Alkermes plc (ALKS) Q4 2024 Earnings Report, Transcript and Summary

Greetings, and welcome to the Alkermes Fourth Quarter 2024 Financial Results Conference Call. My name is Melissa, and I will be your operator for today's call. All participant lines will be placed on mute to prevent any background noise. [Operator Instructions]. Please note this conference call is being recorded. I will now turn the call over to Sandra Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Thank you. You may begin.

Thank you. Good morning. Welcome to the Alkermes plc conference call to discuss our financial results and business update for the quarter and year ended December 31, 2024. With me today are Richard Pops, our CEO, Blair Jackson, our Chief Operating Officer and Todd Nichols, our Chief Commercial Officer. A slide presentation, along with our press release, related financial tables and reconciliations of the GAAP to non-GAAP financial measures that we'll discuss today are available on the Investors section of alkermes.com. We believe the non-GAAP financial results, in conjunction with the GAAP results, are useful in understanding the ongoing economics of our business. Our discussions during this conference call will include forward-looking statements. Actual results could differ materially from these forward-looking statements. Please see Slide 2 of the accompanying presentation, our press release issued this morning, and our most recent annual report filed with the SEC, for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we will open the call for Q&A. And I'll turn the call over to Richard for some opening remarks.

Thank you, Sandy and good morning everyone. So 2024 was a year defined by commercial execution, efficiency and profitability, and pipeline progress. During the year, key achievements across each of these initiatives demonstrated the realization of our goal of becoming a pure play, highly-profitable, fully integrated neuroscience biopharmaceutical company. This morning, we will review our strong 2024 financial performance, will discuss our financial expectations for 2025, and provide our view of the key value creation opportunities for Alkermes in the year ahead. Blair and Todd are going to give you the details, but here is my view in the aggregate. 2024 was a banner financial year for the company. We exceeded $1.5 billion in revenue, primarily driven by our proprietary commercial portfolio of medicines discovered, developed, and commercialized by Alkermes. We managed the business to drive robust profitability and met our EBITDA goal. This yielded more than $450 million of EBITDA from continuing operations while investing in the pipeline programs that we believe will drive the future growth of the company. We used the profits we generated to strengthen the balance sheet -- we repurchased approximately 8 million shares, retired all of our debt and ended the year with $825 million of cash on the balance sheet. We take the same financial ethos into 2025 and will continue to manage the business with a focus on profitability. As we previously outlined on our last earnings call, we expect to generate over $200 million of EBITDA in 2025, while advancing the orexin program as aggressively as we can. The financial expectations for 2025 that Blair will outline next reflect the line of sight we have into the current dynamics, with customers and payers, in the competitive markets where we operate. For our mature products, VIVITROL and ARISTADA, we expect flat to modest growth, and for our most recently launched product, LYBALVI, continued growth and uptake in those markets. We will take you through the specifics, particularly for Q1, so we all can start the year in alignment. As we prepare for key ALKS 2680 Phase 2 data readouts later this year, we are focused on delivering solid and predictable financial performance. All that leads to what we think is the principal value driver for the company in 2025: key data readouts for our lead development candidate, ALKS 2680, which is currently enrolling two well-powered, randomized, placebo-controlled Phase 2 studies in patients with narcolepsy. With planned cumulative enrollment of 160 patients and expected completion in the second half of this year, we designed these studies to provide robust datasets that will highlight the key characteristics of this candidate, and along with that, the commercial opportunity and competitive positioning associated with it. I will provide some additional insights into the 2680 development program later in the call, but for now the point is that ALKS 2680 is on the threshold of revealing its medical and commercial potential. We are a leader in the development of new medicines based on orexin biology, which is one of the most exciting potential new therapeutic categories within neuroscience and represents a transformational opportunity for Alkermes in the years ahead. We have been laying the groundwork for 2025 for several years and we are well positioned heading into this eventful year. So with that as an overall introduction, let me turn over to Blair.

Thank you, Rich. 2024 was Alkermes' strongest year of financial and operational performance to date. Financially, we generated more than $1 billion in revenue from our proprietary commercial product portfolio, delivered EBITDA from continuing operations of approximately $452 million, repurchased $200 million of the company's shares, retired $290 million of debt and ended the year debt-free with approximately $825 million of cash on the balance sheet. Operationally, we completed the sale of our manufacturing business in Ireland, which streamlined our manufacturing footprint and positioned the company to expand gross margins going forward. We also made significant progress advancing our neuroscience development pipeline and are looking forward to important Phase 2 data readouts this year for our lead candidate, ALKS 2680, in narcolepsy. In 2024, we generated total revenues of more than $1.5 billion, driven primarily by our proprietary product portfolio which grew 18% year-over-year and generated more than $1 billion in net sales. For the year, we recorded VIVITROL net sales of $457.3 million, reflecting 14% growth year-over-year. Net sales of the ARISTADA product family increased 6% year-over-year to $346.2 million in 2024; and LYBALVI net sales increased 46% year-over-year to $280 million. Across the proprietary commercial portfolio, due to the timing of shipments ahead of the holidays, the fourth quarter included an extra ordering cycle to cover the first week of the year. Inventory normalized to pre-holiday levels in early January so you can think about this as pulling in one week of orders from Q1 into Q4. These dynamics resulted in year-end wholesaler inventory build of approximately $20 million and primarily impacted VIVITROL and ARISTADA. Our fourth quarter results also reflected gross-to-net favorability primarily related to lower Medicaid and VA utilization and certain other credits. These factors drove a one-time gross-to-net benefit of approximately $12 million for VIVITROL and approximately $3 million for ARISTADA. Taken together, these inventory and gross-to-net dynamics resulted in a proprietary product revenue tailwind of approximately $35 million in Q4. Moving on to our manufacturing and royalty business. For the year, we recorded manufacturing and royalty revenues of $474.1 million, primarily driven by royalties related to long-acting INVEGA products of $236.4 million and revenues from VUMERITY of $134 million. Now, I'll turn to our full-year 2024 operating expenses and our financial results from continuing operations. These results reflect the separation of our former oncology business which was completed during the fourth quarter of 2023. Costs of goods sold were $245.3 million, compared to $253 million for the prior year. R&D expenses were $245.3 million, compared to $270.8 million in the prior year. This consisted of focused investments in our neuroscience development programs, primarily related to the ALKS 2680 clinical program and support activities for our proprietary commercial products. SG&A expenses were $645.2 million, compared to $689.8 million in 2023, as we continued to invest in the growth of LYBALVI and focus on efficiency. Overall, the business drove significant profitability from continuing operations generating GAAP net income of $372.1 million, non-GAAP net income of $494.4 million, and EBITDA of $452.4 million for the year. Turning to our balance sheet. We ended the year in a strong financial position. As I outlined earlier, during the fourth quarter, we prepaid approximately $290 million of our outstanding debt, ending the year debt-free with approximately $825 million in cash and total investments. We continue to have $200 million of remaining share repurchase authorization and going forward, we may opportunistically repurchase shares dependent on market conditions and the capital needs of the business. In 2025, we plan to manage the business to deliver significant profitability and cash flow while investing in the growth opportunities that we believe will be the key drivers of shareholder value. During our third quarter earnings call, we previewed our expectation to generate EBITDA of greater than $200 million for 2025 and today I'll provide more detailed financial expectations. In addition, given the transformation of our business over the last several years and feedback we have received from shareholders, we are transitioning to an adjusted EBITDA metric going forward in lieu of non-GAAP net income, as we believe adjusted EBITDA better captures the dynamics of our underlying business. Our expectations were outlined in the press release and 8-K issued this morning. Starting with the topline, we expect total revenues for 2025 to be in the range of $1.34 billion to $1.43 billion, driven primarily by net sales from our proprietary products in the range of $1.09 to $1.15 billion. As we've previously disclosed, in 2025, we expect manufacturing and royalty revenues to decrease by approximately $215 million compared to 2024 reflecting the expiration of the INVEGA SUSTENNA U.S. royalty in August 2024 and the conclusion of certain legacy manufacturing revenues following the sale of our manufacturing business in Ireland last year. Turning to expenses. Costs of goods sold are expected to be in the range of $185 million to $205 million, reflecting our streamlined manufacturing footprint. R&D expenses are expected to be in the range of $305 million to $335 million. This level of R&D spend is to accommodate our ongoing ALKS 2680 Phase 2 programs in narcolepsy and the planned initiations of the ALKS 2680 Phase 2 program in idiopathic hypersomnia and first in human studies for ALKS 4510 and ALKS 7290, our next orexin 2 receptor agonist candidate. SG&A expenses are expected to be in the range of $655 million to $685 million, which reflects investments in the expansion of our psychiatry sales team, targeted investments in the promotional support for our commercial products and continued focus on operational efficiency. We expect an effective tax rate of approximately 17% in 2025. We are committed to maintaining a robust cash generating business and expect to deliver GAAP net income in the range of $175 million to $205 million, EBITDA in the range of $215 million to $245 million and adjusted EBITDA in the range of $310 million to $340 million. As we look ahead to Q1, due to more pronounced seasonality related to the year-end ordering patterns in Q4 and the dynamics within our royalty and manufacturing portfolio that I previously outlined, I'll provide some additional color on quarterly trending expectations to facilitate modeling. In the first quarter of 2025, we expect our net sales from our proprietary commercial product portfolio to be in the range of $220 million to $240 million. This reflects our expectation of wholesaler inventory normalization related to the extra order cycle in Q4 and usual first quarter inventory drawdown patterns, typical Q1 patient copay and deductible reset dynamics, and historical demand patterns. The royalty and manufacturing revenue will reflect the annual reset of the royalty tiers on the remaining long-acting INVEGA products, the conclusion of certain manufacturing revenue streams, and typical Q1 end-market seasonality. We expect these factors will drive a sequential decrease of approximately $60 million compared to Q4. On the expense side, we expect costs of goods sold in the first quarter of 2025 to be down sequentially from the fourth quarter, consistent with historical Q1 sales patterns. For the first quarter of 2025, we expect R&D expenses to increase approximately $15 million sequentially from Q4, primarily driven by activities related to the ALKS 2680 Phase 2 programs in narcolepsy, and study start-up activities for the idiopathic hypersomnia Phase 2. We expect SG&A expenses to be similar to the first quarter of 2024, reflecting investments in LYBALVI promotional activities and the expansion of our psychiatry field sales force during the quarter. Taken all together, we expect Q1 to be closer to breakeven on an EBITDA basis, with total revenues and profitability to increase significantly in the second quarter and remain fairly consistent overall in the second half of the year. These expectations for quarterly trending are reflected in the full-year financial expectations that I outlined a few moments ago. We entered 2025 well-positioned financially with a strong balance sheet, a substantial commercial business and a continued focus on operational efficiency and profitability. We are investing in the initiatives that we believe will drive the future growth of the company and significant opportunities to create value for shareholders. With that, I will now hand the call to Todd for a review of the commercial portfolio.

Thank you, Blair and good morning everyone. 2024 was an important year of execution of our commercial strategy and I'm pleased that we achieved our expectations of proprietary net sales in excess of $1 billion in 2024, which reflected 18% year-over-year growth. Blair has taken you through the net sales performance, so for my remarks, I will focus on underlying demand trends and our strategic focus areas and expectations for 2025. Starting with VIVITROL. In 2024, VIVITROL net sales grew 14% year-over-year, driven by 6% underlying demand growth. This demand growth reflects strong traction in the alcohol dependence indication, slightly offset by demand in the opioid dependence indication. The alcohol dependence indication represented approximately 75% of VIVITROL volume and it is where we focus our promotional efforts. As we look ahead to 2025, we expect VIVITROL demand to grow at mid-single-digit rates and net sales to be in the range of $440 million to $460 million. Turning to our psychiatry franchise, which includes both ARISTADA and LYBALVI. We are focused on delivering growth across the franchise and are making strategic investments that we believe will drive underlying demand and profitability. For the ARISTADA product family, in 2024, ARISTADA net sales grew 6% year-over-year. In 2025, we expect underlying demand to remain fairly consistent compared to last year and ARISTADA net sales to be in the range of $335 million to $355 million. In 2024, net sales of LYBALVI grew 46% year-over-year, primarily driven by underlying TRx growth of 39%, with growth coming from both the schizophrenia and bipolar I disorder indications. Our promotional and direct-to-consumer advertising activities will continue to focus on driving adoption in both indications, utilizing tailored approaches to effectively target each segment. During the year, we made significant progress in enhancing the access profile for LYBALVI in the commercial payer channel, with additional plans taking effect in January of this year. Looking ahead, in 2025, we expect these improvements will lead to a slight widening of gross-to-net adjustments to the mid-30s as we previously outlined. We are pleased with LYBALVI's access profile today and will remain focused on additional opportunities to enhance our coverage going forward. In 2025, we expect LYBALVI demand to grow by approximately 25% year-over-year and net sales to be in the range of $320 million to $340 million. For both LYBALVI and ARISTADA, as we enter 2025, we will continue to focus on the competitive dynamics in the antipsychotic space as we invest in, and expand our psychiatry sales team in order to preserve a competitive share of voice for LYBALVI and reaccelerate growth for ARISTADA. We plan to complete our sales force expansion in the first quarter and expect contributions from the new sales positions to be tangible a few quarters from now. With the expansion of the sales team, an enhanced access profile for LYBALVI and a strong value proposition for both brands, we believe we are well positioned to achieve our 2025 goals for ARISTADA and LYBALVI. We look forward to sharing our progress with you. With that, I'll pass the call back to Rich.

Okay. Thank you, Todd. We operate in commercial environments that require particular capabilities and scale. Our strategy, and our investments, focus on growth and profitability while enabling broad access to our medicines. We are well positioned there to be successful. Our commercial business is the economic engine of the company. Its cash flows give us the non-dilutive capital to invest aggressively in our development pipeline while maintaining profitability. And that pipeline is now at a stage where it has the potential to be transformative for the company. We see that becoming clear in 2025, with planned Phase 2 data readouts for ALKS 2680 in narcolepsy Type 1 and narcolepsy Type 2. ALKS 2680 is our novel orexin 2 receptor agonist. From the outset, we designed it with a future competitive profile in mind, incorporating things we have learned making medicines for patients in the real-world setting. For ALKS 2680, the goal has been to offer simple, once-daily dosing and importantly, a range of doses to accommodate patients across narcolepsy Type 1, narcolepsy Type 2 and idiopathic hypersomnia. Advancing multiple doses would offer patients and physicians the potential to adjust dosing to individual needs and preference, which is an important feature across many CNS disorders. Let me spend a moment on these hypersomnolence disorders. Orexin is the master regulator of wakefulness. Narcolepsy Type 1 is characterized by the absence or loss of orexin neurons in the brain. In NT1, an orexin 2 receptor agonist has the potential to replace the missing neuropeptide and restore normal wakefulness. Clinical data in NT1 provide strong evidence of this activity. Narcolepsy Type 2 and idiopathic hypersomnia are associated with more normal orexin tone in the brain but may also be associated with aberrant signaling of the orexin system. A foundation of clinical data suggests that an orexin 2 receptor agonist can promote wakefulness in these patients too. Data from our ALKS 2680 Phase 1b study and an early proof-of-concept study conducted by others both demonstrated significant improvements in wakefulness in these disorders. At sufficient doses, we believe based on data observed, that orexin 2 receptor agonists may have significant potential utility in NT2 and IH. From a regulatory and development perspective, we are advancing ALKS 2680 pursuant to a strategy designed with the end goal in mind, which is FDA approval and competitive positioning. With proof-of-concept data from a robust Phase 1b program in patients with narcolepsy in hand, last year, we moved into well-powered, parallel design, confirmatory Phase 2 studies in NT1 and NT2. Each study is designed to enroll 80 patients. These studies will represent a significant additional increment of data for the entire field. When we are done, we will have 160 patients worth of data testing a range of doses over a multi-week period in the outpatient setting. These are studies of sufficient design and duration to more fully characterize safety, tolerability, efficacy and dose response. These data will inform our ALKS 2680 Phase 3 design and also begin to elaborate our potential competitive positioning in the class. I'll give you a quick update on the progress we are making with Vibrance 1 and Vibrance 2, our Phase 2 narcolepsy studies that we initiated last year. We have made significant progress with site initiations and enrollment, and I'm pleased with our momentum. We are now enrolling patients in the U.S., EU and Australia. We expect data from both those studies in the second half of this year. As we exit this quarter, this first quarter, we should have sufficient line-of-sight to estimate completion timing with more specificity. In idiopathic hypersomnia, we submitted an IND to the division of neurology at FDA and are expecting to initiate that Phase 2 study in early Spring. This study will be known as Vibrance-3 and it will share structural features of the narcolepsy studies -- randomized, placebo-controlled double-blind, parallel design for eight weeks. The doses will mirror our NT2 study at 10, 14 and 18 milligrams. Consistent with pivotal studies that have supported approval in idiopathic hypersomnia, we'll use the Epworth Sleepiness Scale as the primary endpoint and the idiopathic hypersomnia severity scale, or IHSS, as a key secondary endpoint. So, in conclusion, for both our narcolepsy and IH, we see the structure and execution of the Phase 2 program as the springboard for Phase 3, registration and commercial positioning. We are planning for success and preparing for the pivotal program with manufacturing, protocol design, and regulatory workstreams all underway. It's going to be an exciting and busy year. So with that, I'll turn the call back to Sandy for the Q&A.

Melissa, we'll open the call for Q&A now please.

Thank you. [Operator Instructions]. Our first question comes from the line of Paul Matteis with Stifel. Please proceed with your question.

Hey, thanks so much for taking my question. I appreciate it. I just had one on the Orexin program. I was curious, with these studies now well underway and specifically related to the NT2 study. I was wondering how close you guys are monitoring adverse events, retention, things like that on a blinded basis, especially as one of the questions to the class is how does tolerability look in larger studies outside of NT1. And so any color you could provide there if it is applicable, would be helpful. And maybe just speak to your confidence again in the therapeutic index across broader populations? Thanks.

Hey Paul, it's Rich. I'll take that one. So obviously, these are blinded studies, multicenter, multi-country, but we monitor safety on an ongoing basis and not just ourselves, our team, but we have a DSMB that meets regularly to look at that. Remember, the structure of the design is a six-week double-blind period with a seven-week extension thereafter. And we expect a high degree of retention throughout the whole program, and we haven't seen anything to dissuade us from that at this point. As I said in the prepared remarks, I think that the logic and the data supporting NT2 is pretty strong, recognizing these slightly higher doses, what we saw in our Phase 1b program is clear dose response notwithstanding the baseline variability that you might see in NT2. So we're encouraged at this point and we look forward to completing study.

Great. Thank you.

Thank you. Our next question comes from the line of Charles Duncan with Cantor Fitzgerald. Please proceed with your questions.

Hey, good morning Rich and team. Congrats on a good year of progress. I wanted to ask a quick commercial question and then a follow-up on the pipeline. With regard to the commercial setting, I guess I'm wondering if you are not if you're considering what you're considering in terms of competitive dynamics for LYBALVI and ARISTADA given BMS and J&J, becoming more active in the space. And I think Todd mentioned expanding the sales force. Can you give some color on, call it, the magnitude of that expansion?

Yes, absolutely, Charles. This is Todd. I'll take that as well. We look at the competitive dynamics all the time. The benefit to our portfolio would be market growth as more companies invest in the category, which we think is a good thing. But it doesn't really change the strategy that we have. We're going to -- in 2025 actions that will again show really strong demand growth for LYBALVI approximately 25%. We're also going to be expanding our sales force, as I said in my prepared remarks, that's been something that we've been watching and preparing for a while, and that's really intended to make sure that we maintain really strong competitive share of voice and that we're able to not only compete effectively, but really maximize the portfolio. As I said in my prepared remarks, it's about demand growth for us, but also profitability. And I think we're right on track for that in 2025.

I mentioned the size of the expansion.

Yes, absolutely. The size of the sales force expansion we're looking at, we're going to add up approximately 80 representatives that will be online at the end of this quarter, and we expect them to be operational in Q2. All of my experience tells me it just takes a couple of quarters for that to play out. They get trained and get into the marketplace to start educating HCP. So our expectation is we'll start to see the benefit of that expansion in the latter part of the year.

Very good. That's helpful. Quickly on Vibrance-1 and 2, realize that by end of the quarter, you'll give more guidance. But when you consider the NT1 patient population versus NT2. Can you provide some color on the interest in the two studies? And could they read out at the same time or is NT1 ahead of NT2 or reverse?

Hey Charles, it's Rich. It's hard to say it sort of jockey for the lead and as the two studies get up and running. NT2 started a little bit later. But with little competition that ramp inside initiations ramp really, really quickly. Vibrance-1, the NT1 study now is open in multiple countries and coming out of the Christmas holidays. We're enrolling aggressively in that one now. So -- it's too early to say, but I think our hope is that they finish roughly at the same time in the second half of the year, hopefully give you more precision probably on the next call.

Excellent. Thanks.

And Charles, I'll just say, as a general matter, the interest in the community of the orexin 2 receptor agonist is extremely high in NT1, NT2 and IH. And I think that, that's the sea change we've seen over the last year or so as more and more practitioners get aware of the developments that are happening in the field, I think the excitement level around the category is building.

Thank you. Our next question comes from the line of Umer Raffat with Evercore ISI. Please proceed with your question.

Hi, guys. Thanks for taking my question. I have two here, if I may. First, a quick one on orexin. Rich, could you remind us if you're expecting the Type 2 study, the Narcolepsy Type 2 to come before Type 1 or not? I know you had commented on the recruitment rates on both trials previously. So I'm just curious. Secondly, on LYBALVI, I'm just still trying to work my way through this. There's -- if we stick to the current gross to net and if we stick to the cadence of Rx growth we've seen in 3Q and 4Q, it could imply a number which is below even the low end of your guidance. But on the flip side, we know there was a little bit of gross net delta as well as some inventory effects that were also helping. So if you could just walk us through some of that that would be very helpful. Thank you.

Good morning, Umer. It's Rich Pops. The NT2 study is enrolling well, and the NT1 study is enrolling well. And the big change since we talked about last coming out of holiday is that lot of our European sites in the NT1 study are up and running now in screening patients. So I think it's a horse race between the two of them. We'll have more precision on the actual completion date in a couple of months' time.

Yes, Umer, this is Todd. I'll comment on the LYBALVI. So if you look at the Q4 dynamics from LYBALVI, we saw approximately 5% TRx growth, which was relatively consistent with Q3, which is a healthy sign. That was really driven by continued expansion with ACP breadth year-over-year ACP breadth, our customer breadth grew by approximately 27%. So it's a really good leading indicator on the health of the brand and how it's expanding. Going into '25, our expectation is that, again, we're going to see -- we're going to see continue to see strong demand growth. There is going to be the typical demand patterns that Blair mentioned in Q1. So we would expect that, but we expect building out of that in Q2, Q3 and Q4. And it's really going to be driven by our sales force expansion. Once we do the sales force expansion, our total footprint will be approximately 400 sales representatives, which is a really good, strong share of voice, and that's going to be supported with expanded market access. So in Q1, we think the market access position for gross to net can expand to around mid-30s. And then it will modulate down in Q2, Q3 and Q4. So the full-year will be around that mid-30 range. And that's a really important attribute for how we see demand growth, because as I said in my prepared remarks, we are entering the year with even a stronger market access position, more patients in commercial, more patients in Medicare Part D have access, and we think that's going to be a big driver of our demand growth for '25.

Thank you. Our next question comes from the line of Akash Tewari with Jefferies. Please proceed with your question.

Hey, this is Amy on for Akash. Thanks so much for taking her questions. So on orexin 2, what's your confidence that ALKS 2680 can differentiate on safety versus TAC 861 in NT1? And what do you think the bar is? And another one, if we can. Some of your competitors in the orexin 2 space are alluding to the ability to proceed into Phase 3 trials with an expedited Phase 2a. What do you think the FDA wants from their Phase 2 studies when it came to dose exploration in end? Thanks so much.

Hi, Amy. It's Rich. I'm afraid I won't give you a whole lot of information about other people's programs. So I'll just tell you about ours. The whole point of our Phase 2 design is by this design, i.e., 80 patients multi-week parallel design with a primary endpoint of six weeks, followed by an open-label safety evaluation with dose ranging is to establish the safety, tolerability, efficacy dose response profile in a rigorous way. So when we complete those studies, we'll have a very, very clear picture of our drug, and then we'll be able to compare it to any other drug that is a similar stage of development. In terms of particular safety, I think as my earlier comment stands, I think until we have the Phase 2 data, we won't be able to say how we're differentiated on the safety basis. But we believe the program is already differentiating it's priority, given the range of doses that we've shown, the dosing flexibility and the overall safety and tolerability we've demonstrated in 1b. All of that needs to be re-perpetuated and expanded in Phase 2, and then we'll have a clear picture. But I think categorically, between ourselves and others in the orexin 2 receptor and its class, it's striking that the overall tolerability we've all demonstrated is largely mild to moderate transient side effects with pretty significant and profound efficacy benefits for patients.

Got it. Thanks so much.

Thank you. Our next question comes from the line of Jessica Fye with JPMorgan. Please proceed with your question.

Hey guys. Good morning. Thanks for taking my question. A question on the 2025 guidance. What does that contemplate for INVEGA TRINZA as it relates to any risk of generic entry? And where does that litigation stand? And can you maybe characterize how much it contributes to the royalty revenue line. Thank you.

Yes. Thank you for the question, Jessica. It's Blair. I think as we move into the beginning of the year, we have a little bit of dynamics as associates with INVEGA, recognizing that the U.S. royalty expired in August of last year. So we'll be resetting to the lower rates as we move into Q1 of this year. And then we'll be achieving royalties moving forward, ex U.S. through 2026 and then the rest of the CABENUVA are no longer acting through 2030. So the INVEGA component of our overall say manufacturing and royalty line is typically in the range of about 40% to 50% depending on where you are moving forward.

Thank you.

Thank you. Our next question comes from the line of Chris Shibutani with Goldman Sachs. Please proceed with your question.

Thank you and good morning. Two maybe broader questions. One, in terms of thinking about clinical development risks for assets for the neuroscience. We've certainly always known that it's very difficult. There's been some recent industry examples where it's been kind of characteristic. Rich, you and your team have been no strangers to going through this. The journey has been long. What are you putting in place with the Orexin program that you think informs and helps mitigate some of the risk? And then second, more of a broad policy related question, Rich, again, you have had seats at some important tables thinking about the implications of health care policy on your business. And I would really appreciate if you could opine on a couple of points, perhaps if I could touch upon NIH-related funding implications on research, tariffs, IRA, a couple of the big pictures, which you have been helpful in the past look to get your insights as it relates to Alkermes and perhaps broadly to the industry? Thank you.

Good morning, Chris. First, on the clinical development risk, which is sort of endemic -- when we think about CNS are you think about clinical development risk and actually expansion of that risk between Phase 2 and Phase 3, that's part of the attractiveness of this orexin program. That often that condition that I just described is often what you find in psychiatric studies where the endpoints are things like PANS or HAMD or MADRS, where you're asking patients how they feel on an ongoing basis with the primary analysis happening often at a time point where you have huge placebo response as patients respond to care in the context of a clinical trial. If you contrast that in something like narcolepsy Type 1, where patients are washed out of all of their medicines. They are highly symptomatic at the data randomization. And they receive a really effective medicine. The placebo response is much more muted, if at all. So it's one of the reasons we are able to see a p value with such a small number of patients in our 1b study. We expect that to continue into Phase 2 and into Phase 3. And for that reason, we see Phase 2 as being very, very indicative of what we would expect to see in a replicate Phase 3 study. And that's why we've powered them so much and make them look as much like pivotal studies as you would want to see in Phase 2. Policy questions along, I won't bore with everything about it, but the overall admonishment that it's very fluid right now, as you would know. Going down your list, NIH funding is something that I think is -- it's going to be focused and be focused on intramural funding at NIH extramural is just so important for the public health and such a track record being valuable. But I think that there's going to be real scrutiny on efficiency and allocation of capital. Tariffs, I think that we've done a tariff analysis on our own business, just given the way our supply chain is configured we don't have a major exposure to tariffs. And I think we all wait to see how significantly, how sensibly those are implemented. Fixes to the IRA, I think are going to be problematic. I think there's some rifle shot fixes that you could anticipate. But I think in the context of reconciliation and all the other moving parts, I don't think they're a top priority right now, but I think there are some rifle shots that are possible that you can always characterize as fixes to the law as opposed to a complete rewiring of the law. Our probably biggest concern and focus there going to be watching from a policy standpoint is if you think of it under the IRA, Medicare Part D was focal in this new regime, you've got to figure that Medicaid is going to be focal just [indiscernible] there. So we want to make sure that in the event that Medicaid is being reconsidered or revamped that our patients, those with serious math of illness and addiction are not disadvantaged. And we think there's a good chance of doing that given the public health.

As always thanks for that awful responses.

All right, Chris. Take care.

Thank you. Our next question comes from the line of Marc Goodman with Leerink Partners. Please proceed with your question.

Yes, can you give us any more color on what's going on with these next-gen erections or when are you going to give us more color on what indications or just anything that you're willing to share just incrementally since we're on a live call here? And then just secondly, I know I've asked you about business development quite often, and obviously, we're spending a great deal of money on orexins and everyone is excited about it, you should be spending the money. They're just curious what's going on behind the scenes and business development? And if -- should we be surprised if there's a deal or not a deal for anything else this year to kind of add to the pipeline? Thanks.

Good morning, Marc. I'd love to give you more information on the next generation erections not going to, because I feel like our teams -- I feel like we're ahead of the curve on this. We identified the fact that we were going to go beyond narcolepsy a couple of years ago, we began a lot of investigated work of going through that panning a filtration to figure out where we think the smartest places are to go next. We gave you a little bit of a directional teas in the JPMorgan presentation where we showed you where we're looking categorically in ultra-orphan as well as broader indications. And we've mentioned that both 4510 and 7290 were the two new erections going into the clinic this year, have different pharmacologic properties that make them somewhat distinct from ALKS 2680. And we'll give you more indications where we're going precisely as we complete the SAD and MAD studies, because those studies are the necessary prerequisite to determine whether we have a safe, well-tolerated drug that's engaging the target, from those studies, we'll go right into what we hope will be that the orexin studies where we go into patient studies in Phase 1b or 2a or we can see early on whether we have signs of signal to confirm the hypothesis. So on the BD side, you can see the pipeline expanding naturally along this orexin wakefulness hypocretin pathways. And that's going to continue to enrich. There are all some degree of covariance between them. So we're always looking for critically clinical stage assets that might broad net portfolio. We're going to stay an independent pure-play neuroscience company with the financial resources we have, we will expand the pipeline. There is no question about it. But we kiss a lot of frogs in the BD side, and we do a lot of analysis. And it's an exception rather than the rule when they get through the filter. So it's hard to predict when that might happen. Also on the commercial side, you've heard us talk about before, we would love to be able to and leverage this commercial infrastructure. And there's just not a whole lot of products, but we're always investigating ones that are emerging or nearing commercialization as well as those in the market. So I don't feel like we have a gun to our head and urgency, but we've got the financial resources and the instinct to do it.

Thank you.

Thank you. Our next question comes from the line of Uy Ear with Mizuho Securities. Please proceed with your question.

Hey guys. Thanks for taking the question. Rich, maybe just a follow-up on your brief comment about Medicaid funding. Maybe just help us understand what the sources for VIVITROL as these days given the shift from opioid to alcohol dependents. And maybe just help us kind of think about if there is in Medicaid cut. How should we sort of think about the potential risk to this product? And along that line, maybe just also help us understand the impact, I guess, from IRA Medicare Part D redesigned for this year and potentially next year? Thanks.

Good morning, Uy. I'll take some of it. Blair, Todd, feel free to chime in. So Medicaid is an important source of business for all of our products, LYBALVI, VIVITROL and ARISTADA. But I don't want anybody to panicky about this yet. This is all very notional. My overarch your comments on that, if you -- if one is ambitious to cut $1 trillion from the federal government, at some point, you're going to be looking at allocation of monies to states under Medicaid. Now schizophrenia drugs, bipolar drugs, and addition drugs are not breaking the bank in Medicaid. There's a lot of other places in Medicaid where you can look to save money. So our -- through the extent that you do see some type of Medicaid reforms count on the fact that we will be in there advocating to maintain access to these types of medicines for patients. They're priced fairly, the gross to nets are high. We are responsible participants in the overall ecosystem. We're not the bad actors -- not imply [indiscernible] is a really bad actor to say we're not the big economic swimming factor that's going to drive this. So I think we're going to have, to the extent that people start focusing on Medicaid. We think there's an opportunity actually to focus on the benefits that medication provide to chronic disease sufferers with addiction and serious method illness. On the Part D side, on the Medicare Part D side, we qualify it for the phasing. So our exposure in 2025 is 1%. So that's a perfect example of how we use our positioning to drive policies that have protected companies like ours and we're providing medicines at fair prices into the system.

Could you also maybe talk a little bit about the sources of funding for VIVITROL? Thanks.

Yes. Absolutely, I can do that. So we look at the total mix. For VIVITROL, it's been relatively stable. About 50% is in the Medicaid channel. 45% or so is in commercial, and that's growing with our focus on apple independence. It's more of a commercial patient, and the remainder is within the PHS segment.

Thank you.

Thank you. Our next question comes from the line of Troy Langford with TD Cowen. Please proceed with your question.

Hi, everyone. Congrats on the quarter and thanks for taking our question. Just really quickly on ALKS 2680. How quickly do you think you also move into pivotal studies in NT1 or NT2 patients upon positive data this year. I guess part of the gating items the initiation of the Phase 3 studies? And do you think we could see a pivotal study before the end of the year.

Yes, let's see how fast we finish up the Phase 2s, but I can tell you a lot of the Phase 2 infrastructure build is anticipatory for Phase 3. And so our hope the way we sequence this, we top-line results in NT2. We schedule end of Phase 2 meeting with FDA. As soon as we can figure out of time based on our completion to have that meeting. Meet with review division in this case, its DPP in divisional psychiatry. Depending on the results, we will probably look to file for breakthrough designation in NT2. And that opens up the line for discussions about accelerated pathways to market. So we're going to be preparing to start Phase 3 as quickly as we can after we complete that in a Phase 2 meeting with FDA.

Okay. Thanks for the additional color.

Thank you. Our next question comes from the line of Douglas Tsao with H.C. Wainwright. Please proceed with your question.

Hi, good morning. Thanks for taking the questions. Maybe as a starting point, Rich, I think it would be helpful to just provide some perspective on what you think your competitive advantages are in the orexin space. Obviously, you have a head start in terms of clinical development across some indications, and it indicates that in future broader ones outside of to sort of wait for the sleep category, you're ahead. So maybe just from a chemistry standpoint, just because obviously, we started to see other companies begin to focus on the erection space. Maybe just walk through some of the challenges that others might experience and why you think that your sort of first mover advantage will prove to be durable? And then I have a follow-up on the LYBALVI? Thanks.

Doug, good morning. Orexin 2 receptors are debroking couple receptors located in the brain. And so from a municipal chemistry perspective, it's a high degree of difficulty challenge because you need to create a small molecule GPCR agonists, which requires a fair amount of structure generally, they need to be orally bioavailable. They need to cross the wording barrier. They need not to be a pump substrate, so they get bumped out of the brain. And then all that has to happen with a pharmacokinetic profile that's consistent with the natural sleep wake cycle. To enable once-a-day dosing. So we know the specific amino acid residues one needs to bind in order to have agonists. We'll publish on the data on our patents so that people will see it in more and more. So the question is if you're coming behind us, how do you actually improve on what we and others are doing? In other words, if we have once a day dosing with a range of doses that are well tolerated that are used in NT1 and NT2 and IH. There's not a lot of space there. Now no drug is ever perfect, right? So until we fully elaborate the characteristics of this drug in the Phase 2 study, it remains at radical. But right now, we're quite pleased with the profile that we have. So I think our competitive advantage right now in the current course rate is that we have positive data in all three differential diagnosis, NT1, NT2, IH. We have a range of doses, therefore, showing dose response and dose proportionality and the dosing between NT1 NT2 and IH are adjacent. That is 4 6, 8 milligrams being tested in Phase 2 for NT1 that abuts immediately against 10, 14 and 18 milligrams in NT2 and IH. So if that turns out to be somewhere close to the ultimate commercial range it allows those patients and doctors to flexibly adjust their dose to accommodate their own individual disease needs and/or aspirational life aspirations as well. So I think that we like the position right now. And we also believe that as the field gets more extensively elaborated, others will come in. And if I feel like narcolepsy is going to be well taken care of if ours and other drugs meet their profile. So then the action becomes the other adjacencies, which we think are quite promising. That's why we're putting 4510 and 7290 in the clinic, because we want to be ahead of that as well. So we're already anticipating success in narcolepsy, recognizing the risk that still exists. But operationally, preparing now for narcolepsy from a commercial perspective, and expanding into new indications to capitalizing on the increasingly credential pharmacology.

And Richard, I can, a follow-up in terms of your earlier comments. So in terms of sort of the multiple characteristics that are needed or sort of boxes you need to check in the orexin space. You would be sort of cautious when you look at some companies that are purporting to have sort of preclinical data or in vitro assays highlighting the sort of potency of their molecules relative to what you indicated have done just given the sort of need to -- there are the challenges around PK and penetration into the brand. Is that fair?

I think that's fair. I think I consider potency and selectivity to be seen in [indiscernible]. I mean you have to have high potency and high selectivity to play. But it's a little bit like saying I have a great race car because it has great tires you got to have an engine too, and you have some doors and some seatbelts and a helmet and all the other things and they can do a race car. So I think that all of those features, any one of those features, the deficiency handling and one of those features is going to lead to some type of competitive disadvantage.

Okay. Great. Thank you so much.

The only comment I'd add to that is that in our experience, nothing really matters until you get into patients because healthy volunteers, we found in our hands that even sleep-deprived healthy volunteers do not recapitulate the sleep pressure of an NT1 patient surge. So dosing is going to be indication-specific. And along with that is tolerability because what you find is that healthy volunteers tolerate different doses than in Q1 patients. And so our view is always, until you get into patients, you really can't get a sense of where you are with respect to therapeutic index, tolerability, safety and dose response.

Thank you. Our next question comes from the line of Joel Beatty with Baird. Please proceed with your question.

Hi, thanks for taking the question. For VIVITROL, what are the key dynamics that impact whether you'll be able to achieve that mid-single digit growth rate in scripts that was mentioned earlier in the call?

Hi, Joe, this is Todd. I'll take that. Our key focus for VIVITROL it is continued expansion in alcohol dependence. That's what's been -- that's what drove the brand in 2024. We actually saw demand growth for apple dependence of approximately 14%, which kind of helped offset some of the headwinds that we've experienced with opioid use disorder. So we really believe that the brand will continue to grow. I think you have to keep in mind, too, VIVITROL is a mature brand. So overall, demand will be consistent with the mature brand, but we still believe that subnational dynamics within the non-retail space, such as in the VA, for example, will continue to drive growth. So our two strategic areas are really the Apple independence indication sub-nationally, making sure that we can continue to drive access and growth within the VA.

Thank you.

We have time for one more question.

Thank you. Our final question comes from the line of David Amsellem with Piper Sandler. Please proceed with your question.

Hi, everyone. Thank you for taking my question. This is Alex on for David. Just one question for me. I know you touched earlier on competitive impacts associated with LYBALVI and why don't you dive more into that. That was developing a long-acting injectable form of olanzapine. I believe that they're submitting an NDA later this year, how would that impact the LYBALVI business? And are you anticipating that as any sort of headwind Also, have you seen any impact from COBENFY yet? Or do you anticipate any -- as that product continues to ramp? Thank you.

Sure. Yes, this is Todd. I'll take the last one first. So at this point, we haven't seen any impact to LYBALVI with COBENFY. In Q4, we saw TRx growth of 5% overall, which is very consistent with Q3, and we expect strong demand growth throughout 2025. I think it's just really important to remember with LYBALVI, it's a broad indication, so bipolar 1 disorder and schizophrenia versus COBENFY just in schizophrenia. And we're actually -- in '24, we saw a robust volume growth with both of those indications. In fact, we saw approximately 20% volume growth in the bipolar disorder indication. So it's a broad indication, broad population, and we feel really confident with our plan for '25, which has really underpinned with the expansion of the sales force. In terms of the potential olanzapine LAI. That's obviously something we always watch competitive dynamics. And we have a really strong capability with the olanzapine molecule. It's something that we know really well. And I think, really, the way that I would think about this is historically, and it hasn't changed, the rate limiting factor regardless of delivery for the olanzapine molecule is really around weight gain and also around metabolics. That's the whole reason why we develop LYBALVI. So LYBALVI, we believe, will continue to show strong growth even in the face of any additional competition.

The only thing I add to that Todd is typically, an LAI interest doesn't affect your oral side of the market. The LAI is its own sort of rarefied aspect. We wish it were a bigger part of the treatment algorithm, but it's relatively small. And LYBALVI obviously operates in that oral category, which is the vast majority of prescriptions.

All right everyone. Thanks for joining us on the call this morning. If there are any follow-up questions, please don't hesitate to reach out to us at the company.

Thank you. This concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.