Good morning, and thank you all for joining us on our fourth quarter and full-year 2023 earnings call. Joining me on the call today are Dr.

Sharon Mates, Chairman and Chief Executive Officer; Mark Neumann, Chief Commercial Officer; Dr. Suresh Durgam, Chief Medical Officer; and Larry Hineline, Chief Financial Officer.

As a reminder, during today's call, we will be making certain forward-looking statements. These forward-looking statements are based on current information, assumptions, and expectations.

These are subject to change and involve a number of risks and uncertainties that might cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports.

You are cautioned not to place undue reliance on these forward-looking statements, and the company disclaims any obligations to update such statements. Sharon?

Thanks, Juan. Good morning, everyone, and welcome to today's call.

We're excited to share our results for the fourth quarter and the full-year 2023. This past year was defined by strong and consistent growth throughout our company.

We achieved major milestones as we established CAPLYTA as a key treatment option for broad patient populations with bipolar depression and schizophrenia. We also advanced our pipeline programs, and look forward to announcing top line results in our major depressive disorder study, Study 501 and Study 502.

Our full-year 2023 total revenues were $464 million. CAPLYTA net sales in 2023 were $462 million, compared to $249 million in 2022, representing an 86% increase.

Similarly, total scripts grew by 85% in 2023, compared to 2022. Demand for CAPLYTA remains strong.

Our well-executed commercial efforts continue to drive prescription growth from both new and existing prescribers. We anticipate continuing strong demand for CAPLYTA.

Based on this positive momentum, I am pleased to report that we expect full-year 2024 CAPLYTA net product sales to be in the range of $645 million to $675 million. Mark will elaborate on our commercial performance and plans for this year in a moment, and then Larry will share additional details regarding our financials.

We continue to strategically invest in our pipeline, and we anticipate further advancements in several of our late, mid, and early-stage clinical programs in 2024. I'd like to share more specifics regarding our plan for expanding CAPLYTA beyond its current indication.

We have two upcoming Phase 3 top line readouts for the use of lumateperone as an adjunctive treatment in major depressive disorder, or MDD. Our 501 study is fully enrolled, and most patients have completed treatment.

We allowed the small number of patients who were in screening when we reached our previously determined enrollment targets to continue and be randomized to the double-blind treatment phase of the study. The rationale for allowing these patients to continue to participate in the double-blind treatment is that we believe that, ethically, if a patient had to participate in the screening process and qualified for enrollment, they should be allowed the possibility of receiving treatment.

As a result, we expect to report top line results from Study 501 in April of this year, rather than late March. We remain on track to report top line results from Study 502 late in the second quarter this year.

Subject to those results, we continue to anticipate filing a supplemental New Drug Application with the FDA in the second-half of this year. We have a high degree of confidence in our MDD program.

As we have previously shared, multiple lines of evidence support this confidence, starting with lumateperone's mechanism of action, simultaneously modulating serotonin, dopamine, and glutamate systems. Importantly, we have significant clinical evidence in several patient populations, including patients with schizophrenia with comorbid depression, patients with bipolar depression, and patients with MDD exhibiting mixed features.

Of note, CAPLYTA is the only anti-psychotic approved for both bipolar I and bipolar II depression, both as monotherapy and as adjunctive therapy. We remain very excited by the possibility of helping millions of patients with MDD.

The significant uptake of the last two anti-psychotics approved for adjunctive treatment in MDD underscores the continued unmet need and the large opportunity in this market. Given the efficacy and safety profile to date, we are confident in CAPLYTA's future potential in this patient population.

As we mentioned to you previously, we were expecting to have a meeting with the FDA to discuss the results of Study 403, particularly with respect to the MDD patient population with mixed features. I am pleased to report that we recently had a constructive meeting.

And as you know, we wait for minutes prior to making any statements regarding our interactions with the FDA. We expect to receive the minutes from the meeting later this quarter, and plan to update you regarding the outcome and next steps at that time.

Beyond our MDD program, we continue to invest in our lumateperone R&D program. Accordingly, we have initiated our lumateperone pediatric program, which includes an open-label safety study in schizophrenia and bipolar disorder, and double-blind placebo-controlled study in bipolar depression, and two double-blind placebo-controlled studies in irritability associated with autism spectrum disorder.

Approximately 2.8% of children in the United States have autism spectrum disorder. Irritability is a common symptom that impairs their daily activities with prevalence estimates ranging from about 25% to 45% of those patients.

There are only two anti-psychotics approved for the treatment of irritability associated with autism spectrum disorder, and two anti-psychotics approved for the treatment of bipolar depression in the pediatric population. We believe lumateperone, with its efficacy and favorable safety profile, if approved, can address the important medical need for these younger patients and their families, especially given the heightened concern regarding metabolic and motor issues these patient populations.

Additionally, in the first-half of 2024, we will continue to advance our long acting injectable lumateperone program studying four different formulations. In summary, we continue the very successful launch of CAPLYTA, and are confident in the continued robust growth throughout 2024.

CAPLYTA is an important treatment option for patients with bipolar disorder and schizophrenia. These conditions account for about 50% of the U.S.

anti-psychotic market's nearly 68 million scripts each year. With the potential addition of MDD, our total addressable market would expand to cover nearly 80% of the market's prescriptions.

In addition, we expect our development programs among younger patient populations and our work with long acting injectables to further maximize the value of our lumateperone portfolio. Outside of lumateperone, our pipeline continues to move forward with several clinical trials underway, and others commencing soon.

ITI-1284 is an important product candidate in our neuropsychiatry portfolio. In the first-half of 2024, we plan to initiate patient enrollment in Phase 2 clinical trial.

Starting with our generalized anxiety disorder program, our first study will evaluate 1284 as adjunctive treatment to SSRIs and SNRIs. Also in the first-half of 2024, we will begin clinical conduct to evaluate ITI-1284 for the treatment of psychosis in Alzheimer's disease and agitation in Alzheimer's disease.

In our phosphodiesterase I inhibitor program, our Lenrispodun Phase 2 clinical trial in Parkinson's disease is ongoing, and we expect to complete enrollment in late 2024, with top line results expected in the first-half of 2025. With respect to our ITI-1020 oncology program, our Phase 1 single ascending dose study in healthy volunteers is progressing.

Our earlier-stage development programs include ITI-333 for opioid use disorder and pain, for which a multiple ascending dose study and a positron emission tomography study are both ongoing. Also in development is our non-hallucinogenic psychedelic program.

This past December, at the American College of Neuropsychopharmacology, we presented the preclinical data from our lead compound, ITI-1549. We are very encouraged by the positive reception our presentation received from the scientific and medical community.

And we look forward to advancing ITI-1549 into human testing in late 2024 or early 2025. In 2023, we presented new CAPLYTA data regarding our development programs at several medical and scientific meetings.

We also published results in various medical journals, demonstrating our progress throughout the course of the year. Looking ahead to 2024, we are starting off operationally and financially strong.

As of December 31, 2023, we had approximately $500 million in cash, cash equivalents, and investment securities, and we have no debt. I'm incredibly proud of our team and our accomplishments, and I'm excited to embark on our next phase of growth in 2024.

I will now turn the call over to Mark to further discuss CAPLYTA's performance and our plans for 2024. Mark?

Thanks, Sharon. Good morning, everyone.

It's great to be with you today. 2023 was a year of tremendous progress in establishing CAPLYTA as the leading treatment option for patients with bipolar depression and schizophrenia, setting the stage for continued robust growth in 2024, and beyond.

We continue to work our way up the physician adoption curve, adding more than 15,000 new first-time prescribers of CAPLYTA during the year, and growing the breadth of our cumulative physician prescriber base since launch to over 36,000 by the end of the year. We also saw consistent quarter-over-quarter increases in the depth of prescribing as existing prescribers identified more and more patients who were appropriate for CAPLYTA treatment.

This progress was driven by our comprehensive promotional activities, including the expansion of our sales force executed in Q2 of 2023, extensive peer-to-peer medical education programming, and robust digital advertising. Complementing our professional promotion was a comprehensive consumer and patient campaign featuring broad national advertising through television and social media to enhance awareness among the 11 million adults with bipolar disorder and to communicate the potential benefits of CAPLYTA for these patients.

For the year, CAPLYTA posted strong growth, increasing total prescriptions by 85% in 2023 versus 2022, and finishing the year with significant momentum, accelerating growth in total prescriptions to 10% sequentially in Q4 versus Q3. We are well-positioned to drive continued robust growth throughout 2024.

CAPLYTA has a very compelling product profile that features strong efficacy and a favorable safety and tolerability profile. In our clinical studies, CAPLYTA's metabolic parameters, which include changes in weight, cholesterol, and glucose, are all similar to placebo.

Equally important, movement disorders, like EPS and akathisia, are also similar to placebo. CAPLYTA's favorable profile is very important, as these side effects can often lead to poor patient compliance and drug discontinuation.

Another real benefit we hear from physicians is that they can start their patients at the effective dose without having to titrate. Instead of waiting days or weeks to complete that process, physicians also appreciate the convenience of CAPLYTA's once daily dosing.

In 2024, we will continue to invest in optimizing the growth of CAPLYTA with several enhancements to our comprehensive promotional plan. As I mentioned previously, we added approximately 50 additional sales representatives late in Q1 of 2023, and those representatives are now firmly established and contributing significantly to our growth.

We've also had consistently favorable results from our comprehensive direct-to-consumer platform, and we will continue these efforts throughout 2024 with a new creative campaign being introduced in Q2. Finally, we continue to enjoy a strong market access position with over 99% of Medicare and Medicaid lives covered and about 90% covered commercial lives.

As I mentioned in our last call, from the end of Q3 2023 and the beginning of the fourth quarter, we negotiated an improvement in the utilization criteria for CAPLYTA with two of the largest Medicare Part D payers. We were able to move CAPLYTA from a prior authorization and two generic steps to unrestricted status with these plans.

We've already seen some initial benefits from this in the fourth quarter, and we expect to see the full impact of these changes this year. In summary, we made tremendous progress with CAPLYTA in 2023, and we are confident that CAPLYTA's favorable product profile, and our incremental promotional investment behind the brand will result in a robust year of CAPLYTA growth in 2024.

I'll now turn the call to Larry to discuss our financial performance. Larry?

Thank you, Mark. I will provide highlights of our financial results for the fourth quarter and year ending December 31, 2023, and our outlook for 2024.

In the fourth quarter, net product sales of CAPLYTA were $131.5 million compared to $87.4 million for the same period in 2022, representing a year-over-year increase of 50.4%. Our increase in net product sales was primarily driven by strong underlying prescription growth, a 55% increase versus the same quarter in 2022, and a 10% sequential increase over the third quarter of 2023.

This increase was partially offset by a higher gross-to-net percentage in the fourth quarter that was at the high end of the low 30s, still in line with our prior guidance. For 2024, we expect CAPLYTA's gross to net percentage to be in the mid-30s throughout the year.

Q4 inventory levels in the trade, measured by days on hand of CAPLYTA at the wholesale level, remain consistent relative to the prior quarter. For the full-year 2023, total revenues were $464.4 million, compared to $250.3 million in 2022.

Net product sales of CAPLYTA were $462.2 million for the full-year 2023, in line with our guidance. This represents an increase of 85.5% compared to 2022.

SG&A expenses were $409.9 million for the year ended December 31, 2023, compared to $358.8 million for the year ended December 31, 2022. R&D expenses were $180.1 million for the year ended December 31, 2023, compared to $134.7 million for the year ended December 31, 2022.

Turning to our outlook for 2024, as Sharon mentioned, we expect CAPLYTA net product sales to be between $645 million and $675 million, reflecting continued strong demand. For 2024, we estimate SG&A expenses to range between $450 million and $480 million, which include approximately $38.6 million of non-cash share-based compensation expense.

This reflects our commitment to continue to effectively and efficiently support CAPLYTA commercialization through investments in our sales organization and marketing activities. For 2024, we estimate R&D expenses to range between $215 million and $240 million, which includes approximately $22.5 million of non-cash share-based compensation expenses.

Our R&D guidance reflects investments to support our broad pipeline. In 2024, we anticipate that a large portion of our total R&D expenditures will be related to our lumateperone development programs as we continue to explore the use of lumateperone in additional patient populations.

Our financial position remains strong. Cash, cash equivalents, investment securities and restricted cash totaled $499.7 million at December 31, 2023.

This concludes our prepared remarks. Operator, please open the line for questions.

Hey, thanks. Good morning, and congrats on the strong execution and the continued progress.

So, for me, wanted to ask on MDD today, what is your guys' latest thinking in terms of what we can expect to see in the top line release, in April? And then our understanding is that two-point placebo-adjusted change should be a good efficacy result.

But is there anything else you would encourage the Street to also look for as we think about CAPLYTA's potential differentiation in adjunctive MD such as response rates, remission rates, safety profile, anything else? Thank you.

Thanks so much for the question, Andrew, and for the kind words. This is Sharon, and I'll start off, and then I'll ask if Suresh has anything he wants to add.

So, typically, in our top line data what we do put out is all of the information that we have at that point. As you know, these are large studies that we do, and so we don't get all of the top line data -- all of the data at one moment in time.

And since we know how anxious both we and the Street are, we put the data out when we get it. So, we certainly expect the primary endpoint, which is change from baseline on MADRS.

And we'll also put out any other data that we have at that point. And you're right that typically in these studies you expect to see a two to four-point change on the MADRS, but on an adjunctive study you expect to be at the lower end, whereas in monotherapy studies you expect to be at the higher end.

So, that's what we're expecting. We power our studies to approximately 90%.

And so, -- and we obviously, as I said in our prepared remarks, we have confidence, both in our program, in these studies, and on lumateperone's performance in these studies. So, with that, I don't know, Suresh, do you have anything you want to add?

Not at this time. You have covered --

Okay.

Thank you.

Thank you.

Hey, and congrats as well from my end on all the continued progress. Maybe continuing on MDD, can you talk -- maybe give us a little bit more of a sense of the degree of over-enrollment you may have in the study, how that might impact powering.

And then, how are you thinking about, as these results come out during the second quarter, where the most differentiation potential could be here in terms of positioning relative to some of the other adjunctive atypicals in the space? Thanks.

Okay, thanks. So, this is Sharon again, and I'll start with regards to, yes, as we've said, patients come into screening, and we did believe that patients who are in screening who pass through successfully through the screening process should be allowed to enter.

Typically, you plan your studies so that you will have at least the number of patients. Whenever you put a protocol in place you say approximately, like we had approximately 470 patients.

We screen appropriately for that. And we had patients come through.

So, it's a small number of patients. It's typically under 5% that you over-enroll, and that is what fit the bill here, that we allowed to come in that you over-screen, and if they pass you allow to go in.

So, that is what we have. But, of course, you do need to wait for them to complete.

So, it's just a couple of weeks later that they are coming through finishing up the study. And that's why the study will read out in April, rather than in March.

So, I think, I don't know, Suresh, did you want to add anything to that?

Yes, I think they were asking about the [powering] (ph). For this --

Okay --

There is not going to be any powering implications because the number is so small, so I would not expect any powering implications.

Right. And on differentiation, you also asked about that.

And I think that CAPLYTA has demonstrated its efficacy and favorable safety and tolerability profile. And with that, we think that there is a real need in the marketplace for additional agents, and that CAPLYTA can perform well in this marketplace.

Thanks, Sharon. Thanks, Suresh.

Hey, guys, this is Na Sun on for Jess. Congratulations on the strong guidance for CAPLYTA in 2024.

Can you walk us through some of the assumptions that's underlying the guidance? What does it mean in terms of patient penetration?

And then how do we think about the gross to net dynamics in 2024? Thanks.

So, maybe I'll ask Mark if you want to talk to the first part. And then, Larry, if you want to talk to the gross to net?

Yes, sure, Sharon. So, the guidance that we put out, the main driver of that guidance is the underlying strong demand trend that we see in the business, and the continued demand for CAPLYTA.

So, any variation around that trend is really where you get the range in the guidance. We expect to continue to penetrate both the schizophrenia and the bipolar depression market, where we focus both on increasing the breadth of prescribing, our prescriber base, as I mentioned in my prepared remarks.

Last year, we added over 15,000 new first-time prescribers of CAPLYTA. We expect to see that continue in 2024.

As well as, at the same time, across the entire prescriber base, of what is now over 36,000, we expect to continue to see increased depth of writing as these existing prescribers get more experience and they find more and more patients that are appropriate for CAPLYTA. So, those are the main factors that go into the guidance range that we provide.

And I think you also had a question on how to think about gross to net for 2024. So, for that I'll turn it over to Larry.

Yes. Yes, thanks, Mark.

Yes, the gross to net in 2024 is going to be -- we project to be in the mid 30s, and that's compared to the low 30s that we saw in 2023. Now, there are several primary drivers for this increase where we have increases in volume going through the commercial channel as a result the strong uptake in the bipolar program.

Plus, there are also been recent improvements in Medicare Part D coverage. So, those two are main drivers for the increase from the low 30s to the mid 30s.

Yes. Why don't you go ahead with our next call please?

Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our question.

For adjunctive MDD, to what extent does the background ADT influence the placebo effect? And, how should we be thinking about placebo response variability between Studies 501, 502 and 505?

Are the three studies balanced in terms of the background regimens? Thanks so much.

Suresh, would you like to look to that?

Yes. Yes, so, in this program for MDD with adjunctive treatment for MDD, we have allowed SSRIs, SNRIs, and antidepressants to be the background.

And all anti that are approved are allowed into this. So, that the background in terms of you are talking about the placebo response, again in all CNS trails and MDD trails, in particular placebo response we try to mitigate it by taking several measures.

So, this is no different in this study also that we are measures allowing for proper adjudication of patients, making sure that they have a right severity that they are coming in. So, we have taken those measures in terms of the placebo response.

In terms of individual medications, we group them based on SSRIs and SNRIs. Individual medications will not be taken into account and just be taken into account from a -- class wise.

And all of the program -- the whole program has been done the same way. So, we allow--

Yes.

Yes, in each of our studies in depression.

That's very helpful.

And also have in addition to -- in addition all the drugs that are approved also are -- are being done the same way.

Thanks.

Hi, guys. This is Mike DiFiore in for Umer.

Thanks so much for taking my question and congrats on all the progress in 2023. Two from me, one is variation of the question just asked.

In the Study 501, the adjunctive MDD trial seems to have a little bit more diverse set of ex-U.S. countries participating compared to Study 502.

And my question is, could there be any local or regional differences in the way medicine is practiced that makes you more or less confident that the -- in Study 502, it would be successful, given that both trials are designed exactly the same? And I have a follow-up.

Yes. So, this is Sharon.

Thanks of the question, Mike. And I'll start and I'll ask Suresh if he wants to fill in.

We plan all of our studies the same way that are late stage global studies. And, that is you look at the different countries.

And we plan for the U.S. to have a proportion of patients and for ex-U.S.

to have a proportion of patients. And that proportion of patients is typically around 30% U.S.

And then, ex-U.S. fills in.

And this is no different. So, 501 and 502 are the same.

I don't -- I didn't quite get your part of the question where you seem to think there is a difference because there isn't any difference. Some of the countries are different.

But, it's ex-U.S. and U.S.

patient population as per what is common practice and what in discussions with the FDA what they like to see.

Got it. That's helpful.

I am sorry. Do you have anything more to add?

I don't know. Suresh, did you have anything to add?

Again, that's true. We have about 30% coming from the U.S.

and ex-U.S. And, the question about different countries but these are all standard practice guidelines that's pretty observed throughout the world.

So, in terms of the practice guidance and other factors, we look into that and we select countries that have similar practice patterns.

Thank you so much.

Right. And to be clear, I couldn't hear what Suresh said.

I will just make clear. We aim for around 30%, give or take a percent or a two on either side.

Got it. That's helpful.

And my follow-up question is -- and forgive me if I missed this, have you met with the FDA to discuss the mix features data in context of the broader adjunctive MDD indication? And if so, would you be able to offer any commentary or color there?

Thank you.

Yes. Thanks, Mike.

Yes, in our prepared remarks I did say that we did recently have a meeting with the FDA and that it was a constructive meeting, and that as is our practice, we always wait for the FDA minutes before we say anything. And so, once we have the minutes, we will further update you on the program and on final meeting.

So, we are good.

Got it. Thank you.

Thanks so much for taking my question. This will be likely for Mark, congrats on the quarter.

So, can you maybe talk about CAPLYTA's growth trajectory moving into first quarter '24? How should we think about a sequential growth versus fourth quarter given the seasonality?

And maybe additional color on the DTC campaign you plan in 2024? Thanks.

Thanks. Mark, you want to take that please?

Yes, sure. Thanks for the question.

So, we had very strong fourth quarter accelerating our total prescription growth to 10%. So, we come into the year in 2024 with significant momentum in that regard.

Typically as you alluded to in the first quarter, you see some typical headwinds associated with patients switching market access plan when you have a product like ours. With an increasing portion of the business commercial channel, you also have increased copay assistance required as patients deductibles reset for the year.

And then, typically that decreases over the course of the year. So, we feel very good about the momentum we have.

The underlying business, the demand in the business, the reception that physicians have had to the product and the feedback that they provide to us on their experience and the patient's experience, but yes, typically in the first quarter you do see some headwinds, and then in the second quarter, you see a reacceleration and growth. So, that's in general how I would think about the upcoming quarters.

Hi, there. Good morning.

Thank you for taking my question. And congrats on the quarter.

Maybe just if you could talk a little bit on the expected size of the sales force expansion that will be necessary if the MDD indication is allowed to move forward under the label? I know you have had some success in MDD in the primary care setting.

So, would you look to expand a little bit more there? And is any of your expense guidance for 2024 earmarked for expansion for MDD?

Or, that will be more of a 2025 move? Thank you.

Mark, would you like to take that?

Yes, sure. Thanks Joseph for the question.

Yes, so the answer to the second part of the question first. Our SG&A guidance for the year for '24 does not contemplate any material expansion in our salesforce.

We continually evaluate our marketing activities and our salesforce sizing, and we take advantage of any opportunities that we see to fuel additional growth, but in terms of any major expansion, we don't contemplate that in 2024. Once we have the data and we understand that we're on the track for filing and approval, we do expect to increase the size of our salesforce to ensure that we're optimizing CAPLYTA and the growth opportunity we would see in MDD, which is a very significant market.

To give you a little bit of background, for bipolar depression and schizophrenia, we currently target about 43,000 physicians that are primarily psychiatrists and the nurse practitioners that support them and a smaller segment of primary care physicians who do treat a lot of bipolar depression and are high-volume prescribers of antipsychotics. They are included in our current 43,000 physician target list.

As we contemplate an approval in MDD, that target list will increase significantly, and it will increase mostly in the area of primary care, because there are many more primary care physicians who are comfortable treating MDD with adjunctive antipsychotics who aren't very high-volume prescribers for bipolar depression, and certainly not for schizophrenia. And it would be for that group of physicians that we would look to expand our salesforce.

Now the 43,000 physicians that we currently call on will be able to leverage them because virtually all of the 43,000 who are high volume prescribers for bipolar depression will also be high volume prescribers for MDD. And they'll have about four or five years of experience with the brand.

So, we think we'll be able to have a really good jumping off point with that group of physicians. And the extent to which we expand our salesforce will be determined by how far and how quickly we want to go into primary care.

And those are the things that we have been working on. And as we get a little bit closer to the talking about our launch plans, we'll come back to you with more specifics about that.

So, hopefully, that background is helpful for you, and I'll leave it at that for now.

Great. Thank you.

Thanks. So, just two quick ones, one is with the MDD label expansion, can you talk to payer access and particularly how we should think about rebating with commercial plans and the gross to net overtime with MDD in the mix.

So, that's number one. And then, number two, regarding deuterated lumateperone, I wanted to get your early thoughts on how you're thinking about the value proposition here in terms of differentiation from the legacy product, particularly on tolerability and safety, given that the current form of lumateperone is ostensibly pretty well-tolerated and widely seen as pretty safe within the category, so, just wanted to get your thoughts on that.

Thank you.

Great. Hi, David.

Thank you for the question. And maybe I'll ask Mark to start out, and then I'll take the 1284, and I may need to ask you to repeat it if I can't remember it by then, but let's start with Mark.

Yes, sure. Thanks for the question, David.

Yes, for the potential label expansion into MDD, we would expect a pretty seamless process to the addition of MDD to the label when it comes to payer access. In general with the antipsychotic category, the payers manage these products at the brand level, not at the indication level, meaning that whatever your coverage is for the existing indication, that coverage gets carried over to the new indication as well.

That's what we experienced when we moved from schizophrenia to the label expansion for bipolar depression, and we've seen similar dynamics with competitive products who have added MDD to an already existing schizophrenia and bipolar depression label. So, we would expect it to be a fairly similar process, and it's another reason why we expect to be able to get off to a quick start with that potential approval in MDD.

So, with that, maybe I'll turn it back over to Sharon for the second question that you had around 1284.

Great. Thanks a lot.

So, just for those listening who may not be familiar with 1284, let me just remind everyone that 1284 is a deuterated form of lumateperone, where the carbon deuterium bonds are strategically replaced with carbon hydrogen bonds. So, it is a new molecular entity and it's formulated as an ODT-SL to be delivered once a day sublingually.

we have done a Phase 1 program that found that 1284 ODT-SL was very rapidly absorbed into the systemic circulation, was metabolically stable, and resulted in high systemic exposure. Just a minute.

Sorry. So, we have, and you're, you were right to point out that that lumateperone has a very good safety and tolerability profile.

What we have seen with 1284 is that we have seen some things in the PK profile that we think may be even more advantageous, especially as we studied it in a small population of the elderly and other populations based on the PK characteristics that we think make it amenable. And that is, so, in the elderly populations with Alzheimer's disease and the general population with GAD.

So, we think, and that's why we're doing these studies. So, we do believe that there are some advantages to 1284 over lumateperone, and we are doing the studies to confirm that.

And we'll keep you apprised of these studies and of the results as we move forward. So, thanks a lot for the question.

Okay. Thanks, Sharon.

Hey, good morning. Thanks for taking my questions.

First, just Sharon, I just wanted to clarify, so is the thinking that you only need one of these three MDD trials coupled with your mixed feature positive trial to satisfy the efficacy requirement for the MDD filing, I just wanted to get your sense of confidence around that. And then, for Mark, just your current kind of understanding of what's going on in the adjunctive landscape for MDD with these atypical antipsychotics.

Is the Vraylar launch kind of lifting all boats, so to speak, with the different atypical, or is there a market share grab game? I'm just wondering how much of a switch dynamic is involved here with some of the agents.

Thanks.

Great, maybe I'll ask Mark to start and then I'll come in.

Yes, sure, Jason, the dynamics that we're seeing in the MDD space for adjunct of antipsychotics is very encouraging to us in terms of the potential opportunity for CAPLYTA in the future and by that I mean Vraylar has had a very successful launch in MDD significantly growing that market, which is not a surprise to us. But rather is confirmation of what we believe to be a very significant unmet medical need in MDD for an adjunct of antipsychotic with a good efficacy and safety profile.

So, we don't believe it's a share grab. Rexulti'sbusiness does not seem to have been impacted significantly by the launch in Vraylar.

So, we think we're seeing a lot of market growth there. And with successful studies and a successful filing and approval, when we get to the market, we see that as a very, very robust opportunity for CAPLYTA.

And to continue on that, and to answer your first question, our MDD platform is composed of two studies for the treatment of -- for adjunctive treatment and MDD. Having said that, we'll see the readouts on these studies, and hopefully they're both positive; if one is positive and one misses, it depends on why it missed and how it missed, and the FDA looks at the totality of your evidence.

And that's where you asked about the mixed features. The mixed features is not part of the adjunctive MDD program.

However, what happens is the FDA does take into account the totality of your evidence. And so, an example of that is Rexulti, where they had two studies, one hit, one miss, but the FDA looks at the totality of your evidence and they then opine.

And so, I think that's where all of our data, any data you have that we have in MDD will be looked at in our submission. So, I think the very, very strong positive data that we had in our mixed feature studies can only help us.

And I'll leave it at that.

Got it. Okay.

Thank you.

Hi. Thanks for taking my questions.

So, may be just a couple on pipeline, for the LAI, I think the press release mentioned that there was some sad data that you had generated. Just what did that show, and what are these four different formulations that you're going after in this new study that you're starting?

And then for lenrispodun, so Parkinson's can be a big market with different segmentation. Are you trying to position this as a monotherapy or adjunctive?

Or is it going after the early or the late stage disease? Thanks.

Okay. Maybe, Suresh, do you want to start?

Or actually, I can start with the LAI and then turn it over to you for the lenrispodun.

Okay.

I'm sorry, guys. I appear to be losing my voice.

So, we did a Phase 1 study, and what the study showed was, in fact, what we're looking for is a formulation that is good for both a one-month and longer duration. The first study showed, first of all, we can administer it.

This was a sub-cu formulation, but it would not be an ideal formulation to go forward with, certainly for greater than one month. So we went back to the drawing board, and based on what we heard about a sub-Q formulation versus other types of formulations, like IM, also based on the site of injection.

And so, the four formulations that we have prepared look at both sub-Q versus IM and the site of administration, and looking at the ability to deliver the molecule over both a one-month and longer duration. So, that's the answer to your first question, and maybe, Suresh, do you want to talk about our Parkinson's study and the patient population?

Yes. So, the Parkinson's study, the lenrispodun, that study is a study in Parkinson's disease.

We are looking at populations where the primary objective is to look at efficacy of lenrispodun as administered once daily as an adjunctive treatment to existing liver topo therapy. So, the patients must be on stable doses of existing levodopa therapy, and our primary endpoint there is looking at the Hauser diary, that is, increase in on-time without troublesome dyskinesia.

We also are looking at the motor aspects, MDS-UPDRS, part two of activities of daily living. In that study, we are also measuring other multiple things, one, looking at measurements in cognition.

We're also looking at several biomarkers of inflammation. This is important for both Parkinson's and also looking at programs outside of the CNS.

And once we look at the data based on the movement measurements, cognition, and inflammation, our next studies will look into defining what the path forward will be for this program.

Okay. Thank you.

Good morning. Great to see all the progress, and thanks for taking my question.

I'm going to ask a bigger picture one. On your MDD program, you're clearly putting a lot of resources behind it.

So, for the benefit of investors, what would be the latest and most accurate characterization from within the company on whether you view the addition of the MDD indication as a nice to have for lumateperone given the size of the market and unmet need, or is it more of a strategic imperative for the company?

Hi, Sumant. That's an interesting question.

Maybe, I don't know, Mark, would you like to start from a commercial perspective, and then we can chime in?

Yes, sure. That is a very interestingly phrased question, Sumant.

And I guess what I would say is we believe with our current business in schizophrenia and bipolar depression, we are still in the early innings of tapping into the opportunity for CAPLYTA, and we see tremendous opportunities for continued growth in bipolar depression as we continue to penetrate that market. Certainly, MDD is equally a large opportunity with significant opportunities for growth, as I just mentioned in answering one of the previous questions, and we would certainly be excited to add that to our label and have the opportunity to bring CAPLYTA to physicians and patients in the area of MDD as well.

I have nothing to add. I think that's a well-stated and well-stated position of the company.

Thanks.

Good morning. Thanks for taking my question, and congrats on all the progress.

My question is more of a clarification question on your comments on the MDD regulatory plan. Would you say that if one study hits and the other misses, you would still go in for a regulatory submission without waiting for the third one to read out?

And then also just going back and thinking about mixed features, what's your latest thinking about the regulatory path forward, and could you use some of the data from the MDD studies that are going to be reading out to pursue a specific label in mixed features? Thank you.

Hi, Ami. Thanks for the question.

I think it's a little too early to comment on how we're going to proceed until we know what the data is, okay? I will tell you that obviously two positive studies we proceed as planned, one positive study and one negative study.

Again, it really, really depends. It really depends on what happened, why you missed, whether or not -- and we would -- we always submit all of our data to the FDA as soon as we can.

So, I think it's a little bit too soon to answer your questions on what happens if, because it depends on what the data says. And I think we can leave it at that.

There may have been -- was there another question in there, or are we good?

My question was also regarding mixed features and what your latest thinking there is.

Well, as we said in our prepared remarks that we did have a very constructive meeting with the FDA, and as always, we wait for our minutes. And once we have our minutes, we'll come back to you.

Thank you.

Operator, may be another question?

Hey, good morning, Sharon, and team. Congrats on a good year, and thanks for taking our questions.

I'm hopping between calls, so sorry if this has already been addressed. But I wondered what your perspectives were with regard to the possibility of muscarinic agonists being approved for monotherapy in schizophrenia later on this year.

And I guess monotherapy in schizophrenia later on this year. And I guess, I'm wondering if you could provide us a little bit of color on your preparation in terms of differentiation of CAPLYTA relative to those candidates and how you're, addressing the prescriber base at this point.

Mark, do you want to take that?

Yes, sure, Charles. So, we have a great deal of confidence in the product that we have in CAPLYTA.

We feel across both schizophrenia and bipolar depression, we see very strong efficacy, a very favorable safety and tolerability profile, and a dosing regimen that physicians and patients really like. And our focus is on educating physicians and patients to make sure that they're aware of CAPLYTA, they understand the potential benefits of CAPLYTA for their patients, and so that's where we put our energy.

New products potentially being added to the mix for physicians is always a good thing. For patients, as you know, in this category, there's a tremendous amount of churn, what we call churn, meaning patients try one therapy often prior to CAPLYTA.

They would experience side effects either on the movement disorder side or on the metabolic side, and so they cycle through multiple different products. So, for them to have another option to choose from is always a good thing for patients.

I would say for us, more and more of our business, as we've talked about in the past, is coming from bipolar depression, and in the future with a successful MDD study, as we just talked about would be coming from that area as well. So, we don't see a significant impact on the CAPLYTA business of any new entrants coming into the market.

So, I hope that addresses your question, Charlie.

Yes.

Right, and I would like to just add to that that we -- I agree, and we as a company think that any new product that can help patients is great for patients, and as Mark said, especially in schizophrenia, these patients cycle through these products. It is part of the disease state.

So, we think it can be a benefit to patients, and that's terrific. Now, having said that, there are 2.4 million patients with schizophrenia, there is four to five times that patient size in bipolar depression, and there are even more patients with MDD, and our business is growing in the bipolar space, and we expect that to continue.

So, as Mark said, as a summary statement, we really do not expect this to really impact our business at all.

That makes sense, Sharon, and Mark, and it doesn't appear that those agents impact depression at all. So, clear differentiation.

One quick point of clarification, though, given what's going on with regard to acquisitions, I think I know the answer to this question, but the small royalty that you pay to Bristol-Myers that is paid to that company without any input on their part, you just send them a check. They have no role in marketing CAPLYTA at this point, right?

They have no role in marketing CAPLYTA.

Okay. Thanks.

Thank you, everyone, for joining us. I know that we're a little bit over in time, so I'll make it very brief.

I think we are very proud of our performance during 2023, and we're really looking forward to 2024 and look forward to updating everybody as we go forward. So, thanks again for joining the call.

And with that, Operator, you can disconnect.