Alkermes plc. Q4 FY2021 Earnings Call

Greetings, and welcome to the Alkermes Fourth Quarter 2021 Earnings Call. My name is Ralph, and I will be your operator for today’s call. Please note that this conference is being recorded. I will now turn the conference call over to Sandra Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Sandy, you may now begin.

Thanks Ralph. Good morning. Welcome to the Alkermes Plc’s conference call to discuss our financial results and business update for the quarter and year ended December 31, 2021. With me today are Richard Pops, our CEO; Iain Brown, our CFO, and Todd Nichols, our Chief Commercial Officer. Before we begin, I encourage everyone to go to the Investors section of alkermes.com to find our press release and related financial tables and 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 2 of the accompanying presentation, our press release issued this morning and our most recent annual and quarterly report filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we’ll open the call for Q&A. I now turn the call over to Richard.

That’s great. Thank you, Sandy. 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. We were successful in all three of those domains. I will start first with the commercial business. The year was highlighted by the FDA approval and launch of LYBALVI, our first oral medicine for the treatment of adults with schizophrenia and for the treatment of adults with bipolar 1 disorder. The launch is off to a strong start. There are reasons why. The nature of the medicine itself—LYBALVI is addressing an unmet need in the market. The launch benefits from the commercial infrastructure we built in psychiatry and our presence and success with ARISTADA. Together, these medicines create an important and growing commercial franchise in psychiatry. We redefined our growth strategy focused on the alcohol dependence indication for VIVITROL. These products—LYBALVI, ARISTADA, and VIVITROL, along with VUMERITY—represent our four key growth drivers. From a pipeline perspective, 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 clinical studies for Nemvaleukin to support potential registration in two tumor types, where patients have limited treatment options and significant unmet need remains. We also initiated our first human study for our HDAC inhibitor ALKS 1140. We nominated and began the IND enabling activities for ALKS 2680, an orexin 2 receptor agonist, and achieved preclinical proof of concept for our tumor-target IL-12 program. From a financial perspective, we executed our plan with respect to our 2021 objectives and we are on track to achieving our long-term profitability targets. We continued our focus on driving operational efficiencies and optimizing our cost structure, focusing on our highest potential programs, as we position the company for long-term growth. In November, we received notice of partial termination from Janssen, an affiliate of J&J, impacting our royalties related to the sales of long-acting INVEGA products in the U.S. J&J has made the surprising assertion that these products do not utilize Alkermes nano-crystal technology. We strongly disagree with J&J’s position. Since receiving this notice, we’ve engaged with J&J, and we will continue to explore whether a mutually agreeable resolution can be reached without the need for arbitration or litigation. We’re prepared to pursue all options at our disposal to enforce our contractual rights and address the unauthorized use of our intellectual property. For the purposes of our 2022 guidance and the updated long-term profitability targets that we’re going to provide today, we’ve removed U.S. royalties from the long-acting INVEGA products beginning this month and all royalties from outside the U.S., beginning in May. However, we believe that 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 clear 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 to shift away from royalties for long-acting INVEGA products and the long-term growth profile of the company remains unchanged. Separate from the modeling, from an operational perspective, upon receiving the notice from J&J, we 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 these adjustments now changes the cost structure and facilitates the bridge to our profitability targets. The value enhancement plan established in 2020 continues to serve as a guide as we look to the future, and we remain committed to our explicit profitability targets. Today, we’re announcing revised long-term profitability targets reflecting our current financial planning and 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, adding 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 longest-serving board members earlier in the year. The 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. With that, as an introduction, I’m going to turn the call over to Iain to take us through the 2021 results and the outlook ahead and then to Todd to provide an update on the launch of LYBALVI and the performance of ARISTADA and VIVITROL.

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 Alkermes-developed products, coupled with 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. 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 in both VIVITROL and ARISTADA as well as growth in VUMERITY at royalty and manufacturing revenues. From a bottom line perspective, we recorded GAAP net loss of $48.2 million compared to $110.9 million in the prior year, and non-GAAP 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. 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 U.S. 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. 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. Gross to net adjustments were 53.7% for the year, relatively consistent with 2020. For the fourth quarter, ARISTADA net sales were $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 LYBALVI, 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. In terms of 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 VUMERITY, 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 INVEGA products contributed $303.1 million during 2021, and royalty manufacturing revenues related to RISPERDAL CONSTA contributed $50.9 million for the year. Turning to expenses, excluding the $25 million development milestone paid to former shareholders of Rodin Therapeutics, total operating expenses in 2021 increased by just 2% even as we invested in the preparation and execution of the commercial launch of LYBALVI and initiated potential registration-enabling studies for Nemvaleukin. 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 were $561 million, an increase of $22.2 million compared to the prior year. This included a $27.4 million increase in selling and marketing expenses in support of the launch of LYBALVI, partially offset by a $5.2 million decrease in G&A expenses year-over-year as we continued to manage the cost structure. 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 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 LYBALVI, 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 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. Alkermes is well-positioned from a cash perspective, and we do not foresee needing to access the capital markets to fund our ongoing business. I will shift now to our financial guidance for 2022. From an operational perspective, we adapted our budget for the year following receipt of a termination notice from J&J, recognizing that resolution of the situation could take time. We further focused spending on our key strategic priorities—the LYBALVI launch, Nemvaleukin registrational studies, and advancing key early-stage programs. Spending 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 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 INVEGA 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 million to $50 million. We’re doing this to be conservative, and 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 a 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 VUMERITY. 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 LYBALVI. While launch years can be very dynamic, we currently expect LYBALVI net sales in the range of $55 million to $75 million for 2022, and we expect the gross to net adjustments to be in the 40% range for the year. For VIVITROL, we expect net sales in the range of $355 million to $385 million, with gross to net adjustments of approximately 52%. For ARISTADA, we expect net sales in the range of $290 million to $320 million, with gross to net adjustments of approximately 55%. In line with historical seasonal patterns, we expect our first quarter 2022 proprietary product net sales to decrease sequentially to ranges of approximately $78 million to $83 million for VIVITROL and approximately $68 million to $73 million for ARISTADA, with growth expected to resume in the second quarter. Additionally, we expect LYBALVI net sales of approximately $8 million 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 million to $225 million, primarily driven by increased volumes of key manufactured products. R&D expenses are expected to be in the range of $385 million to $415 million, reflecting ongoing enrollment in our potential registration enabling Nemvaleukin clinical studies, ongoing phase four commitments for LYBALVI, and continued investment to support our early-stage development assets, including IND enabling activities and the manufacture of clinical trial supplies for ALKS 2680, our orexin 2 receptor agonist. SG&A expenses are expected to be in the range of $575 million to $605 million. The year-over-year increase reflects a full year of investments to drive the launch of LYBALVI. We expect a GAAP tax benefit in the range of $10 million 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 GAAP net loss to be in the range of $180 million to $210 million, and we expect non-GAAP net loss to be in the range of $0 to $30 million. 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 are well on track to do so. Adding back a full year of long-acting INVEGA product royalties to our guidance would yield a non-GAAP net income margin of approximately 19% of total revenue in 2022. Remember, the 2023 target was 25%. Today, we announced revised profitability targets that factor in the removal of these J&J royalties. 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. 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%. 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 years, we’ve positioned the business so 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 long-acting INVEGA products. While the reduction in royalties affects 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 the growth of our diverse portfolio of commercial products—VIVITROL, ARISTADA, and LYBALVI, 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 LYBALVI and advance our pipeline candidates in oncology and neuroscience. With that, I’ll hand the call over to Todd to review our commercial landscape.

Thanks, Iain, 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. With the launch of LYBALVI, our second antipsychotic medication, we are leveraging our established commercial infrastructure, along with the market insights and relationships that we have built through our presence in the market with ARISTADA. 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. ARISTADA gained market share and remained the fastest growing long-acting injectable and ALAI market on a month of therapy basis. We took steps to optimize our commercial field infrastructure to efficiently and effectively launch LYBALVI, which became commercially available in October. Starting there with LYBALVI, it addresses a compelling real-world need of people suffering from schizophrenia and bipolar 1 disorder, offering proven efficacy while being associated with less weight gain versus olanzapine in adults with schizophrenia, in the pivotal Enlightened 2 clinical trial. I’m encouraged by our progress since launch with net sales in the fourth quarter of $8.2 million driven by strong execution and broad healthcare provider awareness of LYBALVI. Early in the launch, we are 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 LYBALVI, despite the holidays and a surge in COVID-19 cases. Total prescriptions reached approximately 3,800 in the fourth quarter. Although it’s early, initial feedback from healthcare providers and patients related to LYBALVI has been positive and adds to our confidence as we continue to execute on the launch. Across indications, data suggests similar utilization between schizophrenia and bipolar 1 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 1 disorder, with significant unmet patient need evidenced by the fact that these patients often cycle through five to seven therapies during their treatment journey. In terms of prescriber adoption, we’re encouraged by the breadth of prescriber adoption and geographic diversity. In the fourth quarter, approximately 1,160 providers wrote a prescription for LYBALVI, 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 LYBALVI among surveyed 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 LYBALVI will be treated like other branded agents, establishing its access profile gradually over the first 12 to 18 months at launch. Timing for coverage decisions will vary among our three main payer channels: Medicaid, Medicare Part D, and commercial plans. Importantly, while 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 LYBALVI. As Iain outlined, we expect LYBALVI 2022 net sales in the range of $55 million 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 ARISTADA 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 ARISTADA continued to be the fastest growing long-acting antipsychotic in the market. Looking ahead, we believe that ARISTADA is well-positioned and that its volume and market share will continue to grow, driven by our once every two-month dosing and our ARISTADA initiate treatment regimen. For 2022, we expect ARISTADA net sales in the range of $290 million to $320 million. This range reflects our continued emphasis on ARISTADA’s differentiated value proposition and assumes a normalization of 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, surpassing our pre-pandemic unit volume and net sales driven by growth in the alcohol dependence indication. Increased adoption of VIVITROL in this indication, along with an overall increase in prescriber breadth in 2021, gives us confidence in the future growth potential of this important medicine. 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. This has impacted demand for VIVITROL and the opioid dependence indication to a greater degree due to detoxification requirements; however, 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 million 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 acknowledge the collective commitment and agility of our commercial team, which has 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 LYBALVI. In 2022, we remain focused on execution, increasing awareness, and delivering growth of LYBALVI, ARISTADA, and VIVITROL. With that, I’ll turn the call back over to Rich.

That’s great. Thank you, Todd. As you’ve just heard, Alkermes is establishing a distinctive commercial presence in the field of neuropsychiatry and addiction. LYBALVI is an important new element. Early trends for the launch have been strong, and feedback from providers indicates that the value proposition is simple, clear, and resonating. This is gratifying and strengthens our belief that LYBALVI has significant potential to be an important medicine in the treatment of schizophrenia and bipolar 1 disorder. The data supporting the weight-mitigating properties of LYBALVI compared to olanzapine continue to accumulate in both real-world settings and in the clinic. Just last week, we announced positive top-line results from the Enlightened Early study, a phase 3B study evaluating the effect of LYBALVI compared to olanzapine on body weight in patients with schizophrenia, schizophreniform disorder, or bipolar 1 disorder who were early in their illness. This study met its pre-specified primary endpoint, as patients treated with LYBALVI experienced significantly less weight gain than patients treated with olanzapine at week 12. Consistent with the Enlightened 2 pivotal study, a numerical difference in average weight gain between treatment arms was observed early in treatment and continued to separate through the study's pre-specified primary endpoint. The safety profile of LYBALVI was consistent with previous studies and its label. We look forward to presenting additional results from Enlightened Early at upcoming scientific meetings. Nemvaleukin is emerging as a differentiated IL-2 variant with accumulating clinical evidence of anti-tumor activity, both alone as mono-therapy and in combination with a checkpoint inhibitor. This week at the ASCO GU meeting, we will present additional data for the mono-therapy expansion stage of ARTISTRY-1 in patients with renal cell carcinoma. The mono-therapy anti-tumor activity has been a key differentiating feature of Nemvaleukin that distinguishes our clinical data from other IL-2 variants in development. We have three key priorities for Nemvaleukin in 2022. First, we’re focused on enrollment of potential registration-enabling clinical studies in mucosal melanoma as mono-therapy and in platinum-resistant ovarian cancer in combination with pembrolizumab; each has been granted Fast Track designation by the FDA based on the significant unmet need and the potential clinical utility of Nemvaleukin's anti-tumor activity in these tumor types. Second, based on anti-tumor 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 weeks or twice every three weeks 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 the pursuit of strategic collaboration. Currently, in our hands, this is a focused program, but we believe the promise of effective, well-tolerated IL-2 variants is its potential use in a range of tumor types, lines of therapy, and combinations. We hope to expand the program in the future via collaboration with other oncology companies, with complementary agents and capabilities. Turning to ALKS 1140, 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 of 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 ALKS 2680. 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 capable of mimicking the efficacy of the natural orexin peptide to increase wakefulness while maintaining a convenient dosing schedule and a well-tolerated profile. IND enabling activities for 2680 are underway, and we hope to enter the clinic later this year or in early 2023. Within our preclinical portfolio of engineered cytokines, we’ve made progress in advancing our tumor-targeted IL-12 oncology agents. IL-12 is one of the most potent inflammatory cytokines and shows 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, which 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 while strictly adhering to our internal R&D stage gates. So I will end there. With a strong start for LYBALVI and a clear path forward for our development programs, we enter 2022 with significant operational momentum and a continued focus on disciplined allocation of capital and driving profitable growth. We believe that we’re well-positioned to continue to create shareholder value, and I look forward to updating you on our progress. With that, I’ll turn the call back over to Sandy to run the Q&A.

Thanks, Richard. Alright, Ralph, I think we’re ready to pivot to the Q&A.

Thanks, Sandy. Our first question comes from Brandon Folkes with Cantor Fitzgerald. Please proceed with your questions.

Alright, thanks for taking the questions. Congratulations on the progress, and thank you for all the color. So maybe just two for me. First, in terms of LYBALVI gross to net weight, what do you think that will stabilize at? Is it sort of closer to the 2022 guidance, or maybe closer to the VIVITROL, ARISTADA number? How do you think about balancing access versus script growth in 2022 and beyond? And maybe I’ll stick around to a follow-up question. Thank you for the updated long-term profitability targets, but it’s going to continue to dig a little. Did you consider putting up revenue targets publicly? Do you think it’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. On the LYBALVI 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 2022. It’s going to be a little bit dynamic as LYBALVI works its way through the access situations in each of the three different channels that we see. Also, the particular indication, whether it’s schizophrenia or bipolar, has implications for gross. 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. Restating the targets really highlights the company’s continued commitment to long-term profitability. I think they are margin targets, so revenue matters and expense management matters. I think right now, we’re really focused on managing profitability through driving the top line through proprietary products—VIVITROL, ARISTADA, LYBALVI—as I mentioned VUMERITY is going to be an important contributor to that as well. We’re very much focused on managing the 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, it’s Rich. I just want to address implicit in your question, which was whether we’re using gross to net in order to gain additional access in the launch year. 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 our contracting strategies as that demand grows over time.

Great, thank you to both of you. I appreciate all the color.

Our next question comes from the line of Vamil Divan with Mizuho Securities. Please proceed with your questions.

Great. Thanks for taking my question. So maybe also one around LYBALVI, one around your guidance. So, like LYBALVI, just curious if you could share a little more in terms of the initial risk in terms of the initial reception you’re seeing from that product in the market. Also in the fourth quarter number, was there. Is there any sort of inventory stocking component that we should keep in mind your guidance for this year? Certainly, it is higher than we were expecting, but just trying to get a sense of the underlying demand. And then second, I like how you’re handling the relative 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? I know you are looking to speak to J&J and kind of open 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, Vamil. It’s Rich. I’ll have Todd answer the first one. I’ll pick up the second.

Yes, I’ll start with LYBALVI. First off, we are really encouraged by the initial launch momentum. As I said in the prepared remarks, and according to ACWIA, we had approximately 3,800 prescriptions, broad healthcare adoption—1,160 providers overall as well—and the feedback we’re getting from ATPs, payers and our team on the ground is consistent throughout our research. Physicians believe in the clinical data for LYBALVI; we are seeing utilization across both schizophrenia and bipolar 1 disorder, and in terms of patient switches, they have come from a variety of therapies including olanzapine as well as other generic and branded agents. This product is addressing significant unmet need, and we think this will enable effective market penetration over the coming months.

And with respect to J&J’s situation, 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 emphasize that our belief in the strength of our argument is stronger than ever. If the virtue, as Iain mentioned in his remarks, is that if you take out the J&J royalties, even for modeling purposes, it reveals the underlying strength and growth in the base business. That is useful, I think, for investors to evaluate. What’s not complicated is that if the J&J numbers come back in, we recognize that we’re planning for the expiration of these royalties over time. 2024 in the U.S., 2026 ex-U.S., so they’re going to go away. What remains is a growing business managed towards increasing profitability.

So thanks for clarifying the inventory. Sorry, I missed it in the prepared remarks; I'm juggling a few different things. Thanks so much.

Our next question is from the line of Akash Tiwari with Jeffries. Please proceed with your question.

So it’s hard to fully back this out, but would it be fair to say that your expectations on LYBALVI 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 regards to the LYBALVI 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, but we went back and we’ve looked at some of the early-stage programs we were working on, and we have either put them to the side or, as they say, if they didn’t meet the internal stage gates, we canceled those. So all that factors into the guidance we provided today for the R&D expense number.

And Akash, it’s Rich. I would just say first, good morning, second of all, the question on the LYBALVI revenue is a good one because it obviously signals to us that there’s great potential for LYBALVI going forward. But the purpose of stating the explicit profitability targets is to indicate that we will manage the business to hit them irrespective of that trajectory. It gets very easy if LYBALVI exceeds expectations, but LYBALVI will continue to grow. VUMERITY is growing, ARISTADA and VIVITROL are strong products. We have a robust top line that we can manage to, and that’s the point.

The next question is from the line of Cory Kasimov with JPMorgan. Please proceed with your questions.

This is Tiffany on for Corey. Congrats on the quarter. I just wanted to ask about how much of an impediment COVID has been with LYBALVI, first quarter on the market obviously 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.

Yes, I’ll take that one. Our original hypothesis going into the launch is that we have real leverage in this business, and that is absolutely playing out. We’re hearing that consistently from our field team and through physicians as well. First and foremost, physicians don’t believe that ARISTADA and LYBALVI 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 launch the product because we have access and relationships with about 60% of our targeted audience. We did see a slowdown in patient diagnosis overall in the market for addiction but also for psychiatry in the fourth quarter. In fact, ACWIA reported a slight slowdown in diagnosed patients and also in-person originating patients. We didn’t experience major headwinds with LYBALVI largely because physicians are comfortable prescribing olanzapine, which makes them more comfortable with LYBALVI regardless of modality, be it in-person, telehealth, or in COVID. That’s an advantage. They’re also more comfortable with ARISTADA because of our presence in the market for so long. So when we have relationships, that helps us mitigate the impact of COVID, but I do acknowledge we saw some delays in patient initiation in the fourth quarter. We believe that’s going to evolve and change throughout the year, and we’re well positioned to maximize our infrastructure.

Our next question is coming from the line of Umer Raffat with Evercore ISI. Please proceed with your question.

Hi, guys. Thanks for taking my question. I have two if I may. First, is it fair to assume, based on the forward-looking guidance you’re putting out for the 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 LYBALVI number in that 2025, 2026 timeframe, it’s hard to get to that 30% net income margin unless I assume that LYBALVI would be closer to $500 million to $600 million in that timeframe rather than $300 million to $400 million in consensus. So am I correct in that direction of at least $200 million of upside in LYBALVI versus what consensus has? Thank you very much.

I think on your last question on the LYBALVI, I think consensus 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, initial gaining access is going to require a 12 to 18 month timeframe. So 2022 will reveal a lot. And with regard to the longer-term profitability targets, we’re really focusing on the non-GAAP net income and EBITDA metrics we talked about today. Again, as we go through 2022 and beyond, we’ll be able to focus on those measures. So we haven’t specifically talked about EPS at this time. We’re just focused on managing the top line and managing the cost structure in order to hit our EBITDA and non-GAAP income measures.

Thank you. Our next question is from the line of Paul Matteis with Stifel. Please proceed with your question.

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 phase one. Any inclinations on indication strategy would be helpful as well. Thank you.

Hi Katie, this is Rich. You may not have heard the prepared remarks. We just gave an update on 1140. It’s in the clinic currently—in its first human study and in the single escalating dose—we’re pausing to properly characterize the safety profile of the metabolite and establish the necessary exposure safety margins pre-clinically before we proceed to the higher doses. We’ve observed lower than predicted systemic exposures of the parent compound with the major active metabolite being present at a higher level. We didn’t see any safety signals in the completed dose escalation cohorts, so we are encouraged to keep going, but we need to do a bit more work preclinically before moving forward with dose escalation.

The next question is from the line of Marc Goodman with SVB Leerink. Please proceed with your question.

You mentioned that you currently have similar utilization for schizophrenia and bipolar 1, but that the utilization may have an implication for gross to net. Just wondering if you expect similar utilization going forward or if a modification of that is anticipated? Thanks.

Yes, absolutely. I’ll take that. It’s a little early right now. Once we get a little bit more time under our belt with utilization claims data, we’ll have a much better line of sight. In general, the way to think about this is that LYBALVI is not being niched into 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 channels, and I would assume that this plays through for LYBALVI over time, but at this point, it’s a bit early to definitively state.

Thank you. The next question is coming from the line of Douglas Tsao with H.C. Wainwright. Please proceed with your question.

Good morning, everyone. Chris here on for Doug. I just have a question about VIVITROL. With COVID seeming to 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 ARISTADA products, how do you expect the changing COVID landscape to impact that? Thank you.

Yes, I’ll start with that, first thinking about VIVITROL. First, 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 is the dual indication it has. VIVITROL is well regarded in the alcohol dependence market overall, and this is driving growth for the entire category. If we take a step back and we look at TRX in terms of months of therapy, the market grew approximately 12% in Q4. VIVITROL continues to outpace that market; VIVITROL grew approximately 19% in terms of months of therapy. We did see some headwinds within the opioid dependence market, which is relatively flat, with a slight decline in that sector. We believe that will resolve as pandemic-related restrictions ease. We're confident in VIVITROL's differentiated treatment option for opioid dependence and our strategy is focused on driving awareness and supporting patient access. For 2022, we expect VIVITROL net sales in the range of $355 million to $385 million as we advance our strategy in the alcohol dependence indication. Overall, we are committed to increasing awareness of VIVITROL's utility.

Thank you. Our next question is from the line of Jason Gerberry with Bank of America. Please proceed with your question.

Hi, guys. Good morning. Thanks for taking my questions. First one for me on nemvaleukin. 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 its physician-administered nature and most combinations are typically IV anyway. So I’m just curious your views on that? Also, how important do you think the melanoma phase 3 is later this year? It seems like investors are focused on that as a potential catalyst for driving more enthusiasm from large pharma partners in the IL-2 mechanism. Then just to summarize on the long-term profitability, it sounds like if you see revenue 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 the 2024, 2025 timeframe, you have the flexibility to flex down your operating spend levels to meet your targets. 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.

Good morning, Jason. I think just to quickly answer the last part, which is yes, I think that’s the right way to think about it. We have, while it’s nice going into this with a billion-dollar top line with this growing revenue line with new products involved. It gives you a lot of flexibility as you model out. Ideally, we will continue to grow that revenue line, but we have a lot of flexibility in the whole P&L. Nemvaleukin is interesting regarding the route of administration; there’s biology and commercial interests in play here. Sub-q could present a different profile than the IV route, especially in how it’s taken up in the body. As we are testing the flexibility, we want to see performance comparisons. IV may be more predictable; however, we are wanting both routes to shine and lead—whether IV or sub-q is clinically beneficial may be determined as we gather more evidence.

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

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

Thank you. This will conclude today’s conference. You may disconnect your lines at this time. We thank you for your participation. Have a wonderful day.