

Yes, Frank.

Yes, okay So, I was just wondering, in terms of the guidance, can you help us understand what the thought process was behind giving guidance for the first time here? And how should we be thinking about the revenues per patients in 2024?

Sandip?

Yes, sure. Look -- Frank, thanks for the question. I mean, our guidance represents what I'd say, the thoughtful and balanced approach, especially the first year we've given guidance. I think we certainly look for opportunities to provide an update as we go throughout the year with respect to the guidance.

And you commented on how we should think about pricing or maybe revenue expectations going forward?

Yes. I think, look, we did take a price increase earlier this year. It was about 7%. A good portion of that usually falls through to the bottom line. So I think, generally, you'll see an impact from that as we go throughout the year. Obviously, in the first quarter, there's usually headwinds regarding gross to net pressure and normal things that happen typically in the seasonality that happens. So you generally don't see as much of that in the first quarter. But generally, as we go throughout the year, you'll see the benefit. It's very similar to the pattern that we've had over the last 3, 4 years.

We'll take our next question from David Amsellem with Piper Sandler.

So, just a couple. First, regarding business development, wanted to get more detailed thoughts on the extent to which you do a larger scale transaction versus something smaller scale along the lines of Zynerba. Just philosophically, how are you thinking about acquisitions in general? And tied to that question is also, would you lever up and lever up significantly to do something? So that's number one. And then number 2, wanted to pick your brain on the orexins. We've seen some data from Takeda, from Alkermes. There are others, of course. Wanted to get your view on the potential long-term impact of the orexin to receptor agonists to the extent one or more reach the market?

Yes. Thanks, David. I think with regards to business development, we're assessing the landscape very actively, and we're open to sort of all opportunities, with regards to a deal similar to Zynerba, that's a good strategic fit as well as something more transformational. We're in a strong sort of financial position to transact. So, we first look for good strategic fit, prefer sort of late-stage assets, but open to earlier stage. And those that could launch both during the WAKIX lifecycle and after. In terms of capacity, I'll ask Sandip to comment on that.

Thanks, Jeff. Yes, look, we have good financial strength and flexibility to execute on business development. We also have access to debt, if appropriate, as well as the capital markets. As also we mentioned, we had over $425 million of cash and cash equivalents available. We're generating significant positive cash flow. Last quarter, it was about $77 million in cash flow generation as well as almost over $219 million last year in cash generation. So, I think we have a good flexibility, as Jeff mentioned, to look at both small add-on transactions, as well as potentially something that's more larger and transformative. But I think the important thing is the filter that Jeff mentioned upfront in terms of making sure it's a good strategic fit for the company. And I think from a capital perspective, we have broad flexibility.

Yes, thanks, Sandip. And David, turning to question about the orexin agonist. I mean you know this space well, as do we, and we're following it closely. So, obviously, a lot of attention lately, given some of the data that has come out. I think at a high level, the programs are still early and they're obviously advancing. I think questions are being generated, both on the safety side and the efficacy side based on the data that has been coming out. Obviously, the target is interesting in terms of the next potential novel mechanism of action for narcolepsy and other central disorders of hypersomnolence. So I think we are following the space closely as the data come out, as more questions have been generated. And I think that they likely come to market if successful towards the end of the decade, towards the end of the WAKIX life cycle. But importantly, it's our belief that narcolepsy will continue to be a polypharmacy market. New entrants can only help this space and more share of voice, more education. So interesting novel target, I think, waits to be seen as these development programs advance, and we'll continue to be a polypharmacy market, and we'll follow them as things go forward.

We'll take our next question from Jason Gerberry with Bank of America.

This is Pavan on for Jason. Our first question is with regards to Zygel asset. Where are you at with enrollment for the Phase III Fragile X syndrome study? And any added clarity as to what assumptions shape your view on mid 2025 timing.? And then a second commercial question, what are your assumptions for average revenue per week ex-patient? Is that a meaningful tailwind for revenue growth in 2024 in your guidance? Or is growth mainly driven by volume?

Thanks for your questions. I'll ask Kumar to comment on the ZYN002 Phase III RECONNECT trial. Very exciting opportunity for us and can provide kind of some more color on where we are there.

Yes. Thank you, Jeff. So, yes, we looked at the time line as we have mentioned previously that we will. And based on the historical recruitment trend and the anticipated recruitment in this particular patient population, we arrived that we will complete enrollment in the first quarter of 2025, and the top line will be in mid-2025. Now that the asset is within [indiscernible], obviously, we will bring all the additional resources and the expertise, not just from a clinical development perspective, but also from the advocacy group perspective as well to try and accelerate the recruitment.

Thanks, Kumar. In terms of revenue per patient, Jeff Dierks, do you want to comment on that?

Sure. So, in looking ahead in '24, question, in terms of just price volume or average revenue per patient, as Sandip shared, we took a 7% price increase in the beginning of the year. And as with previous years, we would expect to capture most of that price increase. And as you're looking at our guidance, right, from $700 million to $720 million, you could see that we're expecting 20%-plus growth. So you could see that the vast majority of the growth we're expecting in '24 is driven by volume. We've talked a lot about the large remaining diagnosed patient opportunity, the meaningfully differentiated product profile for WAKIX. So, we see significant opportunity and room for growth, but hopefully that provides a little bit of context and helps you think about price versus volume assumptions and the average revenue per patient in '24.

And if I could have one follow-up question. What does the appetite for share buybacks in 2024 look like relative to the $100 million in share buybacks that you guys did in 2023?

I think as we've said, we're looking to take an opportunistic approach. And Sandip, do you want to comment further?

Yes. Look, we were very pleased last year that we were able to do approximately $100 million of share repurchase activities over the last couple of quarters. And I think it's really not a question of either/or. We have the flexibility to do both. And with respect to business development, we obviously talked about our strategy there. And then, in terms of the share buyback, again, we'd look at it more opportunistically and at the appropriate levels, we would certainly -- in a great cash position to be able to execute. And we have approximately $150 million of capacity still remaining.

We'll take our next question from Danielle Brill with Raymond James.

I was also hoping you could provide some more color on the assumptions that went into your '24 guidance, specifically around expectations for patient adds. It looks like you're expecting a slowdown in net patient adds each quarter. Are you just being conservative here or is growth starting to moderate? And then as a follow-up, can you remind us what impact the label expansion into the pediatric narcolepsy population will have on the overall TAM for WAKIX?

Thanks, Danielle. Yes, with regards to -- I think that the -- in terms of revenue and revenue guidance, Sandip, do you want to...

Yes, look, I think as we mentioned, we've taken a thoughtful and balanced approach in terms of providing guidance for the first year. We certainly look to provide an update as we go throughout the year. We're not in any way indicating we see great momentum coming out of the fourth quarter and we expect that momentum to sort of carry through for the year. I mean, Jeff Dierks, do you want to comment at all in terms of just overall growth what you're seeing?

Sure. And Danielle, in terms of looking at average patient growth and sort of the assumptions in the '24 guidance, I mean, have you seen -- we've seen demonstrated durable growth in the narcolepsy market, and we've grown average patients every quarter since launch even with availability. But within that durable growth, that growth has evolved every year. And entering our year 5 of our rare orphan launch, we're going to expect that growth to continue to evolve, but follow the previous year's cadence of the quarterly growth as we tap into that large diagnosed patient opportunity. So you'll see the traditional payer headwinds in the first quarter that impact all brands and specialty products. You'll see the traditional fewer patient visits associated with chronically managed conditions and diseases in Q3. And then typically, in previous years, we expect to have the traditional tailwinds in the second and the fourth quarter with stronger prescription demand, again, but I think the takeaway is we're extremely pleased with what we're seeing, confident continued growth, and we really believe that WAKIX is well positioned for future growth in '24.

Thanks. And Danielle, your next question on...

It was on pediatric TAM and how that expands the WAKIX opportunity?

Yes. I think Jeff can speak to that. I think, obviously, positive signals from the agency on the importance of that indication in pediatric narcolepsy patients. So Jeff, what's the opportunity look like?

Sure. So, I mean Danielle, we estimate there's about 4,000 pediatric narcolepsy patients in the U.S. And although it's not a large opportunity, it's an important one. And it's a very underserved patient population with only 1 FDA-approved treatment option being sodium oxybate being a Schedule III REMS product right now. And I think we're very excited about the potential, if successful, to bring a non-scheduled treatment option given what we've seen the impact of narcolepsy on these individuals' lives.

Yes, thanks, Jeff. And Danielle, let me just also add with regards to the pediatric narcolepsy, that sNDA, it's also important that those data, we're also pursuing pediatric exclusivity, which is obviously an important commercial opportunity with regards to an additional 6 months of regulatory exclusivity. So, those data are one component of that, along with the data that we'll be generating in the Phase III Prader-Willi TEMPO study. So, both of these components are important, and we are advancing both of these and making progress in terms of pediatric narcolepsy data through that submission, and then the initiation of the Phase III trial in Prader-Willi Syndrome, and both of those components are sort of what would be required as we pursue pediatric exclusivity and additional 6 months of protection.

We'll take our next question from Graig Suvannavejh with Mizuho.

This is Avantika on for Greg. I just had a question about the -- one about the Fragile X opportunity. I know you said that the timelines have been pushed a little bit due to enrollment. But were there any changes in the trial design as there originally were, which also caused delays? And then also on the pediatric opportunity. I know you said it's a pretty small opportunity, but do you anticipate growing the WAKIX sales force at all, if approved?

With regards to the Fragile X study, Kumar?

Yes. Thank you for the question, Avantika. With Fragile X Syndrome, the timelines were not pushed out. We had mentioned that we will evaluate the timelines once the asset is in house, and we had an opportunity to evaluate the timelines. And based on the historical recruitment trends, and the anticipated recruitment in this patient population, we arrived at completing the enrollment in the first quarter of 2025 with top line anticipated in mid-2025. And there is no change in the study design.

Yes. And I would just add, I think that the opportunity is for Harmony, for us to put our resources towards driving the Phase III RECONNECT trial forward. With regards to the experience of the clinical development team, more capacity from an operational perspective and really engaging with the patient community through our patient advocacy efforts as well to drive that forward towards a significant market opportunity of 80,000 diagnosed patients in the U.S. Turning to pediatric narcolepsy, we keep hearing sort of small market opportunity, but an important one. And I think Jeff sort of alluded to this, an important one in terms of potential new non-scheduled treatment options for pediatric patients living with narcolepsy rather than Schedule II stimulant. So, we are looking forward to working with the agency towards that. And then with regards to the impact on the market opportunity, Jeff?

Sure. So, in looking at the sales force coverage for pediatric narcolepsy, we believe that we're optimized for the narcolepsy opportunity with our existing sales force footprint. There will be some new prescribers that we'll be adding to our target list if successful. But we believe that our current team that is very excited about the potential to bring this forward, is optimized to be able to take on this new opportunity with these additional patients, and with -- the addition of a handful of health care professionals. There is a high overlap between adult narcolepsy prescribing and pediatric narcolepsy prescribing. So we believe we've got relationships established with a good portion of those prescribers, but we are absolutely optimized with our team, and if successful, very excited to bring this new indication forward.

Great. Thanks, Jeff.

And, can I just squeeze in one more. For gross to net, I know you said that there will be headwinds in the first quarter, but can you just quantify what you think it will be for the full year?

Sandip?

Yes. Thanks for the question. As I mentioned, typically in the first quarter, across the industry, there are general headwinds from just higher copay obligations and insurance plans resets in the first quarter. So, we'll see a couple of percentage points impact from that, typically is what we've seen in the past in the first quarter, and that sort of improves as we go throughout the year, generally.

Thank you. I am showing no further questions. I would now like to turn the call back to management for closing remarks.

Thank you, Britney, and thanks, everyone, for joining our call today and for your interest in Harmony. As you heard from us this morning, our strong execution in 2023 and solid momentum going into this year positions Harmony well for continued growth in 2024. We look forward to providing updates as we execute on our growth strategy. Thank you, and have a great day.

This does conclude today's Harmony Biosciences Fourth Quarter and Full Year 2023 Financial Results Conference Call. You may now disconnect your line, and have a wonderful day.