Intra-Cellular Therapies Inc (ITCI) 2022 Q1 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to Intra-Cellular Therapies first quarter earnings call. (Operator Instructions) As a reminder, today's conference call is being recorded. I'd now like to turn the conference over to Dr. Juan Sanchez, Vice President, Corporate Communications and Investor Relations. Juan?

Good morning, and thank you all for joining us on the call today. Our earnings press release provides a corporate update and details of the company's financial results for the first quarter ending March 31, 2022. This press release is available on our website at intracellulartherapies.com.

Joining me on the call today are Dr. Sharon Mates, Chairman and Chief Executive Officer; Mark Neumann, Executive Vice President and Chief Commercial Officer; Dr. Suresh Durgam, Executive Vice President and Chief Medical Officer; and Larry Hineline, Senior Vice President and Chief Financial Officer.

As a reminder, during today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy, safety and intended use of the company's product development candidates, our clinical and nonclinical plans, our plans to present or report additional data, the anticipated conduct and results of ongoing and future clinical trials, plans regarding regulatory filings, future research and development, our plan and expectations regarding the commercialization of CAPLYTA, potential impact of the COVID pandemic on our business, and possible uses of existing cash and investment resources.

These forward-looking statements are based on current information, assumptions and expectations. Those are subject to change and involve a number of risks and uncertainties that may 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're cautioned not to place undue reliance on these forward-looking statements, and the company disclaims any obligations to update such statements. I will now turn the call over to Sharon.

Thanks, Juan. Good morning, everyone, and welcome to today's call. I am pleased to present our first quarter 2022 results and to provide an overview of our strong launch of CAPLYTA in bipolar depression. Additionally, I will share our progress with our lumateperone clinical development programs and other pipeline programs.

We launched CAPLYTA in bipolar depression immediately following its FDA approval in late December of last year and we're off to a great start. Following this important label expansion, CAPLYTA's prescription growth has accelerated significantly. In the first quarter, CAPLYTA new prescriptions increased by 63% and total prescriptions increased by 45% compared to the fourth quarter of 2021. Compared to the first quarter of 2021, in Q1 2022 new prescriptions increased by 154% and total prescriptions increased by 134%. Consistent with the strong demand has been the highly positive feedback we are receiving from physicians regarding CAPLYTA's clinical profile in a broad range of patients with bipolar depression as well as their early experience with patients.

CAPLYTA is an important treatment option to help individuals living with bipolar disorder. We are confident in CAPLYTA's continued growth for several reasons. First, CAPLYTA is a novel antipsychotic with a strong clinical profile, which is clearly reflected in its broad label. There are only a few approved treatments for bipolar depression, which affects more than 11 million U.S. adults. CAPLYTA is the first and only treatment approved for both bipolar I and bipolar II depression in adults, both as monotherapy and as adjunctive therapy with lithium or valproate.

Depressive episodes in patients with bipolar I or bipolar II disorder are significantly more common than mania or hypomania and are linked to worse prognosis, greater impairment, decreased quality of life, higher morbidity and increased suicide rates. The prevalence of bipolar I and bipolar II disorder are similar. Bipolar II is often characterized by a higher frequency of depressive episodes that last longer with lower overall functioning than bipolar I. Prior to CAPLYTA's approval, only 1 drug was approved for bipolar II depression.

Second, physicians and patients are looking for effective treatment with favorable side effect profiles, and CAPLYTA has shown consistent efficacy across a broad patient population with a favorable safety and tolerability profile. Bipolar patients consistently identify weight and akathisia as side effects of great concern. Importantly, across our clinical trials, weight gain was similar to placebo and in fact, in our longer-term open-label studies, patients with bipolar depression had no weight gain from baseline to 6 months, while patients with schizophrenia lost an average of 7 pounds in 1 year.

Additionally, fasting glucose, total cholesterol, triglycerides and EPS, including akathisia, were also similar to placebo. In recent market research, psychiatrists highly rate CAPLYTA's performance on efficacy and safety measures.

Third, CAPLYTA's administration is simple and straightforward. It is a once-a-day medication that does not require dose titration with starting doses of therapeutic dose and can be taken with or without food. To address special populations, we recently received FDA approval for the expansion of the CAPLYTA label. This label provides dose adjustment recommendations for patients concomitantly taking strong or moderate CYP3A4 inhibitors and for patients with moderate or severe hepatic impairment. This label expansion allows an even greater patient population to have access to CAPLYTA.

Finally, our confidence about CAPLYTA's continued growth is further fueled by our strong commercial team, their launch execution and the improving market conditions as COVID continues to subside. Mark will provide more details on our launch in a few minutes.

We're pleased to report that total revenues were $35 million for the first quarter of 2022, representing 120% increase over the same period of 2021 and a 36% increase quarter-over-quarter. Larry will provide additional details in our financial performance in his remarks. In addition to our commercialization of CAPLYTA, we have ongoing programs to expand our label to include the treatment of a broad range of mood disorders, including major depressive disorder, or MDD, and mixed features in MDD with bipolar depression. These disorders, which affect millions of patients have important unmet medical needs.

Patient enrollment is ongoing in our registrational MDD studies evaluating lumateperone as an adjunctive treatment to antidepressants. We expect to file a supplemental new drug application with the FDA for approval of lumateperone as an adjunctive therapy to antidepressants for the treatment of MDD in 2024.

In addition, Study 403, our study evaluating the antidepressant effect of lumateperone in patients who exhibit mixed features with bipolar depression or MDD is ongoing. We expect to complete clinical conduct of this study in the second half of this year. We are also advancing our lumateperone long-acting injectable program for the treatment of schizophrenia, which is currently in Phase I clinical development, addressing different formulations and additional sites of injection.

In addition to lumateperone, we continued to expand our robust pipeline with ITI-1284 ODT-SL, our phosphodiesterase 1 or PDE1 inhibitors, and ITI-333. In 2022, we are advancing ITI-1284 for the treatment of agitation in patients with probable Alzheimer's disease, followed by studies in dementia-related psychosis and certain depressive disorders in the elderly.

We also plan to begin patient enrollment in a Phase II clinical study of our lead PDE1 compound, lenrispodun, for the treatment of Parkinson's disease shortly. In addition, we have successfully completed a Phase I single ascending dose study for ITI-333 and plan to continue its development with neuroimaging studies to support dose selection for future studies, including a Phase I multiple ascending dose study.

We ended the first quarter with $773.2 million in cash, cash equivalents and investment securities. In January, we received $433.7 million in net proceeds from our public offering of common stock. We have no debt.

Across all our efforts, our goal remains the same. We're developing effective, innovative treatments to improve the lives of patients with neuropsychiatric and neurologic disorders. We're very proud of our team and the progress we've made towards our goals. We're encouraged by our performance to start off the year and look forward to bringing CAPLYTA to increasing numbers of patients in the months ahead. I'll now turn the call over to Mark, who will provide additional details about our successful launch. Mark?

Thanks, Sharon, and good morning, everyone. It's great to be here with all of you today. Following the exciting approval of CAPLYTA for both bipolar I and bipolar II depression in late December, Q1 marked the first full quarter of the launch of our expanded label. And as Sharon mentioned, it has been a very successful initial launch. CAPLYTA has seen a robust uptake and strong upward inflection in prescription trends, growing new prescriptions by 63% and total prescriptions by 45% versus the prior quarter. This strong performance is driven by a well-differentiated product profile, broad market access and successful sales and marketing execution.

Initial feedback from physicians is highly positive regarding the favorable efficacy and safety and tolerability profile of CAPLYTA in bipolar depression. We've seen utilization of CAPLYTA across a broad range of patients, including both bipolar I and bipolar II depression and as both monotherapy and adjunctive use. Newly diagnosed patients are being started on CAPLYTA as well as those switching from other antipsychotics. These switches to CAPLYTA are coming from both branded and generic products.

New patient starts as reflected by new-to-brand prescriptions, or NBRx, have increased approximately 300% following CAPLYTA's bipolar depression approval. New-to-brand prescriptions reflect early adoption by prescribers, and this metric is considered a key leading indicator of future prescription growth. We expect the upward trajectory in new-to-brand prescriptions to continue throughout the launch phase of our bipolar depression indications and are confident in continued overall growth of the brand.

We continue to maintain broad formulary coverage for CAPLYTA, including greater than 98% of patients with Medicare Part D and Medicaid and over 80% in the commercial channel. We expect additional coverage gains in the commercial channel in the coming months.

Since the bipolar depression launch, we have seen a rapid increase in the number of commercial patients being prescribed CAPLYTA and expect to see additional growth in this channel through the remainder of the year. Supporting this rapid uptake, our LYTAlink program is effectively supporting patients through the prescription process as well as minimizing out-of-pocket costs for those with commercial insurance. Our sales and marketing team is executing a comprehensive launch plan and our commercial efforts are sized to optimize the large market opportunity in both bipolar depression and schizophrenia.

During the first quarter, we saw improving market conditions relating to patient visits and physician access for our salesforce. Our salesforce continues to seamlessly execute a hybrid commercialization model, combining primarily in-person presentations with supplemental virtual engagements. These efforts are supported by extensive medical education programming and comprehensive digital initiatives to extend the reach to our target physician audience.

We're also proud to announce our new Let in the Light direct-to-consumer campaign, which we launched in early April. Consisting of a national television ad, social media and other digital initiatives, the Let in the Light campaign reaches out to people suffering from bipolar I and bipolar II depression as well as extending awareness to prescribers. We believe patients with bipolar disorder are particularly receptive to this type of campaign because they are typically well informed and vocal about their depressive symptoms and side effects with their existing antipsychotic medications, and they are proactive in discussing these concerns with our physicians.

In summary, I'm very pleased with our current growth trends and the feedback we are hearing from healthcare providers and patients, and I'm excited about our future growth. We have a strong commercial plan in place, and our team will continue to execute to drive results. I'll now turn the call over to Larry. Larry?

Thank you, Mark. I will now provide a summary of our financial results for the first quarter ending March 31, 2022. Total revenues in the first quarter grew to $35 million compared to $15.9 million in the first quarter of 2021. In the first quarter, we recorded net product revenue of CAPLYTA of $34.8 million compared to $15.6 million for the same period in 2021 and $25.5 million in the fourth quarter of 2021. The first quarter of 2022 gross to net percentage was in the low 30s, consistent with our prior guidance.

As Mark mentioned, we had an increase in the number of patients in the commercial channel since the bipolar depression approval. This, together with standard Q1 seasonal payor dynamics, contributed to the gross to net increase over prior quarters. We expect CAPLYTA's gross to net percentage to remain consistently in the low 30s throughout 2022. Cost of product sales were $3.2 million in the first quarter of 2022 compared to $1.5 million for the same period in 2021. Research and development expenses for the first quarter of 2022 were $29 million compared to $15.1 million for the first quarter of 2021. This increase is due to higher lumateperone clinical trial and nonclinical-related costs and an increase in non-lumateperone project costs.

Selling, general and administrative expenses were $75.5 million for the first quarter of 2022 compared to $52.6 million for the same period in 2021. This increase is primarily due to an increase in commercialization, marketing and labor-related costs. Net loss for the first quarter of 2022 was $72.1 million compared to a net loss of $52.7 million for the first quarter of 2021. Cash, cash equivalents, restricted cash and investment securities totaled $773.2 million at March 31, 2022, compared to $413.7 million at December 31, 2021.

On January 7, 2022, we completed a public offering of our common stock, in which we sold approximately 10.95 million shares of common stock for aggregate gross proceeds of $460 million and net proceeds of approximately $433.7 million. This concludes our prepared remarks. Operator, could you please open the line for questions?

(Operator Instructions) Our first question or comment comes from the line of Andrew Tsai from Jefferies.

Last quarter, as well as this quarter, you mentioned there are a set of leading indicators that were looking favorable, which helped drive your confidence. Can you kind of remind us one more time what these leading indicators are? Have any of them have slowed down this quarter, or are all of them still trending in the right direction or even accelerating? Just trying to gauge your confidence that momentum should indeed continue to accelerate throughout 2022.

Good morning, Andrew, and thanks for the question. I'll ask Mark to address that, please.

Yes. Sure, Sharon, and thanks, Andrew, for the question. Yes, there's really 3 leading indicators that we look at. First and foremost, we look at our new-to-brand prescriptions, which really represent the adoption of a new medicine or a new indication for that medicine by prescribers and is really considered to be the key leading indicator of future prescription growth. And with new-to-brand prescriptions since we launched the bipolar depression, we've seen about a 300% increase in that metric and that continues to trend in a very positive direction. We're very pleased with what we're seeing in the new-to-brand prescriptions. Another thing we look at is sample demand, samples of the product.

And since the launch of the bipolar indication, we have been getting, seeing a very high level of demand for samples, and that demand is continuing as physicians are identifying new patients to put on CAPLYTA and looking to start them on a sample to assess the effectiveness and the safety and tolerability. And that sample demand is continuing. And then finally, just the feedback that we get from physicians about their current use and their expected future use of CAPLYTA, and those trends are continuing to look very positive as well. To your point, Andrew, across the board, when we look at the leading indicators, they're all pointing in the right direction and suggesting continued future growth of the brand, especially in the new bipolar indication.

Okay. Very good. And a very quick one is, is it fair to assume there was indeed no warehousing effect in Q1, that sales did grow organically through sales reps and marketing or even word of mouth? Yes, I'll stop there. Thanks.

Yes. Sure, Andrew. That's our assessment and that's our belief that there wasn't a significant bolus of patients out there just waiting to be put on another antipsychotic. We believe this is true organic growth. There's a lot of excitement about the new indication for CAPLYTA. There's a great deal of interest and support of the clinical profile and the feedback that we're getting from physicians of their early experience with their patients has also been very positive. All signs are pointing to a very strong launch and that continuing.

Our next question or comment comes from the line of Jessica Fye from JPMorgan.

Mark, you mentioned you expect new-to-brand scripts to continue to grow throughout the launch phase in bipolar depression. I'm curious, how long is a launch phase in your mind? Second question, should we think of net price over the year improving as it is for some other companies when 1Q often has the highest gross to net discounts? Or maybe because your gross-to-net is being driven by a payor mix shift as bipolar depression use grows, could we expect gross-to-net discounts to widen over the rest of the year? Just looking for a little color there. And lastly, I think you mentioned commercial coverage would continue to grow from around 80% now. Where do you see it leveling out and when could you get there?

Sure. Thanks, Jessica. I'll take the first part of the question and the last part of the question and then perhaps I'll turn it over to Larry to make some comments on net price and gross-to-net. In the launch phase, Jessica, it varies depending on the category, the product, the new indication, new launch, etc. But generally, you can look at the first 6 to 12 months of a product indication as the launch phase. And given the strength that we've seen in the new-to-brand prescriptions, we would expect to see that continue during that timeframe, and all signs are pointing to that happening.

In terms of the commercial coverage, yes, we, as we've said before, we've taken the coverage in the commercial channel from about 55% last year, up over 80% at the time of the launch, and we do expect that to continue to climb in the coming weeks and months. And we would expect to see that move up towards the 85%, 90% range, perhaps even higher. And we think that gives us very broad coverage across all 3 of the channels and combined with our LYTAlink program, really provides strong access to the product for patients. That's not a barrier in the marketplace or for the uptake of the product. With that maybe, Larry, I'll ask you to comment on net price and gross-to-nets.

Sure. Jessica, as you know, we've had a rapid uptake of CAPLYTA in the commercial channel in Q1. And as you know, this is essential for a successful launch. But we're also -- this uptake in the channel did result in higher utilization of our co-pay assistance program, which impacts gross-to-net negatively. And secondly, the seasonal payor dynamics. As you see with many other drugs, the impact of co-pay assistance programs is greater in the first quarter of the year due to the seasonal payor dynamics. Now what we see going for the rest of the year, we're in the low 30s in the first quarter, we see it staying in the low 30s for the rest of the year. And one of the reasons is there's less impact of both seasonality and also the impact of the mix of the Medicaid channel as that decreases. There are pluses and minuses, but we expect to stay in that low 30s range for the remainder of 2022.

Our next question or comment comes from the line of Charles Duncan from Cantor Fitzgerald.

Sharon and team, congratulations on a great first quarter. I did have a kind of a follow-up to an earlier question for Mark regarding the market feedback or if he could just really kind of provide us some color on the kind of feedback he's getting from prescribers. What is it about CAPLYTA and its profile in terms of driving adoption for BPD? Is it really on the efficacy side or safety? And then can you provide us any color on [expect] patients regarding persistency in this particular population versus say the schizophrenic patient population?

Yes, sure, Charles. Thanks for the question. And to answer the first part of the question, it really is all of the things you mentioned. What we're hearing back from physicians is that they are very impressed by the proven efficacy, first and foremost, in both bipolar I and bipolar II and the FDA approved indications in both of those disorders. It all starts with safety. It all starts with efficacy. But what they also really highlight as differentiation for CAPLYTA is the safety and tolerability profile. Sharon had mentioned in her initial comments that both weight gain and akathisia are 2 side effects of great concern to patients with bipolar disorder based on some of the limitations of the existing antipsychotics that they have been using.

And in our clinical trial program, changes in weight were similar to placebo with CAPLYTA and akathisia and other EPS measures were also similar to placebo. And physicians are experiencing the same safety and tolerability profile in the bipolar depression patient population as they saw in the schizophrenia population. That gives them a great deal of confidence that they can prescribe CAPLYTA. They'll see the efficacy and they're assured that there is good and favorable safety and tolerability. And then in addition to that, the dosing, a single 42-milligram dose once a day without regard to food, the physician can start the patient on the effective dose without having to titrate over multiple weeks to get to that point and then maintain the patient on that same dose. And that's being viewed very much as a benefit as well. The second part of your question regarding persistency.

What we have seen historically is that patients with bipolar disorder tend to persist with their medication, their antipsychotic, a bit longer than patients with schizophrenia do. And while it's still too early for us to gauge that with CAPLYTA, we do believe that we will see a similar dynamic in patients with bipolar versus those with schizophrenia. And as we get that data in the coming months, we'll share that with you.

Our next question or comment comes from the line of Brian Abrahams from RBC Capital Markets.

Congrats on the launch. I'm just curious if you could expand a little bit more on access for CAPLYTA now that you've expanded to commercial channels. And with regards to just any potential barriers or step edits, what's sort of the average time to get started on CAPLYTA? And then I'm also curious if you could speak about what type of pull through you might expect from the April DTC campaign and when we might see that start to manifest.

Mark?

Yes, sure. Thanks, Sharon. Thanks, Brian. Yes, so we are very pleased with the broad access that we have across all 3 channels, Medicaid, Medicare Part D, and the commercial channel. Depending on the payor, each one has different utilization criteria. Certain plans make CAPLYTA available unrestricted, which means that the physician can write a prescription for CAPLYTA regardless of the indication if they feel that CAPLYTA is right for that patient. There are others that employ an electronic step edit, which means that they first want to see the patient started on 1, sometimes 2 generic products. The dynamic in bipolar is very similar to schizophrenia that the vast majority of patients have already cycled through 1, 2, 3 different antipsychotics, and this happens behind the scenes at the pharmacy, so it's not something that the physician or their office staff needs to do, and it is not a barrier at all to the patient being prescribed CAPLYTA.

And then there are some that have the prior authorization in place. And typically, the prior authorization is the payor just wants to make sure that the patient is being prescribed CAPLYTA for an on-label indication, either schizophrenia or bipolar depression. And we have the LYTAlink program to help physicians and their office staff to navigate that process. And again, it's not a significant barrier to access to the medicine for patients or for the physicians that are prescribing it. In terms of DTC, we're very pleased with the early metrics that we're seeing in terms of interest that is being generated by looking at the increase in searches on CAPLYTA, increased traffic to our website. And we would expect to see the impact of that in -- typically, you see it in a 4 to 8-week period of time after you begin airing your TV commercial, and we're about a month into the airing as we started it in early April. We look forward to that as well.

Our next question or comment comes from the line of Umer Raffat from Evercore.

This is Mike DiFiore in for Umer. I have a 2-parter on the mix feature study, if I may. The design of Study 403 is very similar to that of the adjunctive MDD trials in terms of the primary endpoint. You have MADRS at day 43 as well as in the number of patients enrolled. I guess my question is, since patients with mixed features have greater symptom severity and are harder to treat, is the powering of 403 adequate? And if you can, what are the powering assumptions of that study? Secondly, again, since this population is historically harder to treat, is there any -- what gives you confidence that lumateperone would be efficacy in handling the mania aspects of these trials? And is mania something that we should be more worried about in this disease state?

Good morning, Mike, and thanks for the question. I think -- I was going to start and then have Suresh add comments, but maybe Suresh, do you want to start and first talk about what mix features is so that everyone on the call understands that and then talk about mania and how we certainly monitor for mania as well as depression and then just talk a little bit about our study design.

Yes. Good morning. In terms of the mix features, patients with both unipolar depression, that is major depressive disorder, and bipolar disorder that exhibit manic symptoms or hypomanic symptoms that are below the clinical pressure of these symptoms during the depressive episode. That is the patient population we are studying. Mix features is specified within the DSM-5 and this applies to patients both in the unipolar depression and also in bipolar depression, and they need to have some symptoms of whether mania or hypomania that is below the clinical threshold. And the importance of this is because these symptoms are difficult to diagnose. They have, these patients have greater severity of illness. They have high suicide rates, they have high recurrence rates, and also the high comorbidities and are difficult to be treated with antidepressants. They poorly respond to antidepressants.

Based on our studies in our bipolar depression in our programs that were completed, we looked at a subset of patients with mixed features and where we have seen an effect in mixed features patients, and that's what led us to design the study for our current study. For patients who will diagnostically meet the criteria for mixed features in the current ongoing 403 Study, and the primary endpoint for this is MADRS at week 6 and second, CGI severity as secondary. And these patients include both patients coming in from major depressive disorder as well as from bipolar I or II who have mixed features. And these studies are adequately powered and we are on target right now for completing the enrollment by end of this year.

And then to address your question, Mike, so first of all, we have not talked about the powering of the study. But obviously, it is powered to be able to look at efficacy appropriately. To your question about the mania, we do and we have in all of our bipolar studies, used the Y-MRS scale to monitor for mania. And we don't see patients slipping into mania overall, and we don't, we have not seen that in any of the bipolar subsets either. I think we're very good in knowing that we're not shifting patients into mania.

Our next question or comment comes from the line of Marc Goodman from SVB Securities.

Mark, are these patients, these mixed patients using antipsychotics anyway? I mean, I guess what I'm getting at is, if they're using it anyway, how important is the new indication? How much of an inflection point should we see when you get that indication hopefully when you do? Just trying to understand how much off-label there's already usage there. And then secondly, can you just give us an update on the depression studies, how enrollment is going? Some companies have had some trouble with enrollment. Obviously, it's not just COVID, it's also because of the Russia-Ukraine engagement. Can you talk about that a little bit and how the enrollment is going?

Mark, do you want to take the first part of the question, and then I'll comment on the clinical trials.

Yes. Maybe just to clarify, Marc, when you're asking that question, is that a follow-on question to the mixed features patient population? Or are you talking about the bipolar indication? Okay, I think we -- Marc may have hung up on that. Sharon, maybe I can speak to the bipolar portion of that, and then maybe you or Suresh could speak to mixed features, if that's the focus of Marc's question. For me, as a commercial person, there's really 2 big advantages to a product being on label for a particular indication. One, when a physician sees that a product has passed the rigor of efficacy and safety and tolerability, and an indication for a specific disorder like this, it gives them a lot of confidence that they can use.

And for CAPLYTA in bipolar depression, when they see both bipolar I and bipolar II depression being on label, this gives them a great degree of confidence that the patient in front of them, whether they have bipolar I or bipolar II, CAPLYTA is an excellent choice for them. The second thing for us is that what this allows a commercial organization to do is to engage in promotional activities around on-label promotion, which other companies with products that aren't labeled for that cannot do. For me, there's those 2 big advantages of having something on-label as we do with bipolar I and bipolar II depression. With that, maybe I'll turn it over to Sharon and Suresh to comment on the second part of the question.

Okay, thanks. And I'll start, and I don't know if Marc was able to rejoin or not, but I know it is an important question about what's happening in Russia and the Ukraine and our enrollment in the MDD study. And I think as we've told you before, for all of our studies, our global studies, and what we have done is put in place mitigation strategies whereby we have been able to mitigate the effects of Russia and the Ukraine enrollment. We can tell you that our studies are ongoing. And what we have done is mitigate, again, for Russia and Ukraine, and we are still on track for our filing in 2024 in MDD as adjunctive treatment in depression.

Our next question or comment comes from the line of Sumant Kulkarni from Canaccord.

Nice to see all the progress. I have a couple of quick ones. First, how important is the recent approval of the 10.5 mg and 21 mg strengths in your ability to round out the currently approved indications and potentially target MDD later? And second, on 1284, is it fair to assume that you're ascending dose studies have already led to selection of optimized doses for clinical studies in the elderly that are set to start later this year?

I'm sorry, I have to tell you I missed that. Can you repeat the question, please?

Sure. The first one is, how important is the recent approval of the 10.5 mg and 21 mg strengths? And the second was, on 1284, do you already have optimized doses selected for the clinical studies in the elderly that are set to start later this year?

Great. Okay, thank you. I'll start, and I'll ask Mark or Suresh if they have any comments to add. The recent approvals of 10.5 and 21 mg are for these special populations, those with hepatic impairment and those with CYP3A4 inhibition. That means they're taking other drugs that inhibit CYP3A4. While these are especially for schizophrenia, because it's a smaller population overall, it impacts a smaller number of people. The larger you get in your indication, obviously, the more patients can be impacted. We think that it is an important option for that small percentage of people who need dose adjustments. That's the first answer. And for 1284, we are still looking at certain things like we wanted to look at brain occupancy of different receptor functions for 1284 to ensure that we have selected the appropriate doses for our next studies. I don't know, Suresh, did you want to add anything on the importance of 10.5 and 21 mg?

Yes. I would say that it is important, especially for the special populations. And for those, there is a small percentage of patients who will be on typically 3 or 4 inhibitors or for any severe hepatic impairment. These doses will provide coverage exposure for those populations. In that sense, it is important. One thing I want to remind is, these doses are just for the special populations. They are not doses for any titration.

Our next question or comment comes from the line of Jason Gerberry from Bank of America.

I guess first one, just curious if you guys have seen any impact at all from the competitive launch of Alkermes' LYBALVI to your schizophrenia business? And then my second question is just looking at VRAYLAR gross-to-net, sort of the gross sales versus net sales dynamic, it looks like around 25% to 30% gross-to-net. Just curious like directionally, given that their sales mix is probably similar to how both the Street forecast CAPLYTA sales mix, is that a good kind of medium-term indicator? Again, on a directional basis, not looking for guidance.

Mark, do you want to take that?

Yes. Maybe I can take the first part, and then I'll have Larry comment on the gross-to-net. Jason, yes, we're focused on CAPLYTA. We're focused on serving patients and driving CAPLYTA business. What I would say about our schizophrenia business is we have seen, in addition to very, very strong growth in bipolar depression, we've also seen our schizophrenia business continue to increase and continue to grow. And I think our expectation is that over time as physicians get more and more awareness of CAPLYTA and more and more experience with CAPLYTA in other indications like bipolar depression, there will be a positive halo on their prescribing in schizophrenia as well, and we are seeing those increases in schizophrenia also. With the second part of the question with the gross-to-nets, perhaps Larry you could comment on that?

Yes. I mean, I really can't comment on another company's gross to net. I did mention that our gross-to-nets in the first quarter was in the low 30s, and that was impacted by seasonal payor dynamics and that with some adjustments up and down, we should still see our gross-to-net going forward in 2022 in the low 30s. I don't know if I can give you any more color than that.

Our next question or comment comes from the line of Corinne Jenkins from Goldman Sachs.

I'm curious if you have any visibility on the patients that are coming on to drug in the bipolar indication if those are primarily bipolar I or bipolar II and how this compares to what you might expect given the more limited competitive options in bipolar II in particular?

I'll just start with an overall -- yes, let me start with an overall statement and turn it over to Mark. We're very excited about the bipolar II indication, and we think there is a large number of patients out there who are either misdiagnosed or underdiagnosed who are candidates or may be candidates for CAPLYTA for bipolar II. We think we see the market continuing to grow with the bipolar II indication. With that, I'm going to turn it over to Mark to give further comments on that.

Yes, sure. And I can comment on characterizing sort of the source of business of CAPLYTA in bipolar depression. And I guess the overarching statement is that we are seeing use across a broad range of patients consistent with the product labeling. We're seeing use in both bipolar I and bipolar II depression. We're seeing use as both monotherapy and as adjunctive use. In terms of the types of patients, we are seeing an increase in the newly diagnosed patients being put on CAPLYTA as well as continued strength in those switching from other antipsychotics. And when we dig a little bit deeper into the switching, we find that switches are coming to CAPLYTA from both generic antipsychotics as well as other branded antipsychotics. We view this as a very healthy sign of the launch and utilization across a broad range of patients suffering from bipolar depression.

Our next question or comment comes from the line of David Amsellem from Piper Sandler.

I just had a couple of questions on the payor landscape. Just thinking longer term, do you envision the loss of exclusivity of LATUDA next year as having any sort of impact on access for CAPLYTA at least in terms of hassle-free access, I should say. That's number one. And then number 2, just with overall utilization of atypicals growing considerably in recent years and continuing to grow, do you think there's going to be, over time, a trend towards tighter control of the category? We haven't seen a ton of it over the last decade or so, but do you think that could happen in the next several years just given the sheer volumes here?

Great. HI, David, and thanks for your question. I will start with the loss of exclusivity of LATUDA and will that have a big impact on us and then ask Mark to comment on the utilization strategies going forward. And we don't believe that the loss of exclusivity of CAPLYTA, sorry, of LATUDA, will have a big effect on CAPLYTA. Because first of all, LATUDA has been around for a very long time and many patients have already cycled through LATUDA. We don't imagine that to be a burden for us for patients who, if they have a step through, they will already have stepped through LATUDA as one of the, as a generic. I think that we're not concerned about that. Mark, do you want to add anything to that? Or do you want to go directly to the second question?

Yes. No, the only thing I would add is, particularly in this category over the years as various brands went generic, that specific brand certainly was impacted by the loss of exclusivity, but the other branded antipsychotics were not significantly impacted. I think there's a historical precedent for that as well. And then in terms of the trends moving forward with payor management of this category, we also don't expect there to be a significant shift in how payors manage this category. They're very comfortable managing the category the way that they have. They like to ensure access to a broad range of antipsychotics for these conditions. They recognize there's an unmet need. They recognize that there is a significant amount of churn whereby patients discontinue their existing antipsychotics and they need other effective and safe and tolerable antipsychotics to go to for their next line of therapy. We don't expect there to be a significant shift in how payors manage this category.

Thank you. I'm showing no additional questions in the queue at this time. I'd like to turn the conference back over to management for any closing remarks.

Great. We're very excited about the progress that we have made on our launch for bipolar, for the treatment of bipolar depression. We look forward to continued progress and we look forward to updating you on this progress and on our pipeline as well as we go forward. With that, Operator, you can disconnect.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.