Earnings Call Transcript - NBIX Q4 2023

Operator, Operator

Good day and welcome to Neurocrine Biosciences’ year-end and fourth quarter results call. At this time, all participants are in a listen-only mode. Later, you will have the opportunity to ask questions during the question and answer session. You may register to ask a question at any time by pressing star, one on your telephone keypad. You may remove yourself by pressing star, two. Please note that today’s call will be recorded and I will be standing by if you should need any assistance. It is now my pleasure to turn the conference over to Todd Tushla, Vice President of Investor Relations. Please go ahead.

Todd Tushla, Vice President of Investor Relations

Thank you, and a good Wednesday morning to everyone. Welcome to Neurocrine Biosciences’ fourth quarter and full year 2023 earnings call. Joining us today are Kevin Gorman, Chief Executive Officer; Matt Abernethy, Chief Financial Officer; Eiry Roberts, Chief Medical Officer; Eric Benevich, Chief Commercial Officer; and Kyle Gano, Chief Business Development and Strategy Officer. During the call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially. I encourage you to review the risk factors discussed in our latest SEC filings. Today’s prepared remarks will be a bit longer in duration versus prior earnings calls as we do have a lot of ground to cover. I can assure you that we will do our best to address all of your questions when we get into Q&A. Now I’ll turn the call over to Kevin.

Kevin Gorman, CEO

Thank you, Todd, and good morning everyone. We had a great 2023. I said the same thing about 2022, and it was great. I said there were very few years you get like 2022, and we then had one of those years in 2023. Both of those years were not without their ups and downs, but on the whole, the business performed exceptionally well. Looking at 2023, again incredible continued growth for Ingrezza in its sixth year on the market, expansion of Ingrezza intellectual property out to 2038, approval of Ingrezza in another indication in Huntington’s disease. We also had crinecerfont Phase III data that exceeded even our high expectations for that, and a clinical pipeline that grew more in that one year than we’ve ever experienced at Neurocrine in the past, and then a preclinical pipeline that is expanding considerably. Now, we expect an equally successful 2024, and I’m not going to go into the details of that because my colleagues will discuss that. But right now, let’s take a snapshot of 2023 from a financial perspective from Matt, who will also provide how we’re viewing 2024. Matt?

Matt Abernethy, CFO

Thanks Kevin. Good morning. 2023, what an incredible year. Record Ingrezza sales growth, positive crinecerfont results, and an advancing R&D pipeline all position us for continued progress for years to come. Prior to jumping into our 2024 financial guidance, I want to provide a few comments associated with our 2023 financial performance. First, Ingrezza sales performance - during the fourth quarter, Ingrezza sales were $500 million, reflecting continued sequential growth driven by new patients, slightly offset by gross-to-net dynamics. 2023 Ingrezza sales finished near $1.84 billion, reflecting over $400 million in year-over-year growth. Next, one of our goals for 2023 was to demonstrate SG&A financial leverage. As you can see, we delivered approximately 400 basis points and 300 basis points of SG&A leverage on a GAAP and non-GAAP basis, respectively. We expect continued progress in 2024, which I’ll discuss shortly. Finally, we generated over $600 million of cash flow in 2023, reflecting strong non-GAAP net income partially offset by $175 million in business development investments. Turning to 2024, this will be another pivotal year for Neurocrine with growing Ingrezza sales, preparing for the commercial launch of crinecerfont, and numerous activities associated with advancing our R&D portfolio highlighted at the recent analyst day. We believe investing in these areas will continue to drive long-term shareholder returns. Now onto our 2024 financial guidance. 2024 Ingrezza net sales guidance is $2.1 billion to $2.2 billion, reflecting strong underlying demand and an improving gross-to-net resulting in over $300 million of sales growth, or 17% at the midpoint. As always, we expect seasonal dynamics to play out similar to what we’ve seen in previous years. 2024 SG&A GAAP operating expense guidance is $930 million to $950 million, or 43% of total revenues at the midpoint, and $830 million to $850 million or 39% of total revenue at the midpoint on a non-GAAP basis. These costs reflect continued investment in Ingrezza and also an incremental $50 million to prepare for the potential crinecerfont launch, as Eric will discuss shortly. Even with the investment in crinecerfont, we expect to demonstrate 400 basis points and 150 basis points in SG&A GAAP and non-GAAP leverage at the midpoint of the range. As you develop your models, we do have a seasonal nature to our spending specific with a step-up in Q1. 2024 R&D GAAP operating expense guidance is $645 million to $675 million or 30% of total revenue at the midpoint, and $570 million to $600 million or 27% of total revenue at the midpoint on a non-GAAP basis. These costs reflect investment in our ongoing 17 clinical programs, including our crinecerfont studies, muscarinic programs, and the early-stage pipeline highlighted at analyst day. Note this guidance range does not include any partnership milestone payments until they are deemed probable. A few other financial metrics to note. We expect costs of revenue to be 2% of sales. Stock-based compensation is expected to be $175 million with $100 million in SG&A and $75 million in R&D, and our non-GAAP effective tax rate is expected to be around 23%. As I reflect on the journey we’ve been on over the past five years, it is quite remarkable. With Ingrezza now trending above $2 billion in sales, the next leg of growth in our story with crinecerfont, an advancing pipeline, and a strong financial profile, we are well positioned for the future and feel quite fortunate. With that, I now hand the call over to Eric Benevich, our Chief Commercial Officer. Eric?

Eric Benevich, Chief Commercial Officer

Thanks Matt. 2023 marked another stellar year for Ingrezza and included several important milestones for the franchise. This includes the continued increase in diagnosis and treatment rates for patients with tardive dyskinesia, the addition of a new indication for chorea associated with Huntington’s disease, and the ANDA litigation settlement that provides exclusivity for 14 more years out to 2038. 2023 was our sixth year in the market since launch. While full-year sales growth of nearly 30% is impressive, that growth speaks volumes about the continued unmet need in both TD and HD chorea. Looking ahead, we still have a tremendous opportunity to help many more patients. While we continue to make steady progress, two-thirds of the approximately 600,000 TD patients in the U.S. remain undiagnosed, and for the approximately 20,000 HC patients with moderate to severe chorea, 80% are still not being treated with a VMAT2 inhibitor, the only FDA approved class of medicines for this indication. This year, our commercial and medical teams will continue to educate and motivate healthcare providers to screen, diagnose, and treat TD and HD chorea patients. In addition, we’ll continue our efforts to reach patients and caregivers to help them recognize their involuntary movements as possibly TD or HD chorea and encourage them to talk with their healthcare provider about diagnosis and, if appropriate, treatment with Ingrezza. Although we have made great progress these past six years, the majority of the opportunity remains ahead of us. The 2024 Ingrezza sales guidance range of $2.1 billion to $2.2 billion is driven primarily by the pace of new patient starts in TD and, to a smaller degree, in HD where Ingrezza is still in its early launch phase after the approval and launch towards the end of last year. Specific to TD, we anticipate robust growth across all three business segments of psychiatry, neurology, and long-term care. Access to Ingrezza remains strong as exemplified by the fact that, regardless of formulary status, greater than 80% of written scripts for Ingrezza get filled and the average out-of-pocket cost is less than $10. Overall, I’m looking forward to another solid year of growth for the franchise as we continue to build these markets. At this time, we’re going to mix things up a little bit versus our normal cadence for prepared remarks. My colleague, Dr. Eiry Roberts, our Chief Medical Officer, and I are going to provide a crinecerfont update. We thought it important to highlight the integrated efforts between our respective organizations to prepare for an anticipated 2025 launch. Eiry, why don’t you start?

Eiry Roberts, Chief Medical Officer

Thanks Eric and good morning everyone. Let me start by reminding everyone of the incredible challenge congenital adrenal hyperplasia patients face today. For these patients, their only real option, lifelong treatment with high-dose glucocorticoids, is both entrenched and flawed. In this paradigm, GCs are tasked with both replacing the missing cortisol and suppressing the excess androgens. Patients therefore face a difficult choice of either taking long-term high-dose GCs to reduce excess androgen and thus face the long-term complications of GC exposure, such as hyperglycemia, dyslipidemia, cardiovascular disease, osteoporosis, psychiatric disturbances, or immunosuppression; or they can try to minimize their GC exposure and live with the consequences of excess androgen production, such as advanced bone age, precocious puberty, short adult stature, irregular menstruation, or infertility. These are the difficult trade-offs patients living with CAH must make every day. With the impressive efficacy and tolerability data from the adults and pediatric registrational studies for crinecerfont, we hope to provide a potentially new paradigm for these patients. To this end, combined efforts between Neurocrine’s medical and commercial organizations are well underway as we prepare to bring crinecerfont to CAH patients in the U.S. and in key European markets. Later this year, we look forward to sharing additional safety and efficacy data from the registrational study in peer-reviewed journals and scientific conferences. In addition, our medical affairs and field teams are highly engaged with thought leaders in the field to develop the extensive educational programs necessary to support launch, while our health outcomes team works to generate and publish critical data necessary to characterize the burden of disease in CAH and support the value proposition of crinecerfont as an effective treatment for patients living with congenital adrenal hyperplasia. Our key focus now within clinical development and regulatory is on the completion of the new drug application for crinecerfont in adults and pediatrics with the FDA. I’m pleased to report that the NDA submission will occur in the second quarter of this year. Recall that the agency granted breakthrough therapy designation for crinecerfont at the end of last year. This designation serves as an acknowledgment of the serious and life-threatening nature of CAH, highlights the significant unmet need that exists in the treatment of the disease with no approved treatment for the past 60-plus years, and identifies crinecerfont as a potentially valuable treatment for patients with CAH. While we are hopeful that the granting of breakthrough designation for crinecerfont will lead to priority review, that decision ultimately rests with the FDA, so we are moving forward in a way that proactively prepares us for all eventualities, including the possibility of an advisory committee. Eric will now cover the preapproval activities within the commercial organization.

Eric Benevich, Chief Commercial Officer

Thanks Eiry. This is an exciting time for our commercial team as we prepare for the launch of crinecerfont. If approved, crinecerfont would not just be the first-ever CRF antagonist but also be the first medication specifically approved for the treatment of CAH. With crinecerfont, we’re presented with the opportunity to build a new market, just like the opportunity we had seven years ago when we set out to launch Ingrezza as the first medication approved for TD. Building a market for crinecerfont in CAH is a privilege; however, much work remains ahead of us. One of our primary areas of focus in 2024 will be the education of all stakeholders in the CAH community. This educational effort will focus on disease state awareness, challenges with currently available treatment strategies, and the recognition of the need for better treatment options. Given the challenges of managing CAH that Eiry highlighted and the extremely impressive efficacy and tolerability data generated from our Phase III studies, we’re excited for the potential of crinecerfont to dramatically change the status quo. We bring forward the possibility of bringing androgens under control while simultaneously reducing GC dose to more replacement levels. In the commercial organization, we’re ramping up educational efforts directed towards patients, parents, family members, and endocrinologists to help the CAH community better understand the nature of their disease, to more fully understand the current unsatisfactory treatment trade-offs between suffering from excess androgen production or the complications of chronic treatment with high-dose glucocorticoids. In a compliant way, we plan to set the table for a new and simpler approach to treating CAH that doesn’t require the current challenging trade-offs. It will take some time to broadly reach and educate the CAH patient community, but the good news is that we have already started that process. As we prepare for an expected launch in the U.S. in 2025, our teams are excited to build another market and bring a potential new medicine to CAH patients who sorely need a better option to manage their disease. Now I’ll hand it back to Eiry.

Eiry Roberts, Chief Medical Officer

Thank you Eric. As we begin the year, Neurocrine’s pipeline is as broad and diversified as it has ever been in our 32-year history. Importantly, 2024 marks a catalyst-rich year. Our Phase II pipeline features several data read-outs this year, all of which remain on track for delivery. This includes NBI-845, the AMPA potentiator for major depressive disorder, with data in the first half; luvadaxistat, the DAAO inhibitor for the cognitive impairment associated with schizophrenia in the second half; and NBI-568, an orthosteric M4 agonist for treatment of psychosis in schizophrenia, also reading out in the second half. In addition to these data read-outs, we are currently initiating a Phase II efficacy study for NBI-770, the oral NMDA NR2B negative allosteric modulator as a potential treatment for major depressive disorder. In the early-stage pipeline, we have made remarkable progress over the recent months with five new programs entering Phase I development. Four of these programs target the muscarinic system, and together with NBI-568, we believe this represents the broadest and deepest muscarinic pipeline of any company in our industry. These Phase I molecules provide the opportunity to explore the potential value of differentiated selective agonism at M1 and M4 receptors while always excluding agonism at M2 and M3. We have the tools to differentiate these molecules in early clinical development and thus determine which neurological and psychiatric disorders might best benefit from this differentiated cell activity. In addition, our Phase I muscarinic portfolio includes an internally discovered selective M4 antagonist, NBI-986, targeted for the treatment of movement disorders. The final new entry in our Phase I portfolio is NBI-890, a next-generation VMAT2 inhibitor targeting a broad range of potential neurological and neuropsychiatric diseases. I’m extremely proud and enthusiastic about the prospects of today’s clinical pipeline and look forward to continuing to partner closely with Jude and his outstanding research and preclinical development team to bring the next generation of innovative small and large molecules from research into the clinic over the coming years. I’ll end here and hand it back to Kevin. Kevin?

Kevin Gorman, CEO

Thank you Eiry. We’ve gone a little longer this morning with our opening remarks, mainly due to the fact that there was a lot that we ended last year on and there is a lot going on here this year. We’re going to do our best to get through as many of your questions as possible before the top of the hour, so Operator, could we open it up for the first question?

Operator, Operator

Our first question will come from Paul Matteis with Stifel. Please go ahead.

Paul Matteis, Analyst

Hey, good morning. Thanks so much for taking my question, I appreciate it. I wanted to ask about the muscarinic read-out coming up in the second half of this year. The study design includes a number of different dose arms, so I was just curious if you could expand upon how you selected those dose arms and how confident you are that you’re in the right range, and then because the study has a number of dose arms and isn’t all that big, are you looking at success in this read-out as hitting a P-value or are we more looking at a dose or two with PANSS changes that look similar to emraclidine and KarXT with acceptable safety? Thanks so much.

Eiry Roberts, Chief Medical Officer

Paul, thanks very much. Thanks for the question. This is a dose-finding study, as you alluded to, for NBI-568, and it is an adaptive design that explores several different dose levels. In terms of the sizing and powering of the study, we are more looking for an effect size that is similar to what has been seen before, and also potentially a somewhat differentiated tolerability profile. It’s not a trial that is powered for individual P-values for different arms, but it is a reasonable size large dose-finding study with over 200 patients ultimately, and we look forward to reading that out in the second half of this year.

Paul Matteis, Analyst

Okay, thank you Eiry.

Operator, Operator

Thank you. Our next question will come from Tazeen Ahmad with Bank of America. Please go ahead.

Tazeen Ahmad, Analyst

Hi guys, good morning. Thanks for taking my question. Mine is on the chorea launch this year. Wanted to get some more color of what type of contribution you’re expecting from that launch, or Ingrezza sales this year, at least directionally. Then I also wanted to follow up on a comment Eric made in the prepared remarks, that I think you said 80% of chorea patients don’t receive any therapy today. You know, Xenazine has been on the market for several years. I was just curious as to why you think they haven’t been able to get bigger share in the years that they’ve been in the market. Thanks.

Eric Benevich, Chief Commercial Officer

Yes, good morning. I’ll take the second question first. You know, what we’ve seen prior to the launch and then now that we’re in the market is that the majority of patients with Huntington’s chorea either don’t get treated at all for their uncontrolled movements, or they get treated with an antipsychotic and may get some partial benefit. Only about 20% of patients with HD chorea get treated with a VMAT2 inhibitor. What our research tells us, and what the prescribers tell us, is that the deficiencies with the tetrabenazine products have led to a fairly high rate of patients not getting treated, either because of perceptions of complicated dosing and titration, concerns about side effects, or in some cases out-of-pocket costs. The profile of Ingrezza in Huntington’s chorea has a lot of the same attributes as its profile in TD and is the reason that it’s the number one most prescribed VMAT2 inhibitor. In terms of simple dosing, there’s no complex titration, it is well tolerated, and as I mentioned in my prepared remarks, the out-of-pocket cost is less than $10 for most patients. We intend to grow not only by growing within the VMAT2 treated class but by expanding the class over time, and to do that, we need to encourage more patients and more providers to be treated altogether within that category of HCC. The first part of your question was really around the relative contribution. It’s small, and the reason that I say that is twofold. One, we’re still just getting off the ground. We’re only about a quarter into the launch now and we’re introducing our data to the Huntington’s treating community in neurology. The second reason is that it’s a rare disease - it’s a much smaller patient population, thankfully, than tardive dyskinesia, and so for every patient with Huntington’s chorea, there are about 40 patients with TD out there, and ultimately TD is and will continue to be the main growth driver for our Ingrezza franchise.

Tazeen Ahmad, Analyst

Okay, thanks Eric.

Operator, Operator

Thank you. Our next question will come from Brian Skorney with Baird. Please go ahead.

Brian Skorney, Analyst

Hey, good morning everyone. Thank you for taking my question. Matt, I was hoping maybe you could help us think about the initial build-out of infrastructure of a CAH launch and how to think about the SG&A guidance for this year versus what’s fully loaded. Then maybe you can just kind of give us some high-level thoughts on what a cadence of launch would look like - do you see this as a market with high levels of patient awareness and building demand, or is this more of a cadence of patients seeing endocrinologists on a yearly basis and that’s a point of discussion for a new therapy happening?

Matt Abernethy, CFO

Yes, so from a financial perspective, we are going to invest around $50 million this year just to prepare for that launch in 2025, so from an SG&A perspective, if you look at it holistically for the company, showing very nice leverage this year and even including that $50 million investment. Eric can get into the details of the build, but we do expect to have the sales force generally in place by the middle of this year to start educational initiatives, and then that will set us up for a launch in 2025. Eric, do you want to comment on the cadence of launch?

Eric Benevich, Chief Commercial Officer

Yes, as I mentioned in my prepared remarks, 2024 is the year of preparing for the launch, but it’s also the year of preparing the market for crinecerfont. To that end, we’re going to start the process of reaching and educating all the key stakeholders in the CAH community, so patients, family members, and endocrinologists. Part of it is educating them on the nature of the disease, the challenges that Eiry highlighted in her prepared remarks of living with CAH on a day-to-day basis, and the limitations of current treatment with high-dose glucocorticoids. As Matt mentioned, we are in the process of scaling up and hiring a sales force, and we’re going to deploy that team a few quarters in advance of the anticipated PDUFA date, and they’ll be getting out there, they’ll be doing disease state education, they’ll be meeting customers, profiling customers, etc. to really set us up for a very strong launch that we expect in 2025.

Operator, Operator

Thank you. Our next question comes from Phil Nadeau with TD Cowen. Please go ahead.

Phil Nadeau, Analyst

Good morning. Congratulations on a successful year. A couple questions for Matt from us, based on the 2024 guidance for Ingrezza. First, Matt, you mentioned that the gross-to-net would improve in 2024. Can you give us some idea of what the net price you’re expecting for Ingrezza is? Then second on the revenue guidance, the bottom end of the 2024 revenue guide implies only about 5% growth versus the Q4 run rate for Ingrezza, so we’re curious to know a bit more about the patient dynamics that could lead to that relatively modest growth versus the 10% that’s assumed at the high end. Thanks.

Matt Abernethy, CFO

Yes, thanks for the question, Phil. Always good to hear from you. As we think about 2024 and overall guidance, it really comes down, as it does every year, to what happens in the first quarter with patient retention, and then also new patient generation. The guide that we provided today really takes into account what we see today, but we of course are always going to work to try to drive as much new patient growth as possible throughout the year, and we’ll of course reassess our guidance when we get to the middle of the year, consistent with past years. From a net price perspective, factoring all the nuts and bolts of price increases and contracting trade-offs, we would expect that net revenue per script will be somewhere over $5,800 net revenue per script, and just as a reference point to remind you, we did land around $5,600 net revenue per script in 2023.

Phil Nadeau, Analyst

Very helpful, thank you.

Operator, Operator

Thank you. Our next question comes from Brian Abrams with RBC Capital Markets. Please go ahead.

Brian Abrams, Analyst

Hey guys, thanks for taking my question. You mentioned the potential to prepare for an advisory committee for crinecerfont. I was wondering if you could maybe speak about what topics you might expect to be discussed there, and I guess how a potential ad-com could tie into laying the groundwork for payors and any discussions you may be having, as well as furthering the educational efforts that you’re going to be initiating this year around the market. Thanks.

Eiry Roberts, Chief Medical Officer

Thank you. I'll address the second part of your question first. Regarding our educational initiatives, it's crucial to recognize that crinecerfont will be the first potential treatment introduced in this area in nearly 60 or 70 years. While we have a knowledgeable group of experts familiar with current treatment options for this patient population, the chance to fundamentally shift the approach to treating this disease necessitates significant engagement in educating clinicians, patients, their families, and all others involved. We are already investing heavily in these efforts on both the medical and commercial fronts, ensuring compliance as we look forward to our anticipated approval. As for the advisory committee, we mention it because of the long gap without a medication in this field. It might also provide an opportunity for the FDA to consult with outside experts who haven't been involved with our program. We don’t have a specific reason to believe an advisory committee will be necessary based on our data; we are very pleased with the results from our Phase III program and confident that our NDA will clearly convey the benefits and tolerability of crinecerfont. While we don't have particular topics in mind, we're preparing for the possibility just in case the FDA chooses to pursue that path.

Brian Abrams, Analyst

Thanks Eiry.

Operator, Operator

Thank you. Our next question comes from Chris Shibutani with Goldman Sachs. Please go ahead.

Stephen, Analyst

Hey team, this is Stephen on for Chris. Thanks for taking our question. I think Eric mentioned in the prepared remarks that you expect growth from all three channels of your commercial organization with regards to Ingrezza this year, so I’m just curious if you can speak about development and progress points made in the long-term care channel and how meaningful we should expect revenues from that channel to be in 2024. Thank you.

Eric Benevich, Chief Commercial Officer

Yes, so all three segments of our business are growing nicely, as I mentioned. Psychiatry continues to drive the majority of the opportunity because that’s where the majority of the patients are being cared for with TD. Neurology and LTC are also doing quite well, and at this point, the contribution from each is pretty similar in terms of our overall business. LTC is the newest segment. As I’ve mentioned before, it’s probably the least developed segment because we really haven’t been in there as long educating the stakeholders, driving screening, diagnosis, and treatment, and it continues to really be growing nicely. In such a short period of time, for it to be contributing to that level, I think it’s a testament to the investment that we made and we’re quite happy with the results.

Stephen, Analyst

Great, thank you.

Operator, Operator

Thank you. Our next question comes from Josh Schimmer with Cantor. Please go ahead.

Josh Schimmer, Analyst

Thanks for taking my questions. Just a couple of quick ones. First, are you seeing any shifts in market share as a result of the once-per-day Austedo launch, and then I noticed you’ve added Efmody, if I’m pronouncing that correctly, to the pipeline. I think in the past, you’ve indicated that might be a product more designed for market building and establishing a sales force, as opposed to generating meaningful revenue. Are you starting to shift that perspective at all? Thank you.

Eric Benevich, Chief Commercial Officer

Yes, I’ll take your first question. The answer is no, we haven’t seen any change in market share. It appears to us that deutetrabenazine XR is cannibalizing deutetrabenazine in terms of their overall business, so it’s more of a shift within that deutetrabenazine franchise than any kind of share gain. The other thing that I’ll say is that we didn’t see a change of market share in 2023, and we don’t expect to see any kind of change in market share, at least any kind of negative change in market share in 2024.

Matt Abernethy, CFO

Yes, the only thing that I’d add, Eric, is that the market itself has just been incredibly rich. There are so many patients that need help with their tardive dyskinesia and there is great unmet need, so when you look at what we were able to achieve this year - a record year-over-year growth of over $400 million, and I would just say from a class perspective, this continues to be a great opportunity, and looking forward to helping more patients who need help with their tardive dyskinesia. Eiry, do you want to comment on Efmody?

Eiry Roberts, Chief Medical Officer

Yes, certainly. Efmody is a steroid treatment that is currently approved in Europe for the treatment of CAH in adults, and as such, I think it potentially has some complementarity to crinecerfont. In the U.S., we do not have an approval for Efmody currently. We are reading out two trials of Efmody in the first half of this year, and based on the data from those two Phase II trials, we’ll update you as to what our next plans are.

Operator, Operator

Thank you. Our next question comes from Anupam Rama with JP Morgan. Please go ahead.

Anupam Rama, Analyst

Hey guys, thanks so much for taking the question. Just maybe a quick pipeline question. The AMPA potentiator in MDD, that’s one of the next catalysts you’re expecting in the first half of ’24. Maybe you could describe the study, the key endpoints, and what you’re looking for in this program to give you confidence to move to the next phase.

Eiry Roberts, Chief Medical Officer

Thanks Anupam. Yes, you’re right - in the first half of this year, we will read out the data from NBI-845, which is our AMPA potentiator as a potential treatment for major depressive disorder. This is a dose-finding study. It compares two different dose levels of the AMPA potentiator to placebo, using a pretty standard primary endpoint of the MADRS score at week 4, and the goal here with this mechanism of action, obviously since its potentially ketamine-like yet through a downstream mechanism associated with NMDA, is that we actually would see a more rapid onset of anti-depressant activity than is seen usually with SSRIs and other treatments. We are looking at MADRS as the primary endpoint, but we have multiple other secondary endpoints within this dose-finding study which allows us to look at function and quality of life, as well as the other psychiatric endpoints, and so in essence we’ll be looking at the totality of the information coming out of this dose-finding study to make a decision as to whether to proceed.

Anupam Rama, Analyst

Thanks so much for taking our question.

Operator, Operator

Thank you. Our next question comes from Carter Gould with Barclays. Please go ahead.

Carter Gould, Analyst

Good morning, and thank you for the question. I have another one for Eiry. This was mentioned briefly at the analyst day but was somewhat overshadowed by other updates. I'm referring to the next-generation VMAT2 inhibitor. Could you discuss the ongoing ATS study and how it impacts your expectations? Also, can you outline your expectations and the progress you foresee regarding this broader initiative and VMAT2 follow-ons over the next 12 to 18 months?

Eiry Roberts, Chief Medical Officer

Yes, so we are just entering the clinic with NBI-890, which is the VMAT2 follow-on, and obviously given the depth of knowledge that we have of this VMAT2 mechanism, this is a really important mechanism and platform for us. Valbenazine is an amazing medication in terms of its profile that Eric alluded to earlier, and so we have had to keep the bar really high in terms of the ability to differentiate with next-generation molecules coming into the clinic. We haven’t talked too much about the profile of this VMAT2 inhibitor yet. We will obviously do that as we generate Phase I data, but we would seek to differentiate with this molecule, both in terms of potential indications that we would go into but also in some of the characteristics of the molecule itself, that might lend itself to other areas such as long-acting intramuscular injection or the approaches that are important in the neuropsychiatric arena.

Operator, Operator

Thank you. We’ll take our next question from Akash Tewari with Jefferies. Please go ahead.

Ivy, Analyst

Good morning. Thanks for taking my question. This is Ivy on for Akash. On your Phase II schizophrenia trial for the M4 agonist, 568, I guess that will be reading out this year. It sounds like you are prioritizing safety over efficacy. How much efficacy are you willing to potentially give up here in comparison to other competitors, like KarXT, in order to move forward into a Phase III study? Thanks.

Eiry Roberts, Chief Medical Officer

Thank you. The NBI-568 molecule is a highly selective M4 agonist, and we have learned from both KarXT and the Cerevel molecule that the M4 mechanism is involved in the psychosis associated with schizophrenia. Agonizing M4 can lead to improvements in PANSS scores and symptoms of psychosis. There are notable differences between the molecules in how they interact with M4, which may affect their effectiveness as well as their tolerability. We are interested in both tolerability and efficacy. This is a dose-finding study, and we will evaluate efficacy through its impact on psychosis scores, as well as tolerability regarding the overall response to this molecule. Both aspects are significant, and integrating the data from the Phase II results will be crucial in guiding our future decisions.

Ivy, Analyst

Thanks.

Operator, Operator

Thank you. Our next question comes from Jay Olson with Oppenheimer. Please go ahead.

Jay Olson, Analyst

Hey, congrats on all the progress, and thanks for taking the question. Just going back to crinecerfont, can you talk about how long patients need to be treated with crinecerfont before they start to experience some of the benefits on the complications of CAH, like cardiovascular or bone density, and do you think you’ll have some of that data when you file? Then separately, do you have any plans to study crinecerfont in other diseases besides CAH? Thank you.

Eiry Roberts, Chief Medical Officer

That’s quite a few questions. Addressing them individually, regarding the effectiveness of crinecerfont and its benefits for androgen control, we observe rapid results, as demonstrated in our Phase II proof-of-concept study where significant reductions in androgens were seen within 14 days of dosing. This trend was consistent in our four-week Phase III study. Crinecerfont effectively controls androgens quickly, which allows clinicians to reduce steroid dosages. By managing androgens and decreasing steroid use, we achieve the long-term clinical benefits. Our NDA submission includes measures of clinical outcomes related to metabolic health, bone health, growth, and other significant factors, based on data extending out to approximately one year and beyond. Notably, we've seen a rollover rate exceeding 95% in both adult and pediatric trials for participants entering the open-label phase, allowing us to gather ongoing long-term data until we reach market readiness. Additionally, we are undertaking a registry effort, named Catalog, to contextualize our clinical outcome data with what is observed in the general CAH population.

Jay Olson, Analyst

Great, thank you, and any plans for other diseases?

Eiry Roberts, Chief Medical Officer

Oh, actually I think we are continuously considering that. Jude also mentioned it during our R&D day that we are focusing on next-generation molecules in CAH and other areas as well, and we will definitely provide more updates on that in the future.

Operator, Operator

Thank you. Our next question comes from Marc Goodman with Leerink. Please go ahead.

Rudy Li, Analyst

Hey, this is Rudy on the line for Marc. Thanks for taking my question. Can you talk about your IP following the recent patent litigation settlement, and just curious what are your current thoughts on the impact of IRA on your pricing towards the end of this decade? Thank you.

Eric Benevich, Chief Commercial Officer

We’re very pleased with the way that the litigation ended. We have protection that goes out into 2038 at this point in time, so I think that really spoke to the impressive patent efforts that we put behind all of our molecules here at Neurocrine. When it comes to the IRA, as you know, the first 10 drugs are under negotiation right now. In September of this year, we’re going to see the first time what those negotiations yielded, so I think we all look forward to seeing that before we can comment any further on what we think the IRA impacts are going to be.

Operator, Operator

Thank you. Our next question comes from Myles Minter with William Blair. Please go ahead.

Myles Minter, Analyst

Hi, congrats on the progress. Thanks for the question. Just a quick one on the Phase I 570 trial, the dual M1/M4 agonist in healthy volunteers, I think that trial initiated in September. Just wondering how dosing is going for that and when we’ll hear about safety for that program. Secondly, would you ever think about running head-to-head studies against 568 or 569 in a CNS indication? Thanks.

Eiry Roberts, Chief Medical Officer

Thanks Myles. On the 570, that’s progressing very well. We are going through the Phase I program and at some point, obviously, we’ll come forward and talk about that more as we enter Phase II - that’s usually what we tend to do in that space, but things are progressing as expected. You know, there’s always a lot of discussion about whether to try to put more than one investigational product into a clinical trial in order to profile them directly with one another. As you can imagine, that is something we’ve talked about in the context of the fact that we have such a broad portfolio of muscarinics. It’s very challenging to do that, though, given the fact that we want to try to accelerate each molecule as much as possible individually, and so at least in my experience over many years in this business, they don’t seem to line up perfectly for you to be able to do that. In the absence of being able to do that, what we are doing is essentially running very, very similar Phase I programs for each of these assets, so that we can look at the same measures, look at the same outcomes, and understand how to compare those individual molecules indirectly.

Myles Minter, Analyst

Fair enough, thanks Eiry.

Operator, Operator

Thank you. Our next question comes from Neena Bitritto-Garg with Deutsche Bank. Please go ahead.

Neena Bitritto-Garg, Analyst

Hey guys, thanks for taking my question. I just wanted to circle back to the MR read-out later this year and Paul’s question originally about dosing. Is there anything else that you can kind of share on the dose levels that you’re testing and dosing frequency, and maybe how they may compare to some of the doses that we’ve seen for emraclidine and KarXT from an activity perspective? Thanks so much.

Eiry Roberts, Chief Medical Officer

We haven’t shared the doses from our Phase II dose-finding study up to this point. Obviously it’s not that long before we get our data, so we’ll get to see that later this year. What I can say is that we’re confident on the dose range that we’re testing, based on an integration of our preclinical data, both efficacy and tolerability from the toxicology program, and also from our Phase I studies where obviously we explored a lot of different pharmacology to understand how to pick the right doses for Phase II.

Neena Bitritto-Garg, Analyst

Got it, thank you.

Operator, Operator

Thank you. Our next question comes from Jeffrey Hung from Morgan Stanley. Please go ahead.

Michael Riad, Analyst

Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions. Could you talk a little bit more about Efmody? What are you hoping to see in the Phase II data, and how would you see this becoming part of the treatment paradigm? Is there anything to suggest maybe different uptake, depending on whether a patient is in early adolescence versus adulthood? Thank you.

Eiry Roberts, Chief Medical Officer

Yes, we really haven’t talked much about the Efmody strategy particularly here in the U.S. As I said, it is an approved product in Europe for CAH, and these are just very straightforward Phase II read-out studies. Once we have the data, I’m sure we’ll talk a little bit more about that and whatever our next steps might be.

Operator, Operator

Thank you. Our next question comes from Danielle Brill with Raymond James. Please go ahead.

Danielle Brill, Analyst

Good morning. Thank you so much for the questions. I guess I’d like an update on the cerebral palsy dyskinesia and schizophrenia studies of valbenazine. Should we expect data from those studies this year, and then what sort of impact to sales might we expect from the sprinkle powder formulation of Ingrezza, once it’s approved? Thanks so much.

Eiry Roberts, Chief Medical Officer

I can give an update on the ATS and DCP programs. Both are enrolling and we anticipate data during next year.

Eric Benevich, Chief Commercial Officer

Yes, and just a quick comment on the sprinkle formulation - obviously it’s not an approved formulation, but we’re looking forward to, upon approval, rolling it out. We estimate that 5% to 10% of patients with either Huntington’s chorea or tardive dyskinesia experience difficulty in swallowing, so this may be a better alternative for them, and so we’re looking forward to introducing that product upon approval.

Operator, Operator

Thank you. Our next question comes from Laura Chico with Wedbush Securities. Please go ahead.

Laura Chico, Analyst

Hey, good morning guys. Thanks for taking the question. Obviously a lot of discussion today on your internal pipeline activities, but wondering if you can discuss your appetite for external BD at this point, and what flexibility does the balance sheet now provide in terms of potential deal size? Thank you.

Kyle Gano, Chief Business Development and Strategy Officer

Hey, this is Kyle. Thanks for the question this morning. I think what you’ve seen here from Neurocrine over the past year was good progress on bringing programs from our internal drug discovery efforts into the clinic - we put five programs in last year. Our team, we work with great urgency here in business development. We don’t feel like we have the need to do something large at this particular time. I think what we would expect here over the near term, midterm is to continue to help our research team accelerate some of their efforts and bring their assets that they’re currently working into the pipeline, to help us transform that pipeline that we’ve been discussing at our R&D day into this next year. In terms of what we’re looking at beyond helping our research colleagues, we’re probably not going to spend a lot of time looking at things that are pre-proof of concept, so it’s earlier stage opportunities to bring in technologies for our research team, and then obviously anything that’s a de-risked, later stage clinical stage asset through commercial are things that would be of interest to us. They are few and far between, as you know, and they are quite expensive as well, so we’d look at those but I think our mind right now is doing what we can to help build the pipeline organically.

Matt Abernethy, CFO

When you think about how we expect to drive shareholder value, you can see where our money’s going - to continue to drive growth in Ingrezza, getting ready to launch crinecerfont - I think that’s going to be a meaningful contributor to both help patients and then also to Neurocrine’s top line, and a lot of investment in our internal research programs. Between all the Phase I starts that we have this year, as well as what Jude highlighted at R&D day, we feel very confident about what we have going forward. We of course have financial flexibility with $1.7 billion in cash, and then also a growing EBITDA profile. We do have the financial flexibility, but right now we’re really prioritizing executing what we have, and we have a lot to look forward to.

Laura Chico, Analyst

Thank you.

Operator, Operator

Thank you. Our next question comes from Sumant Kulkarni with Canaccord Genuity. Please go ahead.

Sumant Kulkarni, Analyst

Morning, thanks for taking my question. On your efforts in major depressive disorder, do you think there is any medicine approaching that indication within episodic versus chronic treatment, and do you expect either 770 or 845 to have an episodic component or a more durable efficacy aspect to treatment?

Eiry Roberts, Chief Medical Officer

I think the goal with our current efforts in both 845 and also 770 is to be able to try to replicate some of the findings that have been seen with ketamine, but to do it in a way that expands on the efficacy that you’ve been seeing in that area. Episodic dosing is part of the consideration there, and we haven’t talked very much about our dosing regimen for our current programs. We have said for 770, this is an oral approach to NR2B NAM - that is the first, to our knowledge, oral approach to this target, and obviously as we endeavor to generate the data from those Phase II studies, we’ll be able to talk more about the plans moving forward.

Sumant Kulkarni, Analyst

Thank you.

Operator, Operator

Thank you. Our next question comes from Evan Siegerman with BMO Capital Markets. Please go ahead.

Unknown Analyst, Analyst

Hi everyone, I'm here for Evan. Thank you for taking our question. Regarding the muscarinics, you're employing M4 agonism in the Phase II trial for schizophrenia, while using antagonism in Phase I for treating movement disorders. Could you elaborate on the differences in the mechanisms of action and what gives you confidence in those indications, as well as how the antagonism may be set apart for movement disorders? Thank you.

Eiry Roberts, Chief Medical Officer

The approaches here are very different. M4 agonism, we are focused on looking at that in the context of treating neuropsychiatric disorders, particularly schizophrenia as the starting indication, and it’s very clear, I think now from data generated in this field, that the M4 system plays a role in the psychosis within schizophrenia. For the M4 antagonist, we’re actually targeting movement disorders, and so in terms of the M4 systems that are associated with abnormal movement within the brain, in diseases such as Parkinson’s tremors, dystonia, that is disrupted, and antagonizing this system, we believe has the potential to add value and to be able to treat those disorders, so it is very different in terms of the approach that we’re taking there.

Operator, Operator

Thank you. We’ll take our next question from David Hoang at Citigroup. Please go ahead.

David Hoang, Analyst

Hi, thanks so much for taking the question. Maybe just to circle back on Ingrezza for a moment, could you talk a little bit about the higher end of the guidance range in 2024, what would be the factors that would play into that, and maybe along those lines, in terms of accessing the remaining two-thirds of undiagnosed TD patients, do you perceive any barriers to reaching that group?

Eric Benevich, Chief Commercial Officer

Yes, as we mentioned earlier in terms of the 2024 guidance range, it’s really driven by the success that we’ll have early in the year in driving new patient starts and continuing to retain existing patients. As we get to the later part of the year or the middle of the year, as Matt said, we’ll reassess and tighten up what our expected guidance is. In terms of being able to continue to develop the market, continue to drive recognition, diagnosis, and treatment, the fundamentals remain the same. When we started with the launch of Ingrezza over six years ago, only a very small fraction of the TD patients had actually been diagnosed, and none had been treated effectively, so we’ve made great progress. Now, we believe that about a third of all TD patients have been diagnosed and yet only about half of the time are they actually offered treatment with a VMAT2 inhibitor, so there is still a lot of room for organic growth and a lot of opportunity to make a big difference in patients’ lives. The fundamentals of what we do, both in terms of educating healthcare providers across psychiatry, neurology, and long-term care, as well as continuing to invest in DTC, to reach and educate those that are suffering from TD, and encouraging them to have that conversation with their doctor. These are the things that we’re doing. We’re very focused on education, as Matt said, and we’re continuing to drive leverage within our existing TD and HD franchises.

Operator, Operator

Thank you. We’ll take our next question from Mohit Bansal with Wells Fargo. Please go ahead.

Mohit Bansal, Analyst

Thank you very much for the question. I have a query regarding expenses. It appears there is some margin improvement in SG&A, but you are also committing to spending on R&D. Given that SG&A remains close to 40% of sales, how should we consider the leverage going forward, especially since CAH may need to invest in launch preparations? Thank you.

Matt Abernethy, CFO

Yes, when we look at the SG&A leverage compared to 2022, we were at 51%. By 2024, excluding crinecerfont, we expect to reduce that to 41%. Achieving a 1,000 basis point improvement over two years is significant, and I’m proud of the team's accomplishments with our investments. Going forward, the investment in crinecerfont will be much less than what we've dedicated to Ingrezza. I anticipate it will have a positive impact early in the launch, and we will provide updated guidance next year regarding expenses and revenue expectations. I believe that adding crinecerfont will support our SG&A leverage goals in the coming years.

Mohit Bansal, Analyst

Excellent, thank you.

Operator, Operator

Your next question comes from Uy Ear from Mizuho. Please go ahead.

Uy Ear, Analyst

Hi guys, thanks for taking my question. Matt, I think you said the 4Q Ingrezza number, the growth was offset by gross-to-net. I was wondering if you can help us understand the dynamics of gross-to-net in the quarter, and as well as the factors that will improve gross-to-net in 2024. Thanks.

Matt Abernethy, CFO

You know, when you think about our Q4 results, it’s our first quarter ever of $500 million in sales, and we’re quite encouraged by what we saw. There’s always quarterly gyrations in terms of whether it’s timing of orders, timing of patients getting refills, etc., and so there’s choppiness to certain quarters. Q3 was a blowout quarter; Q4 was another great quarter, and I think we feel very good with how we’re positioned heading into 2024. The gross-to-net dynamic that I commented on is very consistent with what we’ve had in previous years. There’s an accounting requirement where you have to take an incremental discount on your channel inventory, and so that’s something that put pressure on our numbers a bit in Q4. The only other item that I’d call out as it relates to net revenue per script, we didn’t take our price increase until very late in the quarter, and in previous years there was some level of contribution in our Q4 numbers associated with the price increase. The improvement in this year’s net revenue per script comes down to price increases and then the contract decisions that we make, their trade-offs, and I think that overall, that’s what led to an improved net revenue per script, going from $5,600 in 2023 to something over $5,800 in 2024.

Uy Ear, Analyst

Thanks.

Operator, Operator

Thank you. Our next question comes from David Amsellem with Piper Sandler. Please go ahead.

Schuyler van den Broek, Analyst

Hi, this is Schuyler on for David. First, any thoughts on the potential pricing of crinecerfont and the discussions you’ve been having with payors, and do you expect the reimbursement landscape will be different between adults and pediatrics? Then second, could you provide any updates on the development plan for the M1 preferring agonist, and just talk mechanistically to the value proposition of just targeting M1 versus M4. Thanks.

Eric Benevich, Chief Commercial Officer

Yes, so obviously we’re very enthusiastic about the clinical profile that emerged with crinecerfont. With regards to pricing, it’s a little bit premature to comment on that, other than to say that this is a rare disease and we would expect to have rare disease pricing. We’ve had initial conversations with payors and I’ve been quite pleased, and maybe a little bit surprised - pleasantly - that they seem to be acutely aware of the issues associated with chronic high-dose steroid treatment, and so we’ve got a lot of work to do still in terms of understanding the value that’s emerging from the clinical data. Certainly we believe that the pricing will be in line with the value that we bring to market.

Todd Tushla, Vice President of Investor Relations

Let’s take one final question, please.

Operator, Operator

Our last question comes from Ami Fadia with Needham. Please go ahead. Ami, your line is open. Please go ahead with your question.

Todd Tushla, Vice President of Investor Relations

It sounds like I’ll follow-up with Ami later. Kevin?

Kevin Gorman, CEO

Thank you all for your questions this morning. I really appreciate this opportunity to engage, and we’ll have more discussions in our upcoming meetings. My closing comments are simply this: I hope our enthusiasm for the beginning of 2024 has been clear. We expect to have another great year. There are two key points I'd like to emphasize as I wrap up. First, about three years ago, you saw our investments in Ingrezza increase, including expansions in our sales force and direct-to-consumer efforts. Over the last two years, you've witnessed the significant impact of those investments. We now have a multi-billion dollar product, and the return on these investments has been phenomenal. They will continue, with our focus on the patient and building out this nascent market, which I've been mentioning for six years, and I will continue to do so. This is just the beginning, as there are many more patients who need this drug to lead fulfilling lives. Similarly, with crinecerfont, our investment requirements in this market are smaller due to a smaller patient population. However, I am very confident that our current and future investments will greatly benefit these patients and contribute to Neurocrine's growth. Lastly, our internal research and development investments are set to yield positive results. We have access to a lot more information than you do, but I assure you that in the coming years, you will see advancements in small molecules, which have always been our strength, as well as in large molecules, including peptides, proteins, antibodies, and gene therapies, moving into clinical trials. We are very excited about this and have a lot of work ahead of us. We look forward to discussing more with you in the future. Thank you very much.

Operator, Operator

This does conclude the Neurocrine Biosciences year-end and fourth quarter results call. You may disconnect your line at this time and have a wonderful day.