Alkermes plc

Greetings and welcome to the Alchemy's third quarter 2023 financial results conference call. My name is Donna and I will be your operator for today's call. All participant lines will be placed on mute to prevent background noise. If you should require operator assistance during the conference, please press star zero on your telephone keypad. Please note that this conference is being recorded. I'll now turn the call over to Sandy Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Thank you, Sandy. You may now begin.

Good morning. Welcome to the Alkermes PLC conference call to discuss our financial results and business update for the quarter-ended September 30, 2023, as well as initial clinical data related to ALK2680 presented during this week's World's Week meeting. With me today are Richard Topps, our CEO, Ian Brown, our CFO, Todd Nichols, our Chief Commercial Officer, and Dr. Craig Hopkinson, our Chief Medical Officer. During today's call, we will be referencing slides which are available on the investor events section of our website. Additionally, I encourage everyone to go to the investor section of thealchemy.com to find our press release, related financial tables, and reconciliations of the gaps and non-gap financial measures that we'll discuss today. We believe the non-gap financial results in conjunction with the gap 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 FDC 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. Our prepared remarks today will include initial patient data from our Phase I clinical trial for ALPS 2680. These data may not be indicative of future data from this trial or future results of clinical trials. After our prepared remarks, we will open the call for Q&A, and now I'll turn the call over to Ian.

Thank you, Sandy, and hello, everyone. I'm pleased to report solid results for the third quarter that demonstrate the financial strength of the business. The quarter was highlighted by year-on-year growth across our proprietary commercial products, solid contributions from manufacturing and royalty revenue streams, disciplined expense management, and strong GAAP and non-GAAP profitability. With the favorable outcome of the Janssen arbitration earlier this year, the successful settlement of the Vivitrol patent litigation and the expected completion of the separation of the oncology business in the coming weeks, the potential of the business to deliver enhanced profitability has come more clearly into focus. This has been our plan, and it's gratifying to see it taking shape. For the third quarter, we generated total revenues of $380.9 million, compared to $252.4 million in the same period in the prior year. This reflects the reinstatement of royalties on U.S. sales of the long-acting Invega products and solid performance across our proprietary product portfolio, which grew 16% year over year. Starting with Vivitrol, net sales in the quarter were $99.3 million, reflecting 3% growth year over year, driven by the alcohol dependence indication. Inventory in the channel was stable and growth-to-net deductions were consistent and within normal ranges for the quarter. Moving on to the Aristada product family, for the quarter, Aristada net sales increased 8 percent year-over-year to $81.8 million, primarily driven by underlying demand. Inventory in the channel was stable, and growth to net adjustments were unchanged sequentially. LaVolvi net sales for the quarter were $50.7 million, up 8 percent sequentially. Underlying prescription growth was 10% on a months of therapy basis. During the quarter, inventory in the channel decreased by approximately $1.3 million, and gross to net adjustments of 25.1% reflected the continuation of our contracting strategy in the commercial space and a one-time favorable Medicaid adjustment. Moving on to our manufacturing and royalty business, In the third quarter, we recorded manufacturing and royalty revenues of $149.1 million compared to $52.9 million in the same period in the prior year. Revenues from the Long-Acting and Vega products were $76.1 million compared to $26.7 million in the same period in the prior year, reflecting the favorable resolution of the arbitration related to these products earlier this year. Revenues from Boomerity were $34.6 million compared to $26.3 million in the same period in the prior year. Turning to expenses, total operating expenses were $337.1 million for the third quarter compared to $313 million in the same period in the prior year. R&D expenses for the third quarter decreased to $97.1 million compared to $100.4 million for the same period in the prior year. This reflects lower spending across the Nembolucan and LeBolvi clinical programs, partially offset by increased investment in the AUX2680 clinical program. SG&A expenses increased to $169.4 million from $152.8 million for the same period in the prior year, reflecting continued investment in the launch of LeBolvi particularly the DTC campaign, and certain non-recurring expenses related to the separation of the oncology business. I'm pleased to report that our top-line results, combined with our continued focus on disciplined operating expense management, delivered gap net income of $47.8 million and non-gap net income of $109.5 million for the quarter. Today, we are reiterating our financial expectations for 2023 that we provided in our press release on June 6, 2023. As a reminder, our financial expectations reflect the combined neuroscience and oncology business for the full year. Turning to our balance sheet, we're in a strong financial position as we ended the third quarter with approximately $996 million in cash and total investments, and total debt outstanding of approximately $291 million. We currently expect that on separation, Alchemist will provide $275 million of cash to Mural Oncology, which we believe will enable Mural to fund its operations through top-line data readouts for Artistry 6 and Artistry 7 and into the fourth quarter of 2025. In the coming weeks, we'll provide additional information regarding the separation and distribution of mural shares to our shareholders. Post-separation, Alchemist will emerge as a pure-play neuroscience business with enhanced profitability and a strong balance sheet. Our focus will remain on the execution of our strategic priorities and disciplined management of our cost structure as we invest in those opportunities that we believe will drive future growth, including the AUX2680 development program and the continued launch of Levolvi. And with that, I'll hand the call over to Todd for a review of the proprietary commercial products.

Thank you, Ian, and good morning, everyone. I'm pleased to share that we delivered solid year-over-year growth of 16% across our proprietary commercial portfolio in the third quarter. Our performance during the quarter reflects continued execution of our commercial strategy against the backdrop of some summer seasonality in the psychiatry and addiction treatment markets. We expect growth to accelerate in the fourth quarter and reiterated our expectations for our 2023 proprietary product revenues today. Starting with Lee Balvey, net sales increased 8% sequentially to $50.7 million. Prescriptions grew to approximately 42,000 TRXs for the third quarter, reflecting 10% sequential growth, which was ahead of other entrants in the branded oral antipsychotic market. We expect that growth will accelerate as we head into the fourth quarter, driven by a strong focus on execution, our direct-to-consumer campaign, and underlying seasonal trends. And we are encouraged by prescription trends over the past several weeks. During the quarter, prescriber breadth continued to expand. In our recent market research, healthcare providers cited Libavi's efficacy, weight gain profile, and patient outcomes as key drivers for their increased prescribing. which is encouraging feedback as we think about brand awareness and potential future prescribing patterns. In terms of market access, in Medicare and Medicaid, there is a pathway to access for all patients. In the commercial channel, there were no changes to our commercial access profile during the quarter, and we expect the access profile to remain unchanged for the remainder of 2023. We have ongoing discussions with the commercial payers and have designed our commercial access strategy to best support the long-term growth of the brand, balancing volume growth and the profitability of each unit. As we advance our efforts to drive awareness, our direct-to-consumer campaign is ongoing with increased ad placement in the fall months, in line with TV viewership trends. While it will take time to see the full impact, leading indicators on the effectiveness of the DTC campaign are encouraging. Specifically, we are monitoring the impact of our DTC campaign on internet search metrics, website visits, provider and patient awareness levels, and patient requests. We are excited by the opportunity for Levolvi and are laying the foundation for long-term growth. Turning to the Aristotle product family, net sales in the third quarter grew 8% year-over-year to $81.8 million, driven primarily by demand growth of approximately 8% on a month of therapy basis. We expect this market will continue to be dynamic, and our team will continue to focus on highlighting Aristata's differentiated value proposition, including its once-every-two-month dosing option and the Aristata Initio initiation regimen, both of which are supported by clinical data from our Alpine study. Turning to Vivitrol, net sales in the third quarter increased approximately 3% year-over-year to $99.3 million. The alcohol dependence indication was Vivitrol's primary growth driver, and accounted for approximately two-thirds of the Vivitrol volume. Importantly, against the backdrop of growth in the alcohol dependence treatment market, prescriber breadth for Vivitrol has continued to expand in that indication, which has driven new patient starts over recent quarters. As we think about the long-term opportunity for the brand, during the quarter we were pleased to come to a settlement agreement with Teva to resolve our patent litigation related to Vivitrol. Under the terms of the agreement, Teva will be able to market a generic version in the U.S. beginning in January 2027 or earlier under certain customary circumstances. With this agreement, we were able to appropriately plan for the continued commercialization of Vivitrol and believe that the product will continue to be an important element of our growth and profitability for the next several years. Taking a step back, we are focused on executing our brand strategies for all three products and on delivering our net sales expectations for 2023 across the portfolio. Serious mental illness and addiction are complex conditions with unique and often challenging treatment paradigms that require well-resourced and dynamic commercial efforts to support patient access and drive growth. Our commercial infrastructure is a strategic asset, one that can be leveraged in additional opportunities in these disease spaces as well as in other therapeutic categories, including those that may emerge from our development pipeline or future business development opportunities. With that, I'll pass the call to Craig to discuss our ALX2680 development program.

Thank you, Scott. I'm pleased to be joining you this morning from the World Sleep Meeting, where earlier this week we presented our first clinical data for ALX2680, a novel investigation on reaction 2 receptor agonist for the treatment of narcolepsy. The erection pathway has been established to be closely linked to the pathology of narcolepsy. Erections are neuropeptides that serve as important regulators of the sleep-break cycle by promoting retinitis and suppressing ENT. In particular, narcolepsy type 1, or NT1, is associated with the absence or significant deficiency in erection concentration and the presence of cataplexy. People who live with narcolepsy who do not experience cataplexy have what is called Racalepti type 2 or NP2. Our study fixation was designed to be a currently bioavailable orexin 2 receptor agonist with potency 10 times greater than the natural orexin A peptide and greater than 5,000 volts selectivity when it switched to the orexin 1 receptor. The molecule was designed to address the underlying pathology of Racalepti and to deliver durable and quality of data and cataplexy control, an acceptable safety and tolerability profile, and a wide therapeutic range that can accommodate different doses potentially needed for NP1 and NP2. The molecule is also designed to exhibit some of the kinetics and dynamic profiles that mirrors the National Seed Work Cycle with a low therapeutic dose and one daily oral dosing. The clinical investigation of ALK2680 follows encouraging preclinical data. These preclinical data were also shared in an oral presentation this morning at the World Sleep Meeting. Today I will focus on the review of the Phase 1 safety and vulnerability data of ALK2680 in healthy long years and share initial safety and efficacy findings from patients with narcolepsy type 1. It is gratifying that in our clinical experience today, our 2680 has behaved as we would have expected based on our extensive preclinical work. We are pleased with the clinical profile that is emerging, both in terms of safety and probability, as well as therapeutic activity of the patient. The study design is outlined on slide 16. The phase one study began with single and multiple ascending dose evaluations in 80 healthy volunteers. to assess safety and probability, as well as perform at the kinetic and dynamic profile of L3680. The study is double-blind and placebo-controlled. The single ascending dose of SAD tested two doses of L3680 up to 50 milligrams. In the multiple ascending dose of MAD, subjects received 10 days of one daily doses up to 25 milligrams. Moving on to slide 16. From a safety and tolerability perspective, our key is the profile that we observe for ALS 2680 in healthy volunteers. ALS 2680 was generally well tolerated across all doses tested, and there were no serious or severe adverse events. Most adverse events were mild, occurred early, were transient, and resolved without medical intervention or treatment interruptions. In the SADS, the most common AEs used to be degraded with dizziness, proliferia, which means increased frequency and urge to urinate, nausea, and visual disturbances, and most were observed at or above the 50 milligram dose. In the lab, the most common AEs were insomnia, dizziness, proliferia, and visual disturbances, and most were observed at or above the 8 milligram dose. The visual disturbances were described as blurred vision and increased life sensitivities. As I mentioned, these AEs were transient, resulted in continued dosing of R3680 in the multiple ascending dose values, and did not prevent continued dose escalation. There were no safety signals identified in vital signs, laboratory parameters, or ECG. No hepatotoxicity signals were observed at any dose level. We will continue to accumulate safety data over the course of the development program This will include continuing dose escalation with SAD and the MAD in order to fully characterize the safety and solubility profile of ALS-2680 as the maximum tolerated dose has not yet been identified. In terms of the pharmacokinetic profile on slide 17, we achieved the two design objectives supporting one daily dosing of ALS-2680 and a profile that limits the natural sleep-wake cycle with a half-life of 8 to 10 hours. In the top panel, you can see that systemic exposures increased proportionately with those, however, with the blunted C-MAS profile as depicted in the lower graph. Both of these features were expressed with design intentions. The metabolic profile was also consistent with our design objectives. In the study, two metabolites were observed. These metabolites were consistent with those observed in preclinical studies. None of this contributes to pharmacologic activity, nor would any active.

Craig, one moment. I think our audio is not coming in. Grace, I'm going to just switch the line to see if we can get a better connection.

Donna, can you hear us? Yes, I can. We have you on the backup connection now.

Donna, can you mute the other line, please?

The other line is muted.

Okay, thank you. Collectively, data from the SAT and MAT evaluations support us to move forward into the Phase 1B evaluations in patients. This part of the study is enrolling patients with narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia with up to eight patients per group. Earlier this week, we shared data from the first cohort of four narcolepsy type 1 patients, which was specified and powered to detect any significant effects and dose responses at this interim analysis. Starting with the study design on slide 18, following a two-week washout period of existing medications, Patients were randomized to a crossover design. We each received placebo, one, three, and eight milligrams of ALPS 2680 with a one-day washout period in between each dosing day. The primary endpoints are safety and tolerability. However, the Phase 1b offers the first opportunity to assess proof-of-concept efficacy of single doses of ALPS 2680 compared to placebo and baseline within the same subject via the maintenance of wait-for-risk tests. In terms of baseline characteristics outlined on slide 19, the patient's body demonstrated severe narcolepsy symptoms. Next on slide 20, ALK26AE was generally well tolerated across all doses tested in the NC1 patients. All AEs who were mild only occurred at the eight milligram dose and were largely on target. Note that the most common AE was insomnia, which is directly related to the drug's activity. This is what we were looking for. The occurrence of insomnia at the 8 mg dose was helpful in helping us narrow the planned dose range for future clinical development in NT1. Polyuria and salivary hypersecretion occurred in two of the subjects, and these AEs are expected on-target effects of the erection pathway. There were no serious adverse events, nor any adverse events leading to discontinuation. Additionally, there were no clinically meaningful treatment emergent changes in the barcode parameters or ECG. Turning to slide 21 and their first assessment of ALTS2680 in the maintenance of wakefulness test. The 40-minute maintenance of wakefulness test, or NWT, is administered every two hours post-dosing. The mean score is calculated by averaging the results of the test conducted at hours two, four, six, and eight post-dose. Prior to dosing, patients demonstrated a mean MWT baseline score of three minutes, meaning that they fell asleep within three minutes. At all doses tested and in all patients, ALK2680 significantly improved mean sleep latency for the time that these patients were able to remain awake compared to baseline. There was a clear dose response with mean MWT improvements compared to baseline of 18, 30, and 37 minutes, at one, three, and eight milligrams respectively. Treatment with placebo was associated with a one-minute reduction in MWT scores compared to baseline. Due to the magnitude and consistency of effect at each dose level of ALPS 2680, the improvement compared to placebo was highly statistically significant, despite the relatively small number of patients. Slide 22 shows the time course. ALPS 2680 showed clinically meaningful improvements in NWT from baseline at all doses tested and in all patients. At the 8 mg dose, patients maintained wakefulness for the full 40 minute NWT duration, up to 10 hours post-dose. NWT scores at 3 mg were comparable to 8 mg for the first 6 hours, and both one and three milligrams of ALK3680 show the improved gratefulness up to eight hours post-dose. The tolerability and efficacy profile of ALK3680 shown to date in NT1 is encouraging and informs our approach around dose selection and our expectations as to the tolerability and efficacy in NT2. We've received some questions from investors regarding therapeutic index and potential dosing in NT2. Based on the pathology of NT2 in previous clinical data, we expect these patients to be less sensitive to erection, requiring higher doses for efficacy, and tolerating higher doses before observing limiting side effects. Based on our observed activity to date in NT1 and our modeling, we now believe that NT2 patients may only require a two to three-fold increase at the ALK2680-NT1 dose. With a clear dose response and indication of therapeutic benefit at doses from one to eight milligrams of NT1, and not having reached the maximum tolerated dose in patients or healthy volunteers, we are confident in the dose and flexibility that we are currently enrolling NT2 patients in the study. Concluding on slide 23, I'm pleased with the initial data generated from this innovative and efficiently designed phase one study which support the key design objectives of the molecule. In less than a year, we've been able to establish a preliminary safety and tolerability profile of ALK2680 in healthy volunteers, demonstrate target engagement through EEG evaluations, establish a PK profile that supports one-stage administration with a target dose well below 10 milligrams in NT1 patients, and demonstrate significant weight loss throughout the day. We will continue to enroll the Phase 1b study in narcolepsy in IH patients and look forward to sharing those data. We are also in the process of finalizing the design of a Phase 2 study, which is planned to begin in the first half of 2024. And now I will hand the floor over to Rich.

That's great. Thank you, Craig. So Craig and his teams have accomplished a great deal in the last year to efficiently advance the 2680 development program and generate the data presented this weekend while asleep. ALKS2680 is an Alkermes designed and developed molecule. It's the product of expertise that Alkermes has accumulated in molecular design, medicinal chemistry, pharmacokinetic modeling, and neuroscience drug development. If the pharmacology of ALKS2680 continues to be validated in the clinic, we believe it has the opportunity to be an important new mechanism in the treatment paradigm for patients with narcolepsy. And beyond that, It may provide the foundation to expand the biology of erection agonism into additional potential disease areas, some characterized by excessive daytime sleepiness as well as others. The data Craig summarized advanced the 2680 Development Program past two important stage gates. First, establishment of an initial safety and tolerability profile that supports further clinical development. demonstration of proof of concept through initial evaluations of efficacy using validated measures. An important characteristic relating to both points is potency expressed in the form of expected dose. Our modeling suggested in the initial human data supported a dose range for NT1 patients in between one and eight milligrams. We believe that potency at these dose levels reduces the potential for off-target adverse events and together with the tolerability profile observed to date, provide the wide potential therapeutic index to accommodate dosing in NT1 and NT2. With this initial data set, we believe we have adequate information to complete the design of our Phase II program. As we move into later stage development, we'll further establish the safety, tolerability, and efficacy profile of 2680 through established regulatory endpoints as well as patient-reported outcomes. as we further explore the effects of modulating the erection system. So that's the AUX2680 program. Shifting gears, we expect another transformational event to occur in the coming weeks with a planned separation of our oncology business into an independent, publicly-traded company called Mural Oncology. We're now in the final stages of implementing separation, which has been a significant undertaking from an operational, logistical, legal, and accounting perspective. As we prepare for the launch of Mural, it's important to us that Mural begins its journey as an independent company in a position of strength in terms of its leadership, the ongoing clinical studies, and financial resources. Dr. Caroline Lowe, the CEO-designate of Mural, has recruited a talented management team and board of directors, and I'm confident their leadership will be a strategic asset. The potential registration-enabling studies for Nemalucan in platinum-resistant ovarian cancer and mucosal melanoma are well underway, and we've continued to focus on study enrollment and execution as we prepare for the separation. We believe that separation provides an opportunity to unlock value for both companies, create more optionality for shareholders, and position both companies for success. Post-separation, Alkermes will emerge as a more profitable, pure-play neuroscience company with a clear strategy and well-defined opportunities for value creation. Taking a look back, 2023 has been a very productive year, highlighted by the ongoing launch of the Evaldi, including initiation of the DTC campaign, strong enrollment and execution of our ongoing clinical studies in oncology and in neuroscience, completion of the many work streams to support the separation of the oncology business, and the successful outcomes of the Janssen arbitration and the Vivitrol settlement. Each of these represents an important accomplishment in its own right, but collectively, They transform the financial and growth profile of the company. We believe we're in a position to drive significant value for shareholders to look forward to sharing our progress with you. So with that, I'll turn it back to Sandy to manage the Q&A.

All right. Thanks, Rich. Apologies for the audio quality during some of Craig's remarks. I hope that this line is working better for you. Donna, we'll open the call now for Q&A, and in the meantime, we'll also work on posting the prepared remarks to our website. so that any pieces that were missed can be reviewed on the website.

Thank you. The floor is now open for questions. If you would like to ask a question, please press star 1 on your telephone keypad at this time. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up the handset before pressing the star key. Again, that is star one to register a question at this time. Today's first question is coming from Akash Tiwari of Jefferies. Please go ahead.

Hi, everyone. This is Amy on for Akash. Thanks so much for taking your question. So a couple from us on the orexin program. We've seen that with TAC925 and NT1 that the 11 milligram dose also maxed out on MWT initially, but MWT dropped from 35 plus to 20 on day seven. On the other hand, we're seeing pretty durable effects on the 44 milligram dose at day seven. How do you plan to factor in this long-term durability aspect when selecting the go-forward dose from the three to eight milligram dose range going forward? And then what dose do you expect in NT2 patient? Is it fair to say that your dose could be more in the range of 10 to 12 milligrams rather than four to five X NT1? And then finally, do you expect some of these on-target AEs to attenuate over time? Thanks so much.

Good. Let me address that, each component on its own. So in terms of our dose range for the NT1 population, obviously we had very clear dose response, exactly what we expected to see. And I think this puts us in a position to be able to model out appropriate doses for our Phase II study. We are also looking at the, you know, tactical access that was observed with the TAC program, and obviously this is something that we are going to be modeling into our doses for Phase II as well. In terms of the, let me take the safety question next, because it's linked. Discussions with investigators at the meeting this week, they really are impressed with the safety profile generated today, where we haven't shown side effects at the lower doses. And the side effects that we're seeing at the eight milligram dose are largely on target side effects. These are mild. They resolved spontaneously. We saw no serious or severe adverse events, and essentially, obviously, no discontinuations. And I think importantly, the insomnia is almost viewed to be a biomarker response by our potential investigators for Phase 2. Their belief is that with this mechanism that will attenuate over time, as you had asked. And it will probably, over the first couple of days, normalize. So we're impressed with the safety, encouraged by the safety profile to date, and once again believe that that really sets us up to choose the appropriate doses for phase two. In terms of the NT2 question, We've seen data from the TAC program where the NT2 population is less sensitive to orexin, indicating that higher doses will be needed. At this point in time, given our dose response that we've seen at below 10 milligrams for NT1, we think that this sets us up to sort of narrow the range for NT2 to about two to three-fold, where previously we thought we may need up to five-fold the dose. We're obviously collecting a separate cohort of patients for NT2 at a different dose range, and those data will obviously also be incredibly important in informing that dose range for the NT2 dose for Phase 2.

Great, thank you so much.

Thank you. The next question is coming from David Amsel of Piper Sandler. Please go ahead.

Just a couple. So first on idiopathic hypersomnia, can you talk to dosing there? And what is your plan for IH regarding further development? Is that going to be a backup molecule? So help us talk to your IH thinking. And then secondly, on a different topic, you talked about the commercial organization being a leverageable asset. Makes sense. But does that mean that you're open to or prioritizing the addition of commercial stage or market-ready assets to the portfolio? Thank you.

You want to take the first one, and then Rich can take the second question?

Yeah. We are collecting data on IH patients. We've got a separate cohort in our Phase 1B program. That cohort of patients is currently enrolling. And then based on those data, that once again will inform appropriate doses for IH in our Phase 2 program. We haven't disclosed the dose for our NT2 dose range in the current 1B study, and nor have we disclosed the dose range that we are exploring for IH at this point in time.

And with respect to the question about commercial, yes, I think that the point Todd has made and we've lived through is that building is a commercial presence in order to be able to sell products like the Balvin, Aristar, and Vivitrol. requires far more than just a field force. It requires a lot of infrastructure. And now that we've built that and demonstrated its efficacy through the launch of Evolvi, we do think that that's an asset that we can leverage with additional products from the outside. Thank you.

All right.

Thanks, David. Thank you. The next question is coming from Umar Rafat of Evercore ISI. Please go ahead.

and not showing full safety table for the multi-ascending dose at the conference. So that's one. And then also, as we think about the narcolepsy type 1 and the declaration of dose being somewhere between 3 and 8 milligrams, are we fully confident that we can make that determination based on single-dose data? Because there's been data from other erections suggesting a fading in efficacy beyond the first-dose effect. I'd be curious how you think about that. And finally, if you could just elaborate on LIDALI trends into next year, especially as it relates to where some of the consensus estimates stand versus how you're thinking about it in LIDA DTC. Thank you.

Thank you. We missed the beginning part of your first question on the MAG table.

Oh, I was just asking thought process, and you know how you have the safety table for single-dose NRGC type 1 patients, but not for the multi-ascending dose.

All right. Got it. Thank you.

Yeah.

So as we were designing our presentation for the World Sleep Conference, it was really just an economy of trying to pack a lot of information into a short presentation. In terms of the single ascending dose table, obviously we explored six separate doses there and four separate doses in terms of the in terms of the MAD. And so it just didn't make sense to really sort of try and compress that into the presentation, but rather just focus on the most common adverse events greater than 5%. As you saw, these were largely sort of mild to moderate adverse events. They were all largely sort of self-resolving, and we only had the one treatment discontinuation. So the summary is really reflective of our experience across the set.

and the single, the confidence around the .

Yes, so this is one of those indications where translatability is extremely high. You know, one of the aspects we've got confidence in is the potency of this compound where we have greater than sort of tenfold potency to orexin A. We also are cognizant, as I said previously, of the tachyphylaxis that Cicada had seen. As such, we believe given the clear dose response as well as the durability of response that we've seen with single dosing in a 1B study, this really sets us up well to embark upon our Phase II program, which obviously will explore doses in Phase II for each of these indications.

And then, Ty, did you want to comment on the Levalvi trends for next year and expectations around that?

Absolutely. I'll take that one. So in Q3, the broader category, the branded oral antipsychotic category, did experience some seasonality. We saw that. We believe this is going to rebound in Q4. And as I said earlier, we're actually already seeing that. We started seeing an uptick in TRX prescriptions and NBRX new patient starts at the end of Q3, and that's continuing into Q4, which is encouraging. Going into next year, we are extremely confident about the growth prospects and outlook for LaValvie for several reasons. Breadth of prescribing continues to expand. Our market research, when we talk to HCPs, they tell us their intent to prescribe continues to expand. We are investing, as you know, in a very broad direct-to-consumer campaign. It's still early, but the trend's and the metrics are encouraging there. And also, we always come back to LaVolvi has a very broad, differentiated label, and it's considered one of the most effective agents in the category. So we have a lot of confidence that we're going to see growth in the Q4 and into next year.

Thanks, John. We'll take the next question, please.

Thank you. Next question is coming from Paul Matias of Stiefel. Please go ahead.

Hey, thanks so much for taking my questions. I appreciate it. I had one on orexin and then just one business question. On orexin, can you talk about the multi-dose pharmacokinetic data that you generated? And I guess when you look at the exposure levels over time, in the evening, how low do drug levels get? And are you comfortable that they get low enough where you're going to avoid an insomnia or sleep latency signal? And then second, just on business development, it was interesting to kind of hear a comment there slipped in. I know it's something you probably said before, but What's your current thinking on BD? And if you think about a deal, what's your scope right now on deal size and also whether it would or wouldn't be important for a deal to be accretive or dilutive? Thanks so much.

So I'll take the PK question first. Obviously, for competitive reasons, we haven't disclosed too much in terms of our profile. But the profile that we set out to achieve was achieved in our phase one study. It's a protocol that obviously supports once-daily dosing. And importantly, one of the most important aspects that we were focused on was really a profile that mimics the natural sleep-wake cycle. We achieved that. We've got a half-life of 8 to 10 hours, which I think is ideal for once-daily dosing and to achieve that sort of natural sleep-wake cycle. And essentially, this has been borne out in alpha-H1V, as you can see with our dose response, as well as the durability, as you've seen at the three and eight milligram doses.

And Paul, it's Rich on the yield side. I think if you think of deals in terms of pure pipeline expanders on the R&D side, our long-range forecast with our profitability targets accommodate expansion of R&D spend to some extent, not heroically, but we could pick up something in the development stage and feather it into our existing R&D activities and still hit our profitability targets, which are critical for us. On the commercial side, the extent that we acquired something on the commercial side, we would want and expect that very quickly to go to pre-transaction.

Thank you.

All right.

Thank you all.

Thank you. The next question is coming from Chris Shibutani of Goldman Sachs. Please go ahead.

Great. Thank you very much. Two questions on the orexin and just thinking about the difference between NT type 1 patients and NT type 2. Would you expect that the perhaps lesser sensitivity that's requiring higher doses to also manifest on the safety side as well in terms of lesser likelihood of being exposed to some of the AE aspects that we're seeing. Are they correlated, in other words? And then secondly, with NT type 1, Can you comment about your thinking about cataplexy in particular? What do you perceive as the potential there to influence that profile as we think about differentiating the different treatment options going forward? Any learnings you've had thus far would be helpful.

Thanks, Chris. So, in terms of the read-through on doses for NT2, you know, Patients, obviously, are far less sensitive to orexin with NT2. I think that's based off of some of the data already published. Our expectation originally was that there may be up to a three to five-fold increase in dose needed to cover that population. I think given the potency that we now have established for the compound and our very clear dose response, we believe we can narrow that down to two to three-fold increase. increase in dose in that population to see the required efficacy. I read through on the safety side as exactly as you stated, and that is basically that because of the decreased sensitivity, you will probably only see sort of dose-limiting side effects at much higher exposures as well in that population. So I think they will be pulled through there as well in terms of the dose. In terms of your question on cataplexy, while we didn't collect data or analyze data on cataplexy in our Phase 1b, we did collect sleep diaries. The sleep diaries were really intended to help us inform our powering for Phase 2 as well as eventually for Phase 3. And essentially, what I can tell you there is that anecdotally patients that see a trend towards a decrease in cataplexy in terms of single dosing, some anecdotal information from our investigators was that in some of the patients they were able to watch a two hour comedy movie without seeing an event. We believe it's encouraging, and once again, we will be fully evaluating cataplexy in the design of our phase two study, but this was not analyzed as an endpoint. It's more just for planning purposes for the Web 1B.

Thank you.

Thank you. The next question is coming from Jason Gerberry of Bank of America. Please go ahead.

Hey, guys. Thanks for taking my question. Just wanted to follow up on the first question. So can you share the rate of 8 milligram healthy volunteer MAD, especially for visual disturbance and insomnia? It seems like a potentially relevant dose in all these settings that you'd study your OX2R. And given an NC1, I think the insomnia rate on a small end is 75% visual disturbances in AE of interest. I think this is important. And if you can't share with that, I imagine you have, all eight patients of NC1 data in-house, any observation that the AE profile is consistent with what's been shared so far. And then lastly, just a competitor, WAKIX, missed in IH, wondering how you think about IH now. I guess I wonder, you know, WAKIX is more of an alerting agent. Erexin deficiency is not an issue in IH. You know, is this disease more druggable with something that, you know, helps with sleep consolidation like a ZioWave? So just wondering how you're thinking about IH mechanistically in lieu of the WakeX update. Thanks.

Yeah, in terms of our experience in the SAD and MAD, you know, we only saw the four visual disturbances, two in the SAD, two in the MAD. These were largely sort of mild events, were transient, self-resolving. All patients had, all healthy volunteers had normal neurologic. And so, you know, I wouldn't read too much through into the actual doses of the MAD. You know, we've got an acceptable safety profile and maximum tolerable dose is not being reached, which is why we're moving to even higher exposures in both the SAD and the MAD program, bear in mind that these are non-sleep deprived healthy volunteers. So, you know, they are not sensitive to orexin. In terms of our actual patient experience, to date we haven't seen any visual disturbances in our NT1 cohort today. In terms of your question around way kits and IH, you know, obviously we're in the very early stages of collecting data in idiopathic hypersomnia and I think the profile that emerges from R1B will inform us as to where 2680 falls in terms of addressing that particular indication. I think once again mechanistically we're pretty excited about the potential for Erex and Agonist in IH I will need to be informed by the data as those data come in. Got it. Thanks, guys.

Thank you. The next question is coming from Mark Goodman of LeeRank SCB. Please go ahead.

Yes, good morning. Can you comment on the erection, the blood pressure increase that we saw in that patient? How much increase in blood pressure did we see and And is this something that we should be watching for? And are you planning to do a blood pressure monitoring study? And then secondly, just on Lebaldi, can you just comment on gross tenets going forward and whether this is the process that you had last quarter? Thanks.

Sure. So I think it's especially important to note that we did hourly blood pressure measurements throughout our SAD, MAD, and NT1 patient experience. So we were measuring blood pressure really frequently. We only saw one increase in diastolic blood pressure in the NT1 cohort. This was an increase to 96 diastolic and normalized within two hours of the blood pressure increasing. So once again, it was a very transient increase in one or two weeks. Similarly, we saw a single blood pressure increase in the single ascending dose, and once again within a couple of measurements that had returned back to baseline as well. So, you know, really not seeing any signals there at this point in time. These are just two individuals with one or two individual readings that were in the elevated range.

And then let me take a crack at the gross-to-net question. So I think for LaBalvie gross-to-nets, as I said in the prepared remarks, slightly lower in Q3, 25.1%, really driven by a one-time favorable Medicaid adjustment of about $800,000. I think gross-to-nets has been really consistent over the last few quarters. I think the second half of 2022, we were around 26%. first half of 23, 26%, and that's the expectation through the remainder of the year. We're not providing guidance specifically for 2024 today, but I think the one thing that would potentially change gross-to-nets would be more on the commercial contracting side. Up to now, we've been very much focused on profitability of LeBolbe units. and we've had a pretty disciplined approach to the contracting strategy, so that's maintain growth to net at a relatively consistent 26% level. I think ultimately growth to net's all trend towards that 35% to 40%. It's just a question of timing. So for the remainder of the year, we would expect to continue around the 26% level, and then we'll provide more information specifically to 2024 on our year-end earnings call in February. Thanks.

Thank you. The next question is coming from Yuier of Mizuho. Please go ahead.

Hey, guys. Thanks for taking my question. So could you share what the dose was in the MAD study where you saw insomnia? And, you know, in slides not listed, insomnia is not listed as part of the SAT study. study of just wondering like why is that the case? That's my first question and I guess my second question is so we often get this question over and over you know with the current script trend for liability and like what are other avenues would allow you essentially to hit your 2024 profitability guidance? Thanks.

So in terms of our SAD and MAD experience, essentially the most common adverse event we saw was more hypervigilance. That was equally distributed across placebo and active. So two apiece there. That was more denoted as increased alertness in these patients. But once again, equally matched active versus placebo. And I think the single case of insomnia was seen in the one discontinuation patient at the 25 milligram dose.

Okay, thanks.

Yeah, let me start with just the seasonal trend or the trends in general with Levalvi, which coming through Q3 are solid relative to the seasonal dip. Again, TRXs grew quarter over quarter by 10% year over year by over 80%. So we're really encouraged by that. And that's really being driven by all three parts of our marketing mix, which is our Salesforce promotion, which is driving intent to prescribe increases. Secondly, our discipline market access strategy, as Ian mentioned earlier, we're seeing utilization across all three channels within market access. And again, we're at the very beginning of our DTC campaign, and all of the metrics are heading in the right direction. So we have a lot of confidence in our strategy. Execution is improving quarter over quarter, and utilization and the perception of the brand is improving quarter over quarter. So we have a lot of confidence in what the long-term outlook looks like for LaBalvie.

And then just to add to that, in other aspects of the business, LaBalvie is a key growth driver for us. We anticipate continued growth of Vivitrol, Aristarda, Boomerity should continue to grow as well. I think with the spinoff of the oncology business, that's going to take a significant amount of spend out of the R&D line. Our gross margins should improve as the volumes of all our proprietary products continue to grow. And as you saw, we delivered gap and non-gap profitability this quarter, so hopefully that gives you you know, a path to us being able to achieve the profitability targets next year.

Thank you.

Thank you. The next question is coming from Douglas L. of HC Wainwright. Please go ahead.

Hi, good morning. Just really quickly on the erection, I was just curious if you were seeing any evidence of impact on sleep quality? Obviously, you saw some insomnia, but were there any other impacts on sort of sleep consolidation? Thank you.

Yeah, essentially, you know, sleep quality is going to be a really important endpoint for us moving forward. This wasn't specifically measured given the nature of the design of a single-dose four-way crossover. A study, you know, and anecdotally, the patient's experience was positive, but obviously this will be built into our polysomnography assessments in our Phase II program as we move forward.

And from a tolerability standpoint, would you anticipate this being used in conjunction with one of the sleep-promoting agents?

In conjunction with sleep-promoting agents. Yeah, at this point in time, we're studying 2680 as a model therapy, and our entire program is presiders as such. So I think what will be really important is to really assess sleep quality of 2680 as we get those polysomnography assessments done in the Phase II. We're also building a number of PROs into our Phase II program, and we'll get a better handle on that as well.

Okay, great. Thank you so much. Congrats, Amadea.

Thanks, Doug.

Thank you. The next question is coming from Ash Verma of UBS. Please go ahead.

Hi. Good morning. Thanks for squeezing me in here. So for the Balvi commercial pair discussions, has the aggressive contracting by Latoura over the years or some inching up on GrosvenorNet for this category in general broadly changed the expectations for payers on how much volume they're willing to give in return for a wider growth-to-net. And then second, on the orexins, I just wanted to get your initial reaction on competitor Contessa. We just saw the preclinical data, ORAX 750 showing significant activity at lower doses. Granted, this is preclinical, but just seems to be getting crowded on the orexins. So any thoughts there would be helpful. Thanks.

Yes, I'll start with, yeah. Yeah, I'll start with the market access question. So I think the key elements to keep in mind here is, you know, there's three channels, Medicaid, Medicare, and commercial. There's relatively an equal split across the category, depending upon what the indications are for these brands. We have a pathway of access and really clear line of sight across Medicaid and Medicare, and we see good utilization. Within the commercial space, we do have agreements in place with commercial payers. We are constantly in ongoing discussions. But we know from our history, specifically with Aristotle that we launched several years ago, that once you start going into contracts with large rebates, it's very difficult or virtually impossible to pull those rebates back. So our plan right now is to continue to drive volume through intent of prescribing, which is increasing through patient activation, again, which we're seeing good activation levels with our consumer campaign. And then over time, our belief and our plan is to expand access within the commercial space. But we're doing that in a very measured approach to make sure that we're maximizing the profitability of each unit.

And then with regard to the question on the Syntesa data, I think those data were being presented in parallel with this meeting, so we haven't actually seen those data at this point in time yet, and so...

Thank you. The last question for today is coming from Charles Duncan of Cantor Fitzgerald. Please go ahead.

Hey, good morning everyone. So thanks for taking my questions. I have just a couple of quick ones. For 2680, for you know, if you think about the future for NDA enabling purposes, and given the, you know, potential safety and waning activity of another agent in the class, what is the length of exposure that you are expecting to be a minimum? Is it three, six, or 12 months, or some other period to rule out safety and rule in durable efficacy?

Yeah, obviously as we move forward, you know, and plan our Phase 2 program. We'll be meeting with the agency to discuss those plans. And our belief is that, you know, those discussions will inform the length of both our Phase 2 as well as our Phase 3 program as we move forward.

That makes sense. Last question. Regarding visual disturbances in the human volunteers, and I know it's a very small sample, But I guess I'm wondering if you would speculate on there being a pharmacological target or is that just really a sporadic observation and how normal humans could be different than NT1 patients if there is a target or some reason to wonder about that? Thanks.

Yeah. Interestingly, we've only seen the visual disturbances in healthy volunteers. Once again, we've only seen before out of a denominator of 80 healthy volunteers. These were sort of mild adverse events that were transient, largely just blurred vision and increased light sensitivity. In terms of mechanism, I think at this point in time, it's obviously something that we're evaluating and monitoring for. And we haven't seen any visual disturbances in patients today.

Got it. Thanks for taking the question.

Thank you. At this time, I'd like to turn the floor back over to Ms. Coombs for closing comments.

Thanks, Donna. Thanks, everyone, for joining us on the call today. A copy of the prepared remarks is now posted on our website in case any portions were inaudible and you'd like to reference that. It's on the events section of the website. Please don't hesitate to reach out to us at the company if we can be helpful. Thank you very much.

Ladies and gentlemen, thank you for your participation. This concludes today's event. You may disconnect your line to log off the webcast and enjoy the rest of your day.