Alkermes plc

Greetings, and welcome to the Alkermes Fourth Quarter 2020 Financial Results Conference Call. My name is Rob, and I'll be your operator for today's call. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. Please note that this conference is being recorded. I will now turn the call over to Sandra Coombs, Vice President of Investor Relations. Sandy, 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 31st, 2020. With me today are Richard Potts, our CEO, Ian Brown, our Chief Financial Officer, and Todd Nichols, our Chief Commercial Officer. Before we begin, I encourage everyone to go to the Investor section of Alkermes.com to find our press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we'll discuss today. 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 two of the accompanying presentation, our press release issued this morning, and our most recent annual and quarterly reports 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'll open the call for Q&A, and now I'll turn the call over to Richard.

Thank you, Sandy. Good morning, everyone. I hope you're all well. Let me start by saying in 2020, We demonstrated the resiliency of our organization and our business in response to historic challenges. And we added new scientific, financial, and governance elements to the Alkermes story. Against the backdrop of a challenging and shifting environment, we identified our key strategic priorities and we held ourselves accountable to execute against them. We took pride in the fact that our work directly impacted people whose lives were even more challenged by the pandemic. And we were compelled to figure out ways to keep our medicines accessible. So job one was commercial execution for Vivitrol and Aristata to support patients and to protect the company's top line. As COVID emerged and access to physicians and treatment centers became restricted, we adapted our approach to maintain continuity with prescribers to help ensure continued access to treatment. We developed a hybrid promotional model tailored to each territory. combining in-person and digital interactions, and we expect these adaptations to endure. The second priority was to advance our R&D programs, keeping our most important programs on track by figuring out ways to continue to advance program activity despite limitations on access to our own laboratories and the impact of COVID-19 on clinical trial sites around the world. We were successful in doing that. We prepared for and completed the successful advisory committee meeting for LaValvie, our oral antipsychotic candidate for the treatment of adults with schizophrenia and adults with bipolar I disorder. We significantly advanced Nembomucan and hit key milestones for that program. And we met our goal of nominating our first clinical candidate from our HDAC inhibitor program. The third priority focused on the efficient management of the business from a financial and operational perspective. As the pandemic evolved, we modeled a range of potential revenue disruptions and made adaptations to our cost base throughout the year. In December, we announced our value enhancement plan, designed to drive growth, improve operational and financial performance, and enhance shareholder value. For 2021, we're similarly focused in three major areas, with an explicit goal of revealing and elaborating the value that's embedded in this distinctive company. First, we want to continue to grow our revenue base. We have a substantial and growing top line, driven by important medicines that serve patient needs in difficult-to-treat diseases. Vivitrol, Aristata, and Vumerity, each is a distinctive medicine with its own value proposition. We expect that, if approved, LaValvie will be another important product in our psychiatry portfolio and a new long-term revenue stream for the company. Second is to demonstrate the value of the R&D investments we've been making. After being relatively quiet in 2020, In 2021, we'll reveal more about our efforts in our focus areas of neuroscience and oncology. Later this quarter, we'll host an investor day to give you a better understanding of these programs and some insights into additional candidates that we expect to emerge. The third area of focus is on profitability, making good on the commitments we established in the context of our value enhancement plan. The plan includes a commitment to multi-year profitability targets, a focus on the company's cost structure, exploration of potential strategic opportunities, and continued governance enhancements. Ian will talk more about that in a minute, but we're excited about the plan, and we think it provides a solid foundation for future valuation growth. We also announced some important changes to the leadership team at the beginning of this year. Blair Jackson was appointed to the position of Chief Operating Officer, and Ian Brown was appointed to the role of Chief Financial Officer. They each bring a wealth of experience and institutional knowledge to their new positions. And I'm really pleased to have Blair and Ian assume these key leadership roles at this pivotal time as we position the company for our next stage of growth and advance our commitment to delivering value for all of our stakeholders. So with that as an introduction, I'll hand the call over to Ian for a review of the 2020 results and our 2021 expectations.

That's great. Thank you, Rich. And hello, everyone. I'd just like to kick off by saying how pleased I am to be assuming the role of CFO at this important time in the company's evolution. As we focus on value creation, the strategic priorities for the company are clear. Efficient management of our business from a financial and operational perspective are paramount, and I'm optimistic about our potential to drive meaningful value through these initiatives. At the end of 2020, we announced a value enhancement plan that established long-term profitability targets. The plan includes a commitment to achieving non-GAAP net income of approximately 25% of the company's total revenues in 2023 and approximately 30% in 2024. Over the next few years, we expect that our top line will be driven by growth of our diverse portfolio of commercial products, and we will also focus in parallel on managing the major cost levers within the business, our investments in R&D as we seek to replenish and advance the pipeline, the spend that drives the growth of our proprietary commercial products, and continued efforts to optimize our infrastructure and overall operating model. Turning to our financial performance, I'm pleased with our 2020 results, which demonstrate efficient management of our business in response to the significant disruptions caused by the COVID-19 pandemic. These efforts underscore our focus on execution and reflect our commitment to driving bottom-line growth. For the year, we generated total revenue of $1.04 billion, driven by the strength and resilience of Aristada, the stabilization of Vivitrol in the second half of the year, and our diverse portfolio of manufacturing and royalty revenues. From a bottom line perspective, we recorded a gap net loss of $110.9 million and a non-gap net income of $68.6 million. For purposes of comparison year over year, it's important to remember that our 2019 results included $150 million of revenue related to the approval of Boomerity. If you exclude this milestone revenue from 2019, non-GAAP net income actually improved by more than $100 million year over year, which again demonstrates our commitment to driving bottom line growth. For the full year, we recorded Vivitrol net sales of $310.7 million. Vivitrol was adversely impacted by the pandemic and units decreased 8% year over year. Gross to net adjustments increased to 49.9% for the year from 48.3% in 2019. This was due to an increasing Medicaid population, but was offset in part by favorable adjustments to our sales reserves which improved net sales by approximately $10 million over the course of the year. Vivitrol net sales in the fourth quarter of $80 million were flat sequentially, despite the increased pandemic-related restrictions in the U.S. during this time. Fourth quarter units were 5% lower than Q3, offset by favorable gross-to-net adjustments, which decreased to 50.6% in Q4 from 52.8% in Q3. And in a departure from trends in recent years, we saw minimal inventory build at the year end of approximately $1.5 million. Turning to the Aristada product family, for the year, Aristada net sales increased 27% year-over-year to $241 million, driven by 30% volume growth. Gross to net adjustments were 53.3% for the year, compared to 49% in 2019, due primarily to increased Medicaid utilization. For the fourth quarter, net sales increased 10% sequentially and 21% year-over-year to $68.9 million. Gross to net adjustments increased to 54.1% in the fourth quarter of 2020, and inventory levels increased by approximately $5.2 million. This inventory build was somewhat greater than expected, and we expect will be worked down during the course of the first quarter of 2021. Moving on to our manufacturing and royalty business, for the year we recorded manufacturing and royalty revenues of $484 million, compared to $447.9 million in the prior year. This increase was driven primarily by continued growth from InVegas Astena, as well as revenues from Boomerity, which contributed $22.5 million in the year. In terms of expenses, our total operating expenses in 2020 decreased by nearly $200 million year-over-year. R&D expenses for 2020 were $394.6 million compared to $512.8 million for the same period in the prior year. Now, this decrease reflects our efforts to focus our investment in R&D programs where we see the highest potential return. In 2019, R&D expenses also included a charge related to the acquisition of Rodin in the fourth quarter of that year of $86.6 million. SG&A expenses for 2020 decreased to $538.8 million from $599.4 million in 2019, reflecting the impact in 2020 of the 2019 restructuring of COVID and ongoing expense management measures during the year. Turning to our balance sheet, we ended 2020 with approximately $660 million in cash and total investments, up from $614 million at the start of the year, primarily driven by non-gab net income and working capital changes, partially offset by capital expenditure of approximately $31 million in the year. The company's total debt outstanding was $275 million at the end of the year, resulting in a net cash position of approximately $385 million. I'll shift now to our financial expectations for 2021, which are fully outlined in the press release we issued earlier this morning. Our expectations assume an improvement of pandemic-related conditions in the second half of 2021. If conditions do not improve as anticipated, our ability to meet these expectations could be negatively impacted. These expectations also reflect anticipated growth of our commercial portfolio and focused investments to both support the anticipated launch of Lybuli and advance the clinical development program for Nembolucan. Of note, our expectations do not account for any potential partnerships for Nembolucan or other strategic opportunities across the portfolio. So with that in mind, for the top line, we expect total revenues to be in the range of 1.1 to $1.17 billion. For Vivitrol, we expect net sales in the range of $315 to $345 million, and gross to net adjustments of approximately 54% driven by increased Medicaid utilization. For Aristata, we expect net sales in the range of $260 to $290 million, reflecting anticipated volume growth slightly offset by gross to net adjustments which we expect to increase to approximately 55%, due again to increased Medicaid utilization. In line with historical seasonal patterns, we expect our first quarter 2021 proprietary product net sales will be down sequentially to approximately 65 to 70 million for Vivitrol, and approximately 50 to 55 million for Aristada, with growth expected to resume in the second quarter. It is important to note, however, that we do expect underlying growth in demand for both products, despite the lower sequential net sales numbers. Our expectations for total revenues in 2021 include a modest contribution of up to $10 million of net sales of Lybolby, if approved, as we plan for a launch in the second half of the year. And I'll just note now that as we look ahead to next year and the anticipated expansion of our portfolio, we may transition to provide a total proprietary product net sales range in our guidance rather than ranges broken out by specific product. In terms of our operating expenses for 2021, cost of goods sold is expected to increase with volumes to a range of $190 to $200 million. R&D expenses are expected to be in the range of $400 to $430 million. And it is important to note that this range includes a potential $25 million milestone payment related to the submission of an IND or equivalent for ALX1140, the first clinical candidate to emerge from our HDAC inhibitor platform. Our R&D expense range also reflects increased investment in Nembolucan as we advance the development program, as well as continued investment in life cycle management studies for Lybolvi. SG&A expenses are expected to be in a range of $570 to $600 million, and this year-over-year increase reflects our expected staged investment in sales personnel and marketing support for the anticipated launch of Lybulvy. Overall, we expect 2021 gap net loss to be in the range of $85 to $125 million, and we expect non-gap net income to be in the range of $60 to $100 million. Now, we're committed to achieving the profitability targets set forth in our value enhancement plan. And from a financial perspective, there are a number of ways to achieve them. Irrespective of the revenue trajectory, however, we will manage costs and drive efficiencies to achieve our targets. The investments we are making in 2021 are designed to lay the foundation for growth while maintaining the non-GAAP profitability we achieved in 2020. In 2022, We plan to focus on driving operating leverage from our psychiatry business as we establish the launch trajectory for Lybolvy. So, in conclusion, we enter 2021 well-positioned to execute on our strategic priorities. Our diverse commercial portfolio, the anticipated launch of Lybolvy this year, and the advancement of our Nembalucan program provide a distinct foundation for long-term value creation, and I look forward to sharing updates on our progress. And with that, I'll hand the call over to Todd to review our commercial landscape.

Thanks, Ian. And good morning, everyone. By anyone's estimation, 2020 was a year marked by unforeseen challenges as the nation and our industry responded to the pandemic. We believe we have both a responsibility and an opportunity to help address unmet patient need in serious mental illness and addiction, which has been exacerbated by the pandemic. Our commercial performance last year reflected innovation and adaptation by our team as we supported healthcare providers and helped patients maintain access to their medications in this difficult environment. I am pleased that we ended the year at the high end of our July 2020 net sales guidance ranges for Vivitrol and Aristophe. Starting with Vivitrol, net sales in the fourth quarter were $80 million, flat on a sequential basis to the third quarter. This reflects a continued stabilization following a decline in volume in the spring due to disruptions to the treatment system related to COVID-19. While many treatment providers have adapted their practices and patient access to injections has improved, overall Vivitrol volume remained below last year's Q4 levels with a 14% decline in units year over year. In particular, new patient starts and opioid dependence were lower, primarily due to reduced access to detoxification services. While this trend persisted in the fourth quarter, the environment had improved compared to the height of the pandemic-related disruptions in the second quarter, as 19 of the top 20 states reflected higher volumes in the fourth quarter as compared to Q2. In 2021, we are focused on driving adoption of Vivitrol as a treatment option for alcohol dependence among providers caregivers and patients. The contribution from alcohol dependence and the indication mix for Vivitrol has been on an upward trend, driven by both increased market share and growth of the category. The increased prescribing of medications for the treatment of alcohol dependence is indicative of the growing adoption of evidence-based standards recommended by entities such as SAMHSA, the VA, and American Psychiatric Association. This shift comes at an important time as the incidence of heavy drinking, which may be a sign of alcohol dependence, increased during the pandemic, and as policymakers began to call for flexibility to use existing funds to treat AUD and educate at-risk populations on the treatment of AUD. In 2021, we plan to increase our focus on driving awareness of Vivitrol as a treatment option for alcohol dependence and launch programs to maximize the impact we can have in this area of significant unmet need. We expect 2021 Vivitrol net sales in the range of $315 to $345 million, reflecting our strategy to drive growth in the alcohol dependence indication somewhat offset by continued pressure on new patient starts, particularly in opioid dependence through mid-year. We remain committed to driving awareness of Vivitrol's utility and believe that it will continue to have an important role to play in the treatment paradigm. Let me now turn to the Aristotle product family. Net sales in the fourth quarter increased approximately 21% year-over-year and 10% sequentially to $68.9 million, reflecting underlying demand growth and the inventory build Ian mentioned. Total prescription data for Aristide in the fourth quarter demonstrated strong growth of 16% year-over-year in terms of months of therapy and outpaced the broader, long-acting, atypical antipsychotic market. As a result of the pandemic, we have seen some impact prescribing patterns in the long-acting antipsychotic space. The year-over-year growth rate of the overall long-acting injectable market began to moderate from 13% in Q1 to 5% in Q3 and Q4, as market research showed that psychiatry healthcare providers made fewer treatment changes in the COVID environment. In this challenging year, we executed against our aerostatic growth strategy with encouraging results. Patient volume grew four times faster than the LAI market in 2020, and we made strides with increasing our prescriber breadth and depth of utilization. Our recent market research also indicates that the value proposition of the Aristata two-month dose plus Aristata initio is resonating with healthcare providers, as evidenced by 50% year-over-year TRX growth for the two-month dose on a month-of-therapy basis. We expect Aristata 2021 net sales in the range of $260 to $290 million. This range reflects our continued emphasis on Aristata's differentiated value proposition and assumes a normalization and growth of new patient starts for the overall LAI class in the second half of the year. Lebalvi, our oral investigational antipsychotic designed to offer the efficacy of olanzapine while mitigating its associated weight gain is under review with the FDA. with a PDUFA date of June 1st, 2021. Pending approval and DEA de-scheduling, we are planning for a launch in the second half of 2021. Upon approval evolving, we'll be launching into a largely generic oral market, but one where branded agents can still be successful due to the serious unmet needs that remain. Schizophrenia and bipolar disorder patients commonly cycle through five to seven treatment options on average, And there are approximately 70,000 treatment switches every month. The commercial organization that we have built to support Aristot is also the foundation for the potential upcoming launch of Lebalvi. Our psychiatry infrastructure will serve as a platform to drive growth, operational leverage, and profitability. Late last year, we implemented a reorganization of the commercial infrastructure to streamline the organization and improve efficiencies. with approximately 80 full-time positions reallocated to support the anticipated launch. As a result of this reorganization and the hybrid promotional model developed in response to the pandemic, we have reduced the additional resources required to launch Lvalvi compared to our prior expectations. To maximize the launch opportunity, we plan to make additional staged investments, adding modest incremental headcount in advance of launch and as payer access for Lubavi is established in the launch year. With this commercial organization, we expect to be competitive in the landscape in terms of both reach and share of voice. In conclusion, in 2021, we are focused on commercial execution, increasing awareness and delivering growth of Vivitrol and Aristata. Each of our products plays an important role in the treatment paradigm, and we have an opportunity to drive increased utilization, particularly against the backdrop of the growing need for serious mental illness and addiction treatments. And with that, I'll turn the call back over to Rich.

That's great. Thank you, Todd. So as you've heard, we entered 2021 focused on execution across three domains, growing and diversifying our revenues, demonstrating the value of our R&D investments, and managing the company for growth and long-term profitability. Each represents an important opportunity for value creation. Our R&D is focused on developing high-value candidates in two key therapeutic areas, neuroscience and oncology. I want to start with the neuroscience side with Lebalvi or ALX3831. You'll recall that we received a complete response letter in November, which included a request for information relating to Lebalvi manufacturing. Due to the pandemic, FDA's ability to conduct pre-approval inspections is limited, and as a result, FDA has increasingly relied on remote records requests in order to complete its reviews. We submitted a response to FDA in December. FDA classified the resubmission as a complete Class 2 response and assigned a June 1st PDUFA date, and subsequently requested that we provide additional records related more broadly to the manufacturer of Lombardi. The Class 2 designation was consistent with FDA's recently issued guidance for industry. The CRL and subsequent records requests focused only on manufacturing. No questions or concerns were raised related to clinical efficacy or safety, and no further clinical studies were requested. We'll continue to work closely with the FDA as it completes the review of the NDA, and we look forward to bringing Levalvi to patients as quickly as possible. As you heard from Todd, we believe this is an important medicine that can address a clear unmet need in the schizophrenia and bipolar one markets and enhance our psychiatry franchise. The second development in our neuroscience pipeline is our newest pipeline candidate, ALX1140. This is the first candidate nominated from our platform of selective HDAC inhibitor compounds. This is a novel approach designed to increase functional synaptic connections and synaptic integrity in the brain, with the potential to be used in a range of clinical settings, spanning from rare neurodegenerative and neurodevelopmental conditions to common psychiatric disease. ALX1140 is a small molecule, orally bioavailable compound, designed to selectively modulate the co-rest HDAC complex. This complex exerts epigenetic control over synapse formation and function in the brain, synapses being the critical points of connection and communication between neurons. We had very clear goals for selection of a clinical candidate from this platform, focused on the appropriate selectivity and brain permeability, and evidence of increasing synaptic density in preclinical models, and designed to avoid the known potential hematopoietic side effects. We achieved those goals preclinically with ALX1140 and plan to begin first-in-human studies this year. Turning to the oncology side of our business, we've made excellent progress with Nemvalucan, our novel investigational drug designed to leverage the proven antitumor effects of the interleukin-2 pathway. We've taken a very disciplined, stepwise approach to developing Nembolucan. Our first objective was to confirm the validity of the molecular design by demonstrating clinical pharmacodynamic response as measured by dose-dependent selective expansion of NK and CD8-positive T cells with minimal and non-dose-dependent changes in peripheral regulatory T cells. We achieved that in our first, first, I'm sorry, in our intravenous protocol, which was called Artistry 1, and launched our subcutaneous protocol called Artistry 2. Next, we wanted to establish that the immunological response we were observing translated into anti-tumor activity. That was the major accomplishment in 2020. In Artistry 1, we observed single agent activity with intravenous nebulucan in melanoma and more recently in renal cell carcinoma. These represent the two indications for which recombinant human IL-2 is approved. Demonstrating single-agent activity is an important and, in our view, essential milestone for the program. We've also observed durable and deepening responses in combination with pembrolizumab in multiple tumor types, including in PD-1, PD-L1, unapproved tumor types. Across the Artistry 1 study, Nembolucan has demonstrated a safety profile generally consistent with the anticipated effects of cytokine therapy, with transient fever and chills being the most frequently observed adverse events in both the monotherapy and combination cohorts. We're now focusing the program on initial potential registration pathways. In the monotherapy setting, we're focused on mucosal melanoma. Mucosal melanoma is considered a particularly aggressive form of melanoma, and it's often not discovered until an advanced stage. Treatment options are very limited. In combination with pembrolizumab, we're going to pursue platinum resistant ovarian cancer, another area of unmet need with limited treatment options. We plan to engage with FDA to advance our registration plans and initiate studies this year. Then, finally, we'll look to broaden the program to capture the full medical and economic value of the product. We're now in the process of identifying and selecting additional tumor types and combinations to pursue in collaboration with others. As the data set continues to grow, we see Nemvalucan as being an asset around which we can collaborate and create value. We are excited about the candidates emerging from our R&D platform. The threshold for nomination of new candidates has risen as the healthcare system demands true innovation and focuses on both the economic and the medical value of new medicines. Medicines need to have new properties representing true advances from existing standards of care. Later this quarter, we'll host an investor day where we'll share more details about our development programs, including the discovery and preclinical programs that have been advancing in our labs in recent years. The science is compelling, and we're looking forward to introducing some of the scientists doing the work and sharing their progress. Taking a step back, we are turning the page at Alkermes. The company has made a new commitment to driving profitability in the years ahead, and we've sharpened our focus on value creation. Across every element of our business, we are disciplined in the investments that we make and focused on our execution. While the strategic initiatives included in our value enhancement plan build on the company's previous efforts to optimize our cost structure and focus the business on high value opportunities, the elements of the value enhancement plan represent a new commitment and are integrated into all aspects of our business. This is a multifaceted and dynamic company, and our focus on value creation will be an important guiding principle as the business evolves. So with that, I'm going to hand the call back to Sandy to coordinate the Q&A.

Thanks, Richard. Rob, we'll now open the call for Q&A, please.

Thank you, Sandy. We'll now be conducting the question and answer session. If you'd like to ask a question, please press star 1 from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. In order to allow as many as possible to ask questions, please limit yourself to one question and one follow-up. Our first question comes from the line of Vamil Devan with Mizuho. Please proceed with your questions.

Great. Thanks for taking the questions. So maybe first on your guidance, I do like the detailed product level Guidance you provided sounds like we may not be getting that much longer. But in terms of total sales and also the guidance for Vipachal and Aristata, the ranges you gave this year, you know, a little bit wider than what you've done in the past. So maybe can you just talk a little bit about why, you know, the wider ranges and a little more on your assumptions around those ranges, especially, I guess, in terms of recovery from the pandemic as we go through the year and those are patients' ability to access those two products. And then on 4230, Rich, I think you said, I mean, you mentioned you're having a discussion with the FDA. I think you said you hope to start registrational trials this year. Can you just confirm that that's what you said? Is that already sort of baked into your guidance, sort of on the R&D side, that those will begin at some point in 2021? Thanks.

Hey, Val, it's Rich. I'll let Ian handle the guidance stuff. I'll just take that last question first, which is, yes, we do plan to start the registration studies in both Kroc and in melanoma this year.

Hi, Vamil. So just on your question around guidance, I think, as you know, we went with wider ranges. And I think you answered the question, really. It's really just around that COVID uncertainty. Certainly in the first half of the year, we did say that one of our key assumptions as we put the guidance together was that we did see things turning back to a little bit more of a normal state in the second half of the year. So just to provide a little bit of leeway, we widened the guidance ranges. We did talk obviously about a slightly lower Q1, which we've seen in the last couple of years for both Vivitrol and Aristarda. So that's a typical seasonal pattern. But we expect continued growth in Q2 and beyond. So that's really what drove the wider ranges, just the uncertainty around COVID, certainly in the first half of the year.

Thank you.

The next question is from the line of Paul Matisse with Stiefel. Pleased to see you with your questions.

Yeah, hey, this is Thor on football. Thanks so much for taking the question. Can you talk a little bit about on the 3831 how you expect the cadence of reimbursement to go in the second half post-launch?

Yeah, absolutely. I'll take that as well. So the first thing I would say is we're really excited about this. You know, as you're in my prepared remarks and then also from what Rich said as well, there's a significant unmet need in this category. To date, we've had approximately 50 interactions with payers getting prepared for an eventual launch, and the feedback has been very consistent from what you've heard from us in the past, that they believe that we'll continue to compete in a branded space. You know, there's three categories with this, Medicaid, Medicare, and commercial. And typically in a launch, market access will evolve over the first 12 to 18 months. And that's our planning scenario. So we do know that there's going to be some restrictions at launch. Every product in this category has restrictions. So we do know that there's going to be some restrictions in the form of PAs and step edits, and we're preparing for that. So as we get closer to launch, it'll start to be a little bit more clear, and specifically in the launch year, in the first 18 months, it'll be a lot more clear on what our launch profiles in terms of access looks like.

Great. Thanks so much. Our next question is from the line of Brandon Fulks with Canterford Sherald. Please receive their questions.

Hi. Thanks for taking my question. Maybe just sort of on Vivitrol, And that NIH study, you know, for methamphetamine use disorder, you know, I found that very interesting. So can you maybe help us just think about the potential for the commercial opportunity around this? You know, given that there's no current approved FDA treatment, is this something you think if it was approved or you bought to market would get fast uptake or do you think that it's probably going to be a little bit like alcohol where you're changing sort of the whole treatment paradigm and takes a little bit of time? Yeah, thank you very much.

Good morning. Hey, Brandon. It's Rich. I'll answer that for you. I'm actually quite excited about the data. That study was called ADAPT2. It was published in the New England Journal last month. It followed ADAPT-1, which was the first indication that the combination of Vivitrol and bupropion could have some effect in the treatment of methamphetamine use disorder. As you said, there are no treatments for stimulant use disorders. And in many parts of the country, and you guys know we're on the front lines of this in 50 states, many communities methamphetamine has supplanted opioids as the principal addictive risk in the communities. So there are no treatments, and the data are, you know, it's not a cure-all. It doesn't work for everybody, but it certainly is a therapeutic approach using two well-known FDA-approved agents and a new regimen for Vivitrol, actually, administered once every three weeks in combination with bupropion. The investigators we've spoken to, they're quite excited about the data. Now, the limitations from us from a commercial standpoint is that it's not on the labels. So what we'll do is we plan to have an interaction with FDA and talk about that. And so our argument being that it would make sense for us to be able to talk about it, both the safety and the efficacy, the symmetry and whatnot, as the people on the front lines providing the medicine. I don't know whether we'll be successful with that or not. It's not baked into any of our expectations for 2021 or beyond. I consider that to be upside, but I do believe that there is a, There's an unmet need. It would require, as you said, nothing happens quickly in addiction. It would require a reconsideration of how patients flow into treatment and are treated with methamphetamine use disorder. But I think it's indicative of the broad potential that Vivitrol represents across opioids, alcohol, and potentially other indications. And Todd, if you have any other comments, please.

Yeah, absolutely, Rich. The only thing that I would add to that is if you look at the data that that's produced through SAMHSA, they estimate about 2 million patients suffer from methamphetamine use disorder. So it is a significant unmet need in the marketplace.

Thank you. The next question is from the line of Corey Kasimov with JPMorgan. Please just read their questions.

Hey, good morning, guys. Thanks for taking the questions. Two of them for you. So first, just wanted to get more clarity on Levaldi and the comments around their launch in 2H. If the product is, in fact, approved by the June 1st PDUFA, should we assume launching in July, or is it going to be later than that? And then, secondly, in oncology and nebulucan, and specifically in the sub-Q formulation, how close do you think you are to the recommended phase 2 dose there, and should we be expecting, like, a data update in terms of efficacy results at your upcoming investor day? Thank you.

Good morning, Corey. Good to hear your voice. It's two good questions. We're planning right now to launch sometime after the Paducah Day in the second half. There's a lot of logistical issues that go into the launch itself. We want to get through the FDA approval process, and then we'll give you more precision as we do that. We have moved into the expansion cohort on the weekly. We're starting the expansion at the once-weekly dose. We feel like we've qualified both the once-weekly and the once-every-three-week dose, and we will indeed give you more update on those data as the year goes on, possibly around ASCO, possibly around our investor day. We haven't really decided yet, but that program is moving full steam ahead. Thank you.

Thank you. The next question is from the line of Mark Goodman with SVB Laring. Please proceed with your questions.

Hi, Rich. Can you talk a little bit about monetizing non-core assets? You talked about potentially acquiring an asset to leverage your infrastructure. You talked about partnership discussions for the oncology product business as part of this whole process. restructuring plan and commitment to targets. So I was wondering if you could just give us an indication of what's happened so far, maybe the timing of all this. Should we be expecting anything to be announced in the next six months or whatever? And then just secondly, can you tell us what are you all assuming for the LAI market growth for this year? We know what you're thinking about for Aristana. Thanks.

Good morning, Mark. Yeah, all those things you listed are things that we're looking at. Essentially, we're trying to say, you know, what represents the core essential parts of the business going forward? And then everything is not in that definition. Is there a market price that is in excess of what we might expect it to be or a fair market value that we could monetize in a way? And interestingly, that includes... Obviously, explicitly, 4230 is not an out-license. We're not getting rid of it. It's a really strong asset around which to collaborate and offset R&D expense. We think there's tremendous economic potential for it, so we're not going to let it go. There are other elements of the R&D portfolio that you guys haven't seen that might be the foundation for out-licensing or collaboration. I won't put a timeline around that at all. On the royalty monetization side, interesting, probably the most valuable royalty stream that we have is Vimeri. It's also the one that has the least well-defined trajectory at this moment. As you know, it started slowly in 2020, but recent scriptions have been very positive. It's absolutely changed its slope. So I think as we move through 2021 and we get a better sense of what the ultimate value could be of Vumerity, its virtue as a monetization stream, of course, is that A, the growth is high, and B, it's long-lived. It's got a lot of patent life behind it. So I'll let Ian fill in any other blanks, but essentially we're basically going back and looking at all those different elements of the business.

Yeah, I think that was very comprehensive, Rich. As you say, I think we're actively looking at opportunities across the business. and we'll obviously announce those as they come to fruition. We wouldn't sort of pre-announce anything that we're currently working on.

Yeah, in terms of the LAI category, you know, we're assuming this year that it'll be approximately 7% market growth, and that's really driven, of course, by COVID-related restrictions and also the normalizations of patient flow, which we're assuming will start in the second half of the year.

Our next question comes from the line of Biran Amin with Jefferies. Please proceed with your questions.

Yeah, hi, guys. Thanks for taking my questions. Given your market research, what do you think is the biggest impediment to adoption for light valve V in the U.S.? And I guess what do you think is an untapped opportunity for light valve V for the U.S. launch? And then I guess the second question is, are there any opportunities that you could exploit for light valve V ex-U.S. either yourselves or through partnering?

Yeah, so I'll take that as well. There's, again, there's a, it's a significant market opportunity, something we're really excited about. You know, you're looking at a category north of a, you know, in the space of about three and a half billion in sales for schizophrenia and bipolar. The big opportunity really is the churn in the patient population. You know, Our research is pretty consistent. We've been doing this for a number of years. Patients cycle through five to seven treatment options. That's a leading indicator to say that you have to have individual treatments for different patients as well. When we go deeper into that, we see in the neighborhood of about 70,000 treatment switches or changes every single month. And so it just tells you the churn that is there. The primary reason is that physicians and patients have to make trade-off decisions, and they have to make trade-off decisions for efficacy versus tolerability versus safety as well, and so our research is really consistent with that. The opportunity for us with Labavi is really the powerful efficacy that olanzapine offers. Olanzapine in the U.S. still commands a 20% share for schizophrenia and an 11% share for bipolar, so we think that's a a significant unmet need and also a really big opportunity for Levolvi, and we're very excited about that. As we said earlier, we're planning our commercial launch to make sure that we maximize that opportunity. We're going to have the Salesforce size and structure to reach 80% of the branded marketplace. We're established in the marketplace. We currently call in about 60% of the prescribers, so we're ready for this. This is an opportunity for us where we are going to show leverage. Our focus right now is really the U.S. market. That's the biggest opportunity for this brand. It also obviously commands the highest price point as well, too, so we think it's the best place for us to play in this marketplace is to stay within the U.S. for now.

Our next question comes from the line of Akash Tiwari with Wolf Research. Please proceed with your question.

Hey, thanks so much. Can you remind us of what the current profitability for Vivitrol and Aristata are separately? And in a situation where let's say sales for these products kind of flatten out over the next three to five years, what's kind of the low hanging fruit on the SG&A side that could be cut that would allow you to hit your longer term margin targets? And then on your 2021 R&D spend, can you roughly go over what's your product by product spend particularly for your L2 program and then also for your other undisclosed projects. Thank you.

Okay, so let me try and take those in order. I think on the profitability of our proprietary products, we haven't provided sort of detailed P&Ls for each product, but I'll tell you Vivitrol continues to be a very profitable product for us. Aristata broke into profitability this year. And then, interestingly, as you look at the profiles for 2021, as we launch Libolvi, this is where we start seeing the operating leverage really coming through from a P&L perspective. So some of the cost that was previously being allocated to both Vivitrol and, more importantly, Aristar is now being absorbed by Libolvi. So Aristar becomes incrementally more profitable in 2021 as compared to 2020. And, you know, Libolvi, we believe will take a couple of years to break into profitability, obviously dependent upon the revenue trajectory. I think as sales flatten out and as we look at the SG&A spend, I think on the G&A side, we're very focused on keeping G&A spend as flat as possible and sort of enhancing operational efficiencies within that part of the business. Sales and marketing, we have programs in support of all our proprietary products And I think we can modulate some of that spend with regard to how those products are doing from a revenue perspective. And then in the last question with regard to R&D spend in 2021, our biggest area of spend is going to be Nembalucan. And I think from an external perspective, we provide a breakout of our external expenses by program every quarter. We're anticipating an increase in nebulucan in the region of about $100 million worth of external R&D spend. And then the other two areas of significant investment for us would be, firstly, the LIBALDI program. We have a young adult study ongoing, and then we have a post-marketing commitment with the FDA with regard to a pediatric study. And then, as I mentioned earlier on, we do have the advancement of our HDAC platform, which would include a $25 million milestone payment, which we have factored into the guidance we've issued today. So those would be the three areas of primary focus for the R&D organization in 2021. Thank you.

The next question is from the line of Douglas South with AC Wainwright. Please receive your question.

Hi, good morning. Thanks for taking the questions. Just quickly, I think you mentioned that you had had, subsequent to the resubmission of the NDA and Leibolzi, some interactions with the FDA. Can you just provide some sort of color on what those were? Were those related to the same issues? And then on the HDAC program, I know that there is potential across a number of different indications. Just maybe walk through quickly sort of the selection process and how you anticipate choosing and narrowing down the focus. Thank you.

Hey, Doug, it's rich. Yeah, about the we and a number of other industry participants have been have been treated similarly. And because FDA isn't able to conduct pre approval inspections, they've been relying on would be called the 704 records requests. So when we got the CRL, they'd asked us one question with respect to some development batches. We answered that question completely in the December submission. And then we just got another list of questions. It would be questions in August that you would get if they were on site doing a PAI. So the good news is that you can tell the FDA so far is trying to do this without a pre-approval inspection, which would be good. So we'll continue to answer their questions through this process, hopefully within that envelope of the June 1st DUPA date. And as you've heard us mentioned before, they did issue a guidance for industry. I think in December, early January, saying that essentially all these resubmissions would be considered class two resubmissions. So it's not great for us or for the whole industry, but FDA is trying to deal with the fact that they're trying to protect their inspectorate from going into sites around the country in the midst of COVID. So we'll work our way through that. The HDAC program is fascinating from a translational medicine point of view for what your question indicates. The idea of synaptogenesis and synaptic function crosses multiple diseases. So our plan, and we haven't fully elaborated it yet, but our plan will be in the clinic to actually be interrogating a number of different disease states simultaneously in a basket approach using some of the more advanced biomarkers to look at activity in the brain. And those range from things like SV28 PET to other more traditional EEG or other biomarkers. So our goal will be to look for signal. And we don't think that we'll just have one compound that will move into the clinic. As you know, we've been also working on the HDAC progranulin side as well as the HDAC oncology side. We hope that we're just going to build a foundation of translational medicine as we put these into the clinic. So a long answer to a simple question, but I think we're going to learn a lot with this first compound. That's why 1140 was so important to get our first well-characterized molecule into man so we can begin to really elaborate its potential.

Our next question comes from the line of Jason Gerbery with Bank of America. Please proceed with your question.

Hey, guys. Good morning, and thank you for taking my questions. Maybe, Rich, just on 4230, as it pertains to identifying a partner to share in the cost and risk of developing across a number of tumors here, I'm just wondering how it takes to assume that NECTAR's Phase 3 data later this year, early next year, in some of the larger IO markets might be a gating factor to a deal and ensuring that you get the you know, firm R&D funding commitments behind that or if, you know, yourselves and partners really need to see the applicability of IL-2 in some of these settings before, you know, committing more to investments. And then just one point of clarification, sorry if I missed it, but on the BALVI, is your assumption in your guidance that you'd have a DEA controlled or uncontrolled product? Thanks.

Good morning, Jason. on that last bit. No, we expect decontrol. That's what we've been waiting for. Samidorphin is an antagonist and it's been recommended as such. So it's just going through the process of descheduling. So we expect Mevalpi to be a descheduled drug. Interestingly, on the 4230 question, I actually don't think that the Nectar data are going to be dispositive as to whether or not we will partner. And for a couple of reasons. One is that As more and more data emerge, there's a limited number of people developing these IL-2 mutants, but they're definitely segregating into their own lanes. They're not interchangeable. Our drug is very different than Mectar's drug, very different than Roche's drug, very different than anybody else's drug. And in fact, it's the only one that has a couple of features, one showing clear monotherapy efficacy, number two being developed in a subcutaneous format as well, and showing evidence of activity in these PEMBRO or PD-L1 checkpoint inhibitor unapproved tumor types and monotherapy at the same time. So I think in the cancer world, there are companies that care a lot about cytokines, and they already understand the proven efficacy of IL-2. The question has been, have you really teased out the efficacy piece of IL-2 and left the principal side effects behind? And I think we have an accumulated amount of data now to answer that question. So I think that we're going to be able to have these discussions and collaborate independent of whatever the result is from NECT or anybody else.

Thank you. At this time, there are no additional questions. I'll turn the call back to Sandy Coombs for closing remarks.

Great. Thanks, Rob. Thanks, everybody, for joining us on the call today. Please don't hesitate to reach out to us at the company if you have any follow-up questions. Thank you.

Thank you. This will conclude today's conference. Thank you for your participation. You may now disconnect your lines at this time.