Alkermes plc

Greetings and welcome to the Alkermes fourth quarter 2021 earnings 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 this conference is being recorded. I'll now turn the conference call over to Sandra Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Sandy, you may now begin.

Thanks, Rob. 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, 2021. With me today are Richard Pops, our CEO, Ian Brown, our CFO, 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, related financial tables, and reconciliations of the gap to non-gap 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 statement. 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 now I'll turn the call over to Richard.

That's great. Thank you, Cindy. Good morning, everyone. 2021 was a critical year in the development and evolution of Alkermes. We had three explicit overarching goals, growing our commercial business, expanding and advancing our development pipeline, and driving profitability. And we were successful in all three of those domains. Start first with the commercial business. The year was highlighted by the FDA approval and launch of Lebalvi, our first oral medicine for the treatment of adults with schizophrenia and for the treatment of adults with bipolar I disorder. The launch is off to a strong start, and there are reasons why. First is the nature of the medicine itself. Libalvi is addressing an unmet need in the market. The second is that the launch benefits from the commercial infrastructure we've built in psychiatry and our presence and success with Aristata. With these two medicines, we have an important and growing commercial franchise in psychiatry. For Vivitrol, we redefined and began executing our new growth strategy, focused on the alcohol dependence indication. So these products, Libalvi, Aristata, and Vivitrol, together with Vumerity, represent our four key growth drivers. With respect to the pipeline, we're guided by a focused research and development strategy that prioritizes programs with the highest potential return on investment. During the year, we initiated Nemvalucan clinical studies to support potential registration in two tumor types, where patients have limited treatment options and significant unmet need remains. We also initiated a first-in-human study for our HDAC inhibitor, ALX1140, We nominated and began IND-enabling activities for ALX2680, our orexin receptor 2 agonist, and achieved preclinical proof of concept for our tumor-targeted IL-12 program. From a financial perspective, we executed the plan with respect to our 2021 objectives, and we are on track to achieving our long-term profitability targets. As Ian will outline shortly, we managed the business to achieve the high end of our overall 2021 financial expectations. We continued our focus on driving operational efficiencies and optimizing our cost structure, focusing on our highest potential programs as we positioned the company for long-term growth. As I'm sure you're aware, in November, we received notice of partial termination from Janssen, an affiliate of J&J, that impacts our royalties related to the sales of long-acting and vaguer products in the U.S., J&J has made the surprising assertion that these products do not utilize Alchemy's nanocrystal technology, despite having paid us know-how royalties for 12 years. We strongly disagree with J&J's position. Since the receipt of this notice, we've engaged with J&J and will continue to explore whether a mutually agreeable resolution can be reached without the need for arbitration and litigation. But that said, we're prepared to pursue all the options at our disposal to enforce our contractual rights and address any unauthorized use of our intellectual property. For the purposes of the 2022 guidance and the updated long-term profitability targets that we're going to provide today, we've removed from our models U.S. royalties from the long-acting and VEGA products beginning this month and all royalties from outside the U.S. beginning in May of this year. We have not received a notice of termination related to the ex-U.S. territories. However, we believe excluding these ex-U.S. revenues provides a conservative financial planning scenario. I want to underscore that removing these cash flows from our guidance and profitability targets is for planning purposes and does not in any way reflect our belief in the strength of our legal position on the matter. This approach also has the beneficial effect of providing a clearer picture of the strength of the underlying business driven by our proprietary products in Vumerity, and the operating leverage that we've engineered into the business. Regardless of the outcome of the situation with J&J, we have been positioning the business over several years to shift away from royalties from the long-acting Invega products, and the long-term growth profile of the company remains unchanged. Separate from the modeling, from an operational perspective, following receipt of the notice from J&J, we went back and made cuts to our original 2022 budget, recognizing that even if we are successful in our interactions with J&J, that outcome could take some time. Making adjustments now changes the cost structure and facilitates the bridge to our profitability targets. The value enhancement plan that we established in 2020 continues to serve as a guide as we look to the future and we remain committed to the achievement of explicit profitability targets. This formal commitment is beneficial for our shareholders and it's beneficial for the company in managing the business as we drive the competitive allocation of capital. Today, we're announcing revised long-term profitability targets that reflect our current financial planning, as well as feedback from our board and interactions with many of our institutional shareholders over the past few months. With respect to the board, we continued our ongoing board refreshment efforts in 2021 with the addition of two highly qualified new independent directors, one of whom was named to the board just last quarter as part of an agreement with Sarissa Capital. This followed the retirement of two of our longer serving board members earlier in the year. This evolution of our board has resulted in the appointment of six new independent directors since 2019. These new directors bring important financial, strategic, governance, operational, oncology, medical and public health expertise that aligns with our business strategy of advancing and commercializing important medicines in neuroscience and oncology. We will continue to consider additional board refreshment that adds expertise and experience that may help us advance that strategy. So with that as an introduction, I'm going to turn the call over to Ian to take us through the 2021 results and the outlook ahead, and then to Todd to provide an update on the launch of Libalvi and the performance of Aristata and Vivitrol. Ian.

Thank you, Rich, and hello, everyone. Our 2021 results reflect strong execution against our strategic priorities as we manage the business to the high end of our revenue expectations and exceeded expectations on the bottom line. I'm pleased with these results, which reflect the company's progress over the last several years in fueling top-line growth through Alchemy's developed products, coupled with a continued focus on disciplined expense management and operational efficiencies. In the next few minutes, I'll take you through the details of our 2021 results, then turn to our 2022 financial expectations and underlying assumptions, and then finish with our updated long-term profitability targets. So starting with our 2021 financial performance, we generated total revenues of $1.17 billion, representing a year-over-year increase of approximately 13%. This increase was primarily driven by double-digit year-over-year growth of both Vivitrol and Aristata, as well as growth in Boomerity royalty and manufacturing revenues. From a bottom-line perspective, we recorded gap net loss of $48.2 million compared to $110.9 million in the prior year, and non-gap net income of $129.1 million for the year compared to $68.6 million in 2020. Turning to Vivitrol, in 2021, we recorded net sales of $343.9 million, up 11% year over year, driven primarily by an increase in units of approximately 10%. This increase reflects the execution of our strategy to increase awareness and drive adoption of Vivitrol as an important treatment option for alcohol dependence. Year over year, gross to net adjustments increased to 51.5% from 49.9% in 2020, primarily reflecting an increase in Medicaid utilization. Now, in the fourth quarter, Vivitrol net sales were $92 million, reflecting 4% growth sequentially and 15% growth year over year. Gross to net adjustments of 50.2% reflected favorability in Medicaid utilization and a continued lower rate of returns. Inventory levels increased by approximately $3 million in the fourth quarter, which we expect will be drawn down in the first quarter of 2022, as is typically the case. It should be noted that in the latter half of the fourth quarter, we saw increased pandemic-related disruptions in the US for Vivitrol due to the most recent surge in COVID-19 cases. This resulted in a 1% decrease in units shipped in Q4 as compared to Q3. As you can imagine, we're actively monitoring these trends as we enter 2022, and Todd will provide additional color in a few minutes. Moving on to the Aristada product family, for the year, Aristada net sales increased 14% to $275.4 million, primarily driven by 11% volume growth. Growth to net adjustments were 53.7% for the year, relatively consistent with 2020. For the fourth quarter, Aristada net sales was $78.7 million, up 14% both sequentially and year over year. Gross to net adjustments decreased to 51.8% in the fourth quarter from 54.8% in the third quarter, primarily driven by a one-time favorable adjustment of approximately $3.5 million to our Medicaid sales reserves. In addition, inventory levels increased by approximately $3 million at the end of the year. Turning to Levolvi, which we made commercially available in late October, we were pleased to record $8.2 million of net sales in the quarter. This included approximately $4.5 million related to launch stocking, and consistent with our expectations, gross to net adjustments were approximately 35% during the quarter. Moving on to our manufacturing and royalty business, for the year we recorded manufacturing and royalty revenues of $541.8 million, compared to $484 million in the prior year. This increase was driven primarily by the growth of Boomerity, which contributed $87.4 million of royalty and manufacturing revenues during the year, compared to $22.5 million in the prior year. Royalties from the Long-Acting and Vega products contributed $303.1 million during 2021, and royalty and manufacturing revenues related to Risperdal-Konster contributed $50.9 million for the year. Turning to expenses, Excluding the $25 million development milestone paid to former shareholders of Rodan Therapeutics, total operating expenses in 2021 increased by just 2%, even as we invested in the preparation and execution of the commercial launch for Libalvi and initiated potential registration enabling studies for Nembalucan. Cost of goods sold for 2021 increased approximately $19 million year over year to $197.4 million, primarily driven by higher volumes of key manufactured products. R&D expenses for 2021 were $406.5 million, reflecting an $11.9 million increase over the prior year. However, excluding the $25 million development milestone, R&D expenses decreased compared to last year, reflecting data-driven investment in our development candidates and strict adherence to internal stage gates in the development process. SG&A expenses for 2021 of $561 million increased $22.2 million as compared to the prior year. This included a $27.4 million increase in selling and marketing expenses in support of the launch of Levolvi, partially offset by a $5.2 million decrease in G&A expenses year over year as we continue to manage the cost structure. So taking a step back, we've done significant work over the past few years to improve our operational efficiency, optimize our cost structure, and invest in the strategic priorities that we believe will position the company for future growth. In 2021, we restructured our commercial organization to increase efficiencies for the launch of Levolvi, implemented various other headcount optimization and operational efficiency initiatives, continued to prioritize our highest potential pipeline development programs, and discontinued programs that were not meeting our internal stage gate criteria. This is going to be a continued focus for us as we go forward. Turning to our balance sheet, we ended 2021 with approximately $766 million in cash and total of investments, up from approximately $660 million at the end of 2020, primarily driven by cash flows from operating activities. The company's total debt outstanding was $295 million at the end of the year, resulting in a net cash position of approximately $470 million. Alchemies is well positioned from a cash perspective, and we do not foresee needing to access the capital markets to fund our ongoing business. I'll shift now to our financial guidance for 2022. From an operational perspective, we adapted our budget for the year following receipt of the termination notice from J&J, recognizing that resolution of the situation could take time. We further focused spend on our key strategic priorities, the LaVolvi launch, the Nembalucan registrational studies, and advancing key early stage programs. Spend in other areas of the business was prioritized to key business continuity initiatives, such as the supply of commercial products, supporting patient access to our medicines, and foundational G&A functions. Investments outside of these core areas were scaled back, eliminated, or delayed. Now, let me review some key assumptions underlying our financial guidance. Our expectations assume a decrease in pandemic-related disruptions. If current disruptions do not decrease as anticipated, or if new COVID-19-related disruptions emerge, the company's ability to meet these expectations could be negatively impacted. As it relates to the long-acting and vague of products, For 2022, we are including one month of royalty revenue from sales in the U.S. and five months of royalty revenue from sales outside the U.S. Together, this represents estimated royalty revenue in the range of $45 to $50 million. We're doing this to be conservative. We have not received a notice of termination from J&J related to royalties from these products in any markets outside the U.S., And as you heard from Rich, we strongly disagree with their termination of the license agreement in the U.S. That said, we believe this is the most appropriate approach for financial planning purposes as we work through the situation with J&J. This approach has the added virtue of highlighting the expected long-term growth of the underlying business driven by our proprietary products and boomerity. So with all that in mind, for the top line, we expect total revenues for 2022 to be in the range of $1 billion to $1.09 billion. For our proprietary products, I'll start with Levolvi. While launch years can be very dynamic, we currently expect Levolvi net sales in the range of $55 to $75 million for 2022. And we expect the growth to net adjustments will be in the 40% range for the year. For Vivitrol, we expect net sales in the range of $355 to $385 million, and gross to net adjustments of approximately 52%. For Aristata, we expect net sales in the range of $290 to $320 million, and gross to net adjustments of approximately 55%. In line with historical seasonal patterns, we expect our first quarter 2022 proprietary product net sales will decrease sequentially to ranges of approximately $78 to $83 million for Vivitrol and approximately $68 to $73 million for Aristarda, with growth then expected to resume in the second quarter. In addition, we expect LeBolvinet sales of approximately $8 to $10 million in the first quarter as the remaining launch stocking is consumed. In terms of our operating expenses for 2022, Cost of goods sold is expected to increase to a range of $215 to $225 million, primarily driven by increased volumes of key manufactured products. R&D expenses are expected to be in the range of $385 to $415 million, reflecting ongoing enrollment in our potential registration-enabling Nemboloocan clinical studies, ongoing Phase IV commitments for LIVOLVI, and continued investment to support our early-stage development assets, including IND-enabling activities and the manufacture of clinical trial supply for ALKS2680, our orexin-2 receptor agonist. SG&A expenses are expected to be in the range of $575 to $605 million. The year-over-year increase reflects a full year of investments to drive the launch of Evolvi. We expect a gap tax benefit in the range of $10 to $15 million, based on the new rules around the capitalization of R&D expenses for tax purposes and the interplay with our foreign-derived intangible income benefit. Any change in tax legislation in this area during the year could impact these expectations. We expect 2022 gap net loss to be in the range of $180 to $210 million, and we expect non-GAAP net loss to be in the range of $0 to $30 million. And I'll direct you to our press release issued this morning for a full outline of our financial guidance for the year. Taking a step back, we've been managing the business to achieve the long-term profitability targets established in 2020, and we were well on track to do so. Simply adding back a full year of long-acting and vaguer product royalties to our guidance would yield a non-GAAP net income margin of approximately 19% of total revenue in 2022. Remember, the 23 target was 25%. Today, we announced revised profitability targets that factor in the removal of these J&J loyalties. The new targets demonstrate our continued commitment to driving long-term profitability and additional expense management efforts. We are now committed to achieving non-GAAP net income margins of 25% in 2025 and 30% in 2026, and EBITDA margins of 20% in 2025 and 25% in 2026. In order to provide a bridge to these margins, we also expect a non-GAAP net income margin in 2024 in the range of 15% to 20%. Now, should our interactions with J&J have a favorable outcome or should the license agreement not be terminated outside the U.S., we will be well positioned to accelerate the achievement of these targets. Over the last several years, we've been positioning the business such that our top-line performance will be fueled primarily by the growth of our proprietary products as we prepare for the anticipated expiration of royalties related to sales of the long-acting Invega products. And while the reduction in royalties impacts our near-term profitability and cash flow, it does not impact the growth drivers underlying the long-term valuation of the company. Going forward, we expect our top line will be driven by growth of our diverse portfolio of commercial products, Vivitrol, Aristada, and Levolvi, along with Vumerity. At the same time, we remain committed to efficient management of our cost structure, as we leverage our commercial infrastructure to drive the launch of Libolvi and advance our pipeline candidates in oncology and neuroscience. And with that, I'll hand the call over to Todd to review our commercial landscape.

Thanks, Ian, and good morning, everyone. The fourth quarter marked the beginning of a new chapter for Alkermes within the commercial neuropsychiatry landscape. Over several years, we have built a substantial and sophisticated set of capabilities necessary to commercialize medicines for patients with serious mental illness. In Delonte of Lee Balvey, our second antipsychotic medication, we are leveraging our established commercial infrastructure, as well as the market insights and relationships that we have built through our presence in the market with Aristotle. These capabilities and insights are valuable assets, and we expect they will provide a strong platform for growth. Overall, I'm encouraged with our performance in 2021 as our team delivered strong commercial execution against the backdrop of dynamic market conditions. Vivitrol surpassed pre-pandemic volumes, driven by our strategic focus on the alcohol dependence indication. Aristata gained market share and remained the fastest growing long-acting injectable in the LAI market on a month of therapy basis. And we took steps to optimize our commercial field infrastructure to efficiently and effectively launch Lebalvi, which we made commercially available in October. So starting there with Lebalvi. Lebalvi addresses a compelling real-world need of people suffering from schizophrenia and bipolar I disorder, offering proven efficacy while being associated with less weight gain versus olanzapine in adults with schizophrenia in the pivotal Enlightened II clinical trial. I'm encouraged by the progress that we have made since launch, with net sales in the fourth quarter of $8.2 million, driven by strong execution and broad healthcare provider awareness of Lubavi. Early in the launch, we were focused on two primary key performance indicators, total prescriptions and prescriber breadth. In the fourth quarter, we established a strong trajectory in terms of weekly total prescriptions of Lubavi, despite the holidays and the surge in COVID-19 cases. Total prescriptions, as measured by Acuvia, reached approximately 3,800 in the fourth quarter. Although it's early, the initial feedback from healthcare providers and patients related to Lebalvi has been positive and adds to our confidence as we continue to execute on the launch. Across indications, data suggests similar utilization in schizophrenia and bipolar I disorder. And in terms of source of business, patient switches have come from a broad range of therapies, including olanzapine, as well as other generic and branded agents. The oral atypical antipsychotic market represents a substantial opportunity due to the size of the patient populations in schizophrenia and bipolar I disorder, and a significant unmet patient need evidenced by the fact that these patients often cycle through five to seven therapies during their treatment journey. Turning to prescriber adoption, we are encouraged by the breadth of prescriber adoption and geographic diversity. In the fourth quarter, approximately 1,160 providers wrote a prescription for Lebalvi, and adoption has continued to grow in the early weeks of 2022. Our healthcare provider targeting strategy is highly selective, and we have seen strong conversion among healthcare providers that we anticipated would be early adopters. Our market data demonstrated aided awareness of Lebalvi among survey prescribers of greater than 75% in December. which we are pleased with at this early stage of the launch and which reflects an increase of more than 25 percentage points since September. In terms of access and reimbursement, initial payer coverage has been in line with our expectations. We continue to expect that Libavi will be treated like other branded agents and that its access profile will be established gradually over the first 12 to 18 months of launch. Timing for coverage decisions will vary among our three main payer channels, Medicaid, Medicare Part D, and commercial plans. Importantly, as we await coverage decisions, there is a pathway to access for patients in each of these three channels. Feedback from the field has indicated that our patient support programs have been effective in assisting eligible patients to gain access to Libavi. As Ian outlined, we expect LeBall to be 2022 net sales in the range of $55 to $75 million. Based on initial trends observed in launch, we believe we are well-positioned to achieve these expectations and look forward to providing further updates throughout the year. For the Aristotle product family, net sales in the fourth quarter increased approximately 14% year-over-year to $78.7 million, driven by TRX growth of 13% year-over-year on a month of therapy basis as the Aristata continued to be the fastest-growing long-acting antipsychotic in the market. Looking ahead, we believe that Aristata is well-positioned and that its volume and market share will continue to grow, driven by our once-every-two-month dosing and our Aristata Initio treatment initiation regimen. For 2022, we expect Aristata net sales in the range of $290 to $320 million. This range reflects our continued emphasis on Aristotle's differentiated value proposition and assumes a normalization new patient starts for the overall LAI class throughout the year. Moving to Vivitrol, net sales in the fourth quarter increased approximately 15% year-over-year to $92 million. Importantly, in 2021, we reestablished growth for Vivitrol as we surpassed our pre-pandemic unit volume in net sales, driven by growth in the alcohol dependence indication. The increased adoption of Vivitrol in this indication and the overall increase in prescriber breadth in 2021 give us confidence in the future growth potential of this important medicine. As Ian mentioned, during the fourth quarter, pandemic-related disruptions persisted in the addiction treatment system. While outpatient clinics have been more resilient, residential treatment centers have reported they are still below full capacity. Though this has impacted demand for Vivitrol and the opioid dependence indication to a greater degree, due to detoxification requirements, we have seen signs of stabilization since the height of the pandemic. We believe that Vivitrol is an important and differentiated treatment option for opioid dependence and are focused on driving awareness and supporting patient access. For 2022, we expect Vivitrol net sales in the range of $355 to $385 million as we advance our strategy to drive growth in the alcohol dependence indication. Across both indications, we remain committed to driving awareness of Vivitrol's utility and believe it will continue to have an important role to play in the treatment paradigm. Before I turn the call over to Rich, I'd like to take a moment to acknowledge the collective commitment and agility of our commercial team, which have enabled us to adapt our commercial model to the changing dynamics of our business over the past several years. Growing sales of our products to new all-time highs in 2021 and building momentum leading into the commercial launch of Levolvi. In 2022, we remain focused on execution, increasing awareness, and delivering growth of Levolvi, Aristata, and Vivitrol. And with that, I'll turn the call back over to Rich.

That's great. Thank you, Todd. So as you've just heard, Alkermes is establishing a distinctive commercial presence in the field of neuropsychiatry and addiction. Levolvi is an important new element. Early trends from the launch have been strong, and feedback from providers indicates that the value proposition is simple, clear, and resonating. This is gratifying, and it strengthens our belief that Levolvi has significant potential to be important medicine in the treatment of schizophrenia and bipolar I disorder. The data supporting the weight-mitigating properties of Levolvi compared to olanzapine continue to accumulate in the real-world setting and in the clinic. Just last week, we announced positive top-line results from the Enlighten Early Study, a Phase 3B study evaluating the effect of Libalfi compared to olanzapine on body weight in patients with schizophrenia, schizophreniform disorder, or bipolar I disorder who were early in their illness. This study met its pre-specified primary endpoint as patients treated with Libalfi experienced significantly less weight gain than patients treated with olanzapine at Week 12. Consistent with the Enlightened II pivotal study, a numerical difference in average weight gain between treatment arms was observed early in treatment and continue to separate through the study's pre-specified primary endpoint. The safety profile of Luvolvi was consistent with previous studies and with its label, so we'll look forward to presenting additional results from Enlighten early at upcoming scientific meetings. Now, Melugin is emerging as a differentiated IL-2 variant with accumulating clinical evidence of anti-tumor activity, both alone as monotherapy and in combination with the checkpoint inhibitor. This week at the ASCO GU meeting, we will present additional data from the monotherapy expansion stage of Artistry 1 in patients with renal cell carcinoma. The monotherapy antitumor activity has been a key differentiating feature of Nemvalucan that distinguishes our clinical data from other IL-2 variants in development. We have three key priorities for Nemvalucan in 2022. First, we're focused on the enrollment of potential registration-enabling clinical studies in mucosal melanoma as monotherapy, and in platinum-resistant ovarian cancer in combination with pembrolizumab. Each has been granted fast-track designation by FDA based on the significant unmet need and the potential clinical utility of nevalucan's antitumor activity in these tumor types. Second, based on antitumor activity and tolerability signals that have emerged from our initial IV program, We're evaluating multiple dosing options to support flexibility and the potential for broader clinical utility. Toward the end of the first quarter, we plan to initiate clinical evaluation of less frequent IV dosing schedules. Based on the results of predictive modeling, we plan to study once every three week or twice every three week dosing. We're also accumulating data on anti-tumor activity and durability from our ongoing Artistry 2 subcutaneous once weekly dosing study. By the end of 2022, we expect to have a clearer picture of each of these administration routes and schedules. The third priority is pursuit of strategic collaboration. Currently, in our hands, this is a focused program, but we believe the promise of an effective, well-tolerated IL-2 variant is its potential use in a range of tumor types, lines of therapies, and combinations. We hope to expand the program in the future via collaboration with other oncology companies with complementary agents and capabilities. Turning to Alex1140, our HDAC inhibitor candidate. We initiated the first in human single escalating dose study in the fourth quarter. And with initial data already in hand, we're making some adjustments to the plan. After three dose escalations, we observed lower than predicted systemic exposures of the parent compound and higher level of the major active metabolite. Importantly, we didn't observe any safety signals in the completed dose escalation cohorts. So we expect to continue dose escalation, but we'll first pause to properly characterize the safety profile for the metabolite and establish the necessary exposure safety margins pre-clinically before we proceed to the higher doses. We have set clear stage gates and we're focused on asking the right questions early in the development program as we advance this novel program. I'll end with an update on our most advanced preclinical programs in neuroscience and oncology. In the fourth quarter, we formally nominated our orexin-2 receptor agonist candidate, now known as ALX2680. The orexin pathway and its central role in the sleep-wake cycle are well characterized. In designing 2680, our objective was to optimize the PK-PD relationship to make a molecule that could mimic the efficacy of the natural orexin peptide to increase wakefulness, with a convenient dosing schedule and a well-tolerated profile. IND-enabling activities for 2680 are underway, and we're hoping to enter the clinic later this year or in early 2023. Within our preclinical portfolio of engineered cytokines, we've made progress to advance our tumor-targeted IL-12 oncology agents. IL-12 is one of the most potent inflammatory cytokines and has strong biological potential as an anti-cancer agent. However, The use of systemic IL-12 has been limited by severe toxicity. We recently achieved an important milestone, establishing preclinical proof of concept for our construct. This triggers progression to the next stage of the program, and we expect to generate additional preclinical data to further validate our approach this year. Our R&D programs represent potential future growth drivers. In each program, we're focused on interrogating and addressing key critical questions early on and strictly adhering to our internal R&D stage gates. So I will end there. With a strong start for Lebalvi and a clear path forward for our development programs, we enter 2022 with a lot of operational momentum and a continued focus on discipline and allocation of capital and driving profitable growth. We believe that we're well-positioned to continue to create shareholder value, and I'll look forward to updating you on our progress. So with that, I'll turn the call back to Sandy to run the Q&A.

Thanks, Richard. All right, Rob, I think we're ready to pivot to the Q&A.

Thanks, Sandy. If you'd like to ask a question at this time, please press star 1 from your telephone keypad and a confirmation tone to 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. One moment, please, while we poll for questions. And once again, it's star one to ask a question. Thank you. Thank you. And our first question comes from the line of Brandon Folks with Cantor Fitzgerald. Please receive your question.

Hi. Thanks for taking my questions. Congratulations on the progress, and thank you for all the color. So maybe just two from me. First, in terms of light bulb, gross to net, where do you where do you think that will stabilize at? Is it sort of closer to that 2022 guidance or maybe closer to the Vivitrol and Aristotle number? How do you think about balancing access versus script growth in 2022 and beyond? And then maybe I'll ask my second one, because it probably goes a little bit in line with that. Thank you for the updated longer term profitability targets, but going to continue to dig a little. Did you consider putting up revenue targets publicly? Do you think that's something you could put out in the future just to sort of shore up that you do have growth in the business? Thank you.

Okay, so why don't I take a crack at those two? Thanks for the questions, Brandon. I think on the Le Bowl v. Gross to Nets, what we said is we would expect that to settle out in the long term in the mid-40% range, so that would be slightly higher than the 40% range we talked about for fiscal 22. It's going to be a little bit dynamic as LoBolvi sort of works its way through the access situations in each of the three different channels that we see. And also, the particular indication, whether it's schizophrenia or bipolar, has an implication for gross to net as well. But I think we said at launch we would expect mid-30s initially going to mid-40s steady state. On the long-term profitability targets, I'll just try and make a couple of comments there to provide a little bit more color. So I think restating the targets really highlights the company's continued commitment to long-term profitability. I think there are margin targets, so revenue matters and expense management matters. I think right now we're really focused on managing driving the profitability through driving the top line through the proprietary products, Vivitrol, Aristar, and Lebalvi, as I mentioned. Vumerit is going to be an important contributor to that as well. And we're very much focused on managing cost structure. So we're not going to provide long-term revenue targets at this point in time, but all to say we're really focused on managing the income statement to be able to achieve these targets in 2024, 2025, and 2026.

Hey, Brandon, this is Rich. I just want to implicit in your question, the first question was a concept I want to make sure we address, which is whether or not we're using gross to net in order to gain additional access in the launch year. And that has not been our strategy. Our strategy has been to drive demand for the product through physicians' desire to use it with their patients and then evolve into our contracting strategy as that demand grows over time.

Great. Thank you to both of you. I appreciate all the color.

Thanks, Brandon.

Our next question is from the line of Emile Devon with Mizuho Securities. Please receive your questions.

Great. Thanks for taking my question. So maybe also one around Libelvy and one around for forward guidance. So Libelvy, I'm just curious if you could share a little bit more in terms of the initial reception you're seeing from that product in the market and also in the fourth quarter. number, is there any sort of inventory stocking component that we should sort of keep in mind? Your guidance for this year certainly is higher than what we were expecting, but just trying to get a sense of the underlying demand. And then second, I like how you're sort of handling the royalty situation from a forward-looking perspective, but can you just give us a sense, because we get this question a lot around timing and when we might hear more on the royalty, but I know you're sort of looking to speak to Jane Day and kind of open to all options. But I don't know if there's anything you can share around how long this process might take to play out and when we might hear more from all of you. Thank you.

Good morning. I'm with Rich. I'll have Todd answer the first one. I'll pick up the second.

Okay, great. Yeah, I'll start with Labavi. So first off is We are really encouraged by the initial launch momentum, as I said in the prepared remarks. And Q4, according to IQVIA, approximately 3,800 prescriptions, broad healthcare adoption, 1,160 providers overall as well, and the feedback. So we're spending a lot of time doing market research with our customers and also talking to our field organization as well. And our feedback from HCPs, payers, and our team on the ground is really consistent throughout the research. What we're hearing is that the clinical profile, the Levalvi clinical data, is being well received. We're seeing very clearly the broad indications and the utility for different patient types. So that's the switch market, it's schizophrenia, it's bipolar across the board. We're seeing broad utilization across all four doses, which was a key strategic advantage for the product. And physicians are telling us they think that this is a a key differentiator. So the value proposition, it's early, but our belief is the value proposition is resonating right now. And we really have an opportunity to capitalize just on the efficacy of olanzapine with a low incidence of long-term weight gain from our clinical program. So we're encouraged right now. The feedback from HCPs is good. The feedback from patients is good right now. And the driver, again, is that it's a positive response to olanzapine, but the patients are experiencing less weight gain. So we're encouraged by the initial feedback.

That's right. And then, Vamil, just to add one thing specifically around the inventory, I did mention in the earlier comments that we had about $4.5 million of stocking inventory and that that would burn off in Q1. And that's why I pointed you towards the $8 to $10 million of net sales in the first quarter of this year.

And with respect to J&J, Vamil, I can't really give you any precision around timing. We have begun the engagement with J&J, which is encouraging in that sense. I just want to say that our belief in the strength of our argument is stronger than ever. It was always strong and it's undiminished. But it's interesting, the virtue, as Ian mentioned in his remarks, If you take out the J&J royalties, even for the modeling purposes, as you know, it does reveal the underlying strength and the growth in the base business. And that actually is really useful, I think, for investors to take a look at. What's not complicated, if the J&J numbers come back in, recognize that we're planning for the expiration of those royalties over time anyway, 2024 in the U.S., 2026 ex-U.S. So they're going to go away. And what is left is this growing business that's being effectively managed towards increasing profitability.

Okay, thanks. Thanks also for clarifying the inventory. Sorry, I missed out on the paragraph mark, juggling a few different things. Thanks so much.

No problem.

The next question is from the line of Akash Tiwari with Jefferies. Please just use your questions.

Hey, guys. So it's hard to fully back this out, but would it be fair to say that your expectations on Lebaldi performance between now and 2025 would have to be higher than that in consensus for you to hit your long-term margin targets. Do you agree with that or not? And then, with your new long-term guidance, what programs were specifically discontinued and what was the cost savings associated with that, both in 2022 and beyond? Thank you.

So, I'll take a crack at that one. With regard to the La Balvie sales, I think it's fair to say that the company's expectations are probably slightly more robust than the street's current level of consensus. So take that for what you will. And then on the R&D side, I'm not going to go into specific programs. I think we went back in and we've looked at some of the early stage programs that we were working on, and we've either parked those to the side or, as they say, if they didn't meet the internal stage gates, we cancelled those. So all that really factored into the guidance that we provided today for the R&D expense number.

Thank you.

And, Akash, it's Rich. I would just say, first, good morning. Second of all, the question on the LeVolvi revenue is a good one, because obviously we believe that there's great potential for LeVolvi going forward. But the purpose of stating the explicit profitability targets is to say we're going to drive the business from the management side to hit them irrespective of that trajectory. It gets very easy if LaVolvi exceeds expectations. But LaVolvi is going to continue to grow. Vimerity is growing. Aristot and Vivitrol are strong products. So we have a robust top line that we can manage to, and that's the point.

Thank you. The next question is from the line of Corey Kazimoff, JP Morgan. Please receive your questions.

Hey, this is Tiffany on for Corey. Congrats on the quarter. I just wanted to ask on how much of an impediment COVID has been with Wabalbi's first quarter on the market. Obviously, it looks pretty solid overall, but just wondering kind of COVID headwinds and how they play into that. And then Also, how much you're able to leverage your presence with Aristada to overcome some of these obstacles. Thanks.

Yeah, I'll take that one. You know, our original hypothesis going into the launch is that we had real leverage in the business, and that is absolutely playing out right now. We're hearing that consistently from our field team, also through physicians, through our surveys as well, too. First and foremost is physicians don't believe that Aristada and LaValvie compete. They think that they're synergistic together, and we're seeing leverage in our business with our field infrastructure. That's the reason why we didn't have to have such a dramatic increase in our SG&A expenses to actually launch the product, because we have access and we have relationships with about 60% of our targeted audience. To the earlier comments we made in our prepared remarks, we did see a slowdown in patient diagnosis. overall in the market for addiction, but also for psychiatry as well in the fourth quarter. In fact, Acuvia reported a little bit of a slowdown in diagnosed patients and also patients originating in person as well, too. We didn't quite see any headwinds there for Lebalvi for the main reason why that You know, physicians, our targets are very comfortable with olanzapine. And by being comfortable with olanzapine, regardless of the modality, in-person, telehealth, or in COVID, they're more comfortable prescribing a product like Lebalvi. So that's an advantage for Lebalvi. They're also more comfortable with Aristata because of our presence in the market for so long. So when we have relationships, that helps us from, you know, from a COVID impact perspective. But we did see some delays in patient initiation in the fourth quarter, as we said. We believe that that's going to completely evolve and change throughout the year. We're well-positioned to maximize our infrastructure.

Great. Thank you.

Our next question is coming from the line of Umar Rafat with Evercore ISI. Please, just use your question.

Hi, guys. Thanks for taking my question. I have two, if I may. Is it fair to assume, based on the forward-looking guidance you guys are putting out, medium term, you're setting an EPS floor of at least 250? Am I correct in doing that sort of math? And then secondly, as it relates to specifically on liability number in that 2025-26 timeframe, it's hard to get to that 30% net income margin unless I assume that liability would be closer to $500 million to $600 million in that timeframe rather than the $300 million to $400 million in consensus. So am I correct in that direction of at least $200 million upside on LaValvie versus what ConsenSys has? Thank you very much.

Well, I think on your last question on LaValvie, I think ConsenSys continues to evolve with regard to that product. We're obviously in the launch phase. I think 2022 is going to tell us a lot about the future trajectory of the product. As we mentioned, that initial gaining access is going to take a 12 to 18-month time frame. 2022 is going to reveal a lot. And then with regard to the longer-term profitability targets, you know, we're really focused in on the non-gabinet income and the EBITDA measures that we talked to today. And again, as we go through 22 and beyond, we'll be able to focus on those measures. So, we haven't specifically talked about EPS at this point in time, We're just focused on managing the top line and managing the cost structure in order to be able to hit EBITDA and long-term income measures.

Thank you. Our next question is from the line of Paul Matisse with Stifel.

Please proceed with your question.

Hey, this is Katie on for Paul. Just a quick question from us. We were wondering if you could clarify where 1140 is in development and what you're looking to see in order to enter a phase one, and any inclinations on indication strategy would be helpful as well. Thank you.

Katie, it's Rich. You may not have heard the prepared remarks, but we just gave an update on the 1140. It's in the clinic right now, so it's in its first human study in a single escalating dose, and we're pausing right now after three dose escalations because we have a higher than predicted presence of the primary metabolite, which is metabolized at a higher level in humans than in animals. And we want to just reestablish those exposure margins in animals before we continue the dose escalation. We've seen no safety signals, so we're encouraged to keep going, but we just need to do a little bit more work preclinically before we continue the escalation.

Makes sense. Thanks.

You're welcome.

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

Hi, thanks. This is Madhulan for Mark. You mentioned that you currently have similar utilization for schizophrenia and bipolar I, but that the utilization may have an implication for gross to net. So just wondering if you expect similar utilization going forward or a modification of that. Thanks.

Yeah, absolutely. I'll take that. It's a little early right now. Once we get a little bit more time in our belt with utilization claims data, we'll have a much better line of sight. I would say in general, the way to think about this is that Mabalvi is not being niched in any one patient population. We're seeing broad utilization across schizophrenia and bipolar as well. Typically, in the bipolar market, you see a little bit higher concentration of reimbursement through commercial. We would assume that that would play through for LaVolvi over time, but at this point right now, it's a little early. Thank you.

The next question is coming from the line of Doug Sell with HC Wainwright. Please proceed with your question.

Good morning, everyone. Chris Bialis here. I'm with Doug. So I just have a question about Vivitrol, you know, with COVID seeing the ease, how do you expect this to alter kind of the alcohol versus opioid use disorder mix?

And I guess similarly for the breakdown of the different Aristotle products, how do you, how do you expect the change in COVID landscape to impact that? Thank you.

Yep. Yeah, I'll, I'll start with that with first thinking about, about Vivitrol. First is we're really encouraged that in 2021, we actually reestablished growth for Vivitrol. We actually exceeded our pre-pandemic volumes, which is just a really strong indication of the strength of the team and the value proposition of Vivitrol. The way we're thinking about Vivitrol now in the future is the dual indication. Vivitrol is well regarded in the AD market, and AD market overall is driving growth for the entire category. So if we take a step back and we look at TRXs in terms of months of therapy, if you look at Q4, the market grew approximately 12%. Vivitrol continues to outpace that market. Vivitrol grew approximately 19% in terms of months of therapy. We did see some headwinds, as I said earlier, within the OD market. The OD market is relatively flat. Vivitrol had a slight decline within the OD market. We think that that will resolve itself over time. as pandemic-related restrictions ease, as patients get access to treatment, mainly in the controlled setting category overall. Long-term, we see the strongest market growth potential for the category being in alcohol dependence, and Vivitrol, as I said earlier, is very well received. Additionally, when we talk to our customers through all of our market research, You know, approximately 80% of surveyed HCPs believe that the prevalence of AD is increasing over the past year. And about 70% of those HCPs believe that the medication is an important part of the journey. So we think Vivitrol is very well positioned for sustained growth over time, being mainly driven from the alcohol dependence indication. As I said earlier, thinking a little bit about Aristata, Aristata continues to outpace the broader long-acting market as well. The market has seen a slowdown. We saw a slowdown in 20, a slowdown in 21. The market continues to grow, but just not at the pace that we saw pre-pandemic. Aristot is growing three times faster than the market. We see that in terms of TRX MOTs. We also see that with new patient starts, which we define as MBRX, as Aristot continues to outpace the market. And it's really being driven by the value propositions, you know, Physicians are telling us that awareness levels are increasing. They believe in 1064, which is our two-dose option, and also our initio regimen as well, too. So we believe that Aristotle will continue to grow, and our assumptions are that Aristotle will continue to outpace the market.

Awesome.

Thanks for the detail. Thank you. The next question is from the line of Jason Gerber, Bank of America. Please receive your question.

Hey, guys. Good morning. Thanks for taking my questions. First one for me on Nemvalucan. Just as we think about IV shorter infusion formats versus sub-Q, what do you think is more important to driving a high-value partnership? I would assume IV, just given it's physician-administered and most of these combinations are IV anyway. So I'm just curious your views on that. And then ultimately also, how important do you think the BEMPEG melanoma phase three is later this year? It seems like investors are focused on that as potentially a catalyst for driving more enthusiasm from large pharma partners in aisle two as a mechanism. And then just to summarize on the long-term profitability, it sounds like if you see revenues scale upwards and beat consensus in a meaningful way, you can maintain the current operating spend, maybe even grow it, but Alternatively, if revenues are falling short in that 24, 25 timeframe, you have the flexibility to flex down your operating spend levels to make the target. So there's a bit of fluidity in it, but it sounds like those would be the scenarios. Is that the right way to think about it? Thanks.

More to Jason. I think just I'll quickly answer the last part, which is yes. I think that's the right way to think, but you can give more color on that. But that's exactly right. We have a It's nice going into this with a billion-dollar top line with this growing revenue line with new products involved in it, so it gives you a lot of flexibility as you model out. Ideally, we'll continue to grow that revenue line, but we have a lot of flexibility in the whole P&L. Nemalucan is interesting. On the route of administration, there's biology and there's commercial in play here because the sub-Q biology, even with the data we've shown so far, has a differential profile from the IV, which may be Good, bad, or indifferent. Interferon gamma levels are different. NK levels are different via the sub-Q root. And so we're seeing responses sub-Q. We want to see the durability of it versus the IV responses. So we think that's a really important route. But depending on the physician you talk to, sub-Q or less frequent IV are both important. What we're testing in the clinic on the IV side is maybe once every three-week cycle or twice every three-week cycle IV, which we think is really commercially attractive. And the modeling exercise that I referred to where modeling IV to IV is probably much more predictable, reliable than modeling IV to sub Q. So we'll determine both empirically, but I think resolution of both the route and the schedule are really important foundations for expanding the program via collaboration. I do think The whole field is waiting with some anticipation to see the BEMPEG Phase 3s. We've always said that we think the correlation between the outcomes of Nemvalucan and BEMPEG is limited at best. But with that said, I think from an investor perspective, people do want to see whether that casts a shadow or a halo around the IL-2 space.

Great. Thank you.

Thank you. At this time, we've reached the end of our question and answer session, and I'll hand the floor back to management for closing remarks.

Great. Thanks, everyone, for joining us on the call today, and we'll be here at the company if you need anything else. Thanks so much.

Thank you. This will conclude today's conference. We disconnect your lines at this time, and we thank you for your participation. Have a wonderful day.