Intra-Cellular Therapies Inc (ITCI) 2020 Q4 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Intra-Cellular Therapies Fourth Quarter and Year-end 2020 Financial Results Conference Call. (Operator Instructions) As a reminder, today's conference call is being recorded.

I would now like to turn the conference over to your host, Dr. Juan Sanchez, Vice President, Corporate Communications and Investor Relations. Please go ahead.

Good morning, and thank you all for joining us for today's conference call. Our earnings press release provides a corporate update and details of the company's financial results for the fourth quarter and year ended December 31, 2020. This press release crossed the wire a short time ago and 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, Senior 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-19 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 that 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 report. 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, and welcome, everyone, to today's call. 2020 was a transformational year for Intra-Cellular Therapies, and I am proud of our team's successful execution of our commercial objectives and development programs, particularly given the challenging environment that COVID-19 has caused. We successfully launched our first FDA-approved product, CAPLYTA, for the treatment of schizophrenia in adults just as the pandemic began to cause major disruptions in patient care. Throughout the year, we also made substantial progress on our bipolar depression program, and we advanced other clinical development programs.

This year, in addition to our ongoing commercial efforts for CAPLYTA, we are pursuing advances in 3 major areas. First, we look forward to expanding our CAPLYTA label with indications in bipolar depression. We recently submitted the supplemental new drug applications for CAPLYTA and anticipate an FDA target action date in the second half of this year. Second, we will continue our late-stage development programs for lumateperone in depressive disorders. Third, we will continue to advance the clinical development of our long-acting injectable formulation of lumateperone, ITI-333; and our PDE1 inhibitors; as well as ITI-1284, our newly introduced program.

Before I give an overview of our commercial efforts, I want to take a step back and put our progress in the context of our company's mission. ITCI has set out to create better medicines to provide benefit for people who are living with some of the most difficult diseases to treat. We developed lumateperone with strong belief in its potential to help patients living with highly prevalent neuropsychiatric conditions like schizophrenia, bipolar disorder and major depressive disorder. Our first focus was schizophrenia, which affects about 2.4 million adults in the United States. Antipsychotics have side effects that contribute to patients cycling through medicines or discontinuing use. CAPLYTA has demonstrated efficacy and a favorable safety and tolerability profile to help address significant unmet needs in schizophrenia.

Another condition in need of additional treatment options is bipolar disorder with more than 11 million American adults affected by this disorder. Bipolar depression is the most common and most difficult-to-treat manifestation of this disorder but only a few approved therapies exist for these depressive episodes and only one is approved for bipolar II patients and only as a monotherapy.

In addition, there is a large unmet need for patients with major depressive disorder. Each year, more than 17 million adults are affected with this condition in America. However, over 50% of these patients fail to respond adequately to first-line therapies and require additional treatment. There are few antipsychotics approved for adjunctive treatment of depression, and there are safety and tolerability trade-offs with these drugs for patients. In sum, there is a significant need for effective, safe and well-tolerated treatments for these major neuropsychiatric conditions. We believe lumateperone will be an important addition to available options for these patients.

Now let me give you some highlights of the past year. We are pleased with CAPLYTA quarter-over-quarter prescription growth. In Q4, prescriptions grew 77% compared to the prior quarter. Net product revenues of CAPLYTA for the fourth quarter were $12.4 million compared to $7.4 million in the third quarter. For the full year, CAPLYTA generated $22.5 million in revenue. Larry Hineline, our Chief Financial Officer, will provide further details on our financial performance later in our remarks.

We began the year 2020 by hiring our national sales team to launch CAPLYTA, and we strengthened our infrastructure to successfully commercialize our first product. CAPLYTA was launched in late March 2020, coinciding with the start of major COVID-19 disruptions. Our team quickly adapted our commercialization model to include in-person and virtual sales force interactions and medical education. We accompanied those efforts with digital marketing initiatives and direct-to-consumer promotion. In spite of the COVID-19 challenges, we have had a strong commercial launch of CAPLYTA, and Mark Neumann, our Chief Commercial Officer, will provide further details during his remarks.

In addition to launching CAPLYTA, we are proud of our other accomplishments as well. In September of 2020, we reported positive results from Study 402, our Phase III study that evaluated lumateperone as an adjunctive therapy to mood stabilizers in bipolar depression. Lumateperone 42 milligrams met the primary endpoint for improvement in depression. This follows the positive results from Study 404, evaluating lumateperone as a monotherapy. These 2 studies serve as the basis of our sNDA filings for bipolar depression. Both studies demonstrated robust efficacy and a favorable tolerability and safety profile consistent with the findings in all our previous studies.

Looking ahead to 2021, we are positioned to expand our CAPLYTA label. If approved, CAPLYTA would be the first therapy indicated for the treatment of depressive episodes associated with bipolar I or bipolar II disorder, both as monotherapy and as adjunctive therapy with lithium or valproate in adults.

We will continue to make progress in our depressive disorders program this year. Our large late-stage Study 403 is ongoing and is evaluating the antidepressant effect of lumateperone in patients who exhibit mixed features with bipolar depression or mixed features with major depressive disorder. We expect results from this study in the second half of 2022.

In 2020, we began our adjunctive MDD program and anticipate enrolling patients in 2 Phase III studies evaluating lumateperone as an adjunctive treatment in major depressive disorder later this year. In addition, we are advancing our long-acting injectable formulation of lumateperone. Our single ascending dose Phase I study is in progress, and we anticipate initial results in the second half of 2021.

Finally, we are continuing to advance our other pipeline programs. I'd like to start with 1284, which is the most recent addition to our pipeline. 1284 is a deuterated form of lumateperone, delivered sublingually as an orally disintegrating tablet, abbreviated as ODT-SL. ITI-1284 ODT-SL may offer pharmacologic benefits and ease of use for patients, particularly in elderly population. Our recently completed Phase I program found that ITI-1284 was rapidly absorbed into the systemic circulation, was metabolically stable and resulted in high systemic exposure. We plan to initiate studies evaluating ITI-1284 for the treatment of behavioral disturbances in patients with dementia, the treatment of dementia-related psychosis and for the treatment of certain depressive disorders in the elderly. We expect to initiate these studies late this year and next year.

Next, I'll discuss our phosphodiesterase type 1 inhibitor program. Our PDE1 inhibitor program is focused on diseases in which the PDE1 enzyme is overexpressed and/or abnormal immune cell function contributes to disease pathology. This provides opportunities to pursue innovative treatments for multiple diseases, including Parkinson's, heart failure and other disease states. We have already reported positive results from Phase I/II studies, evaluate lenrispodun, formerly known as ITI-214, in patients with Parkinson's disease and in patients with chronic systolic heart failure. We plan to advance lenrispodun into a Phase II clinical study in Parkinson's disease later this year.

Another program in our pipeline is our ITI-333 platform with ITI-333 , our lead compound, in development for the treatment of opioid use disorder. We initiated a Phase I single ascending dose study, evaluating the safety, tolerability and pharmacokinetics of ITI-333 in healthy volunteers. We anticipate results from this study in the second half of this year. We look forward to providing more details on these programs and our pipeline during an R&D Day which we anticipate conducting in Q3. Finally, we ended the year with approximately $659 million in cash, cash equivalents and investments. Larry will provide additional details in his remarks.

In summary, I'm very proud of all our accomplishments in the past year, and I look forward to continued growth and expansion in the year ahead.

I'll now turn the call over to Mark Neumann for details on our commercial efforts. Mark?

Thank you, Sharon, and good morning, everyone. Looking back on the year, ITCI delivered strong commercial execution, enabling a successful launch of CAPLYTA, even in the midst of the COVID-19 pandemic. In late March, we pivoted from an in-person commercial launch to an all virtual one in very short order. Our team demonstrated agility, creativity and ingenuity to adapt to the new commercial environment that COVID-19 created. As Sharon mentioned, we deployed a hybrid model of in-person and virtual programs for sales interactions and medical education. We also increased our digital marketing initiatives and direct-to-consumer promotion. These efforts were clearly successful based on the performance of CAPLYTA in the market.

CAPLYTA's market access position continues to be strong with coverage standing at more than 95% of covered lives in both Medicare Part D and State Medicaid. These are the major payer channels in schizophrenia, representing approximately 70% to 85% of all prescriptions for schizophrenia. Our LYTAlink patient support program continues to be highly competitive and effective in assisting prescribing physicians and eligible patients to gain access to CAPLYTA.

We have seen consistent robust prescription growth since launch, and this performance extended through the end of 2020. Specifically, during the fourth quarter, CAPLYTA's total prescriptions increased 77% relative to Q3. Keep in mind, this was during a time when the overall antipsychotic market was essentially flat because of COVID constraints. And while COVID continues to impact patient care, we are confident that CAPLYTA's prescription numbers will continue to grow.

We're also very encouraged to see that both patients and doctors continue to report highly positive experiences with CAPLYTA. In market research surveys, CAPLYTA prescribers rated higher for overall drug performance compared to other branded antipsychotics that have been on the market for a much longer period of time. They highlight the efficacy and favorable metabolic weight and movement disorder profile and the ease of reaching a therapeutic dose with no need for titration.

Another indicator that CAPLYTA is being well received by patients is the rate at which they are refilling their prescriptions. We are pleased with the refill rate for CAPLYTA, showing that many patients who have started CAPLYTA tend to stay on it longer than we see for other products at the same time in their launch. We are extremely pleased to see our product performing so well in the marketplace, and we will continue to adapt our commercial efforts to the fluid COVID environment in 2021 to bring CAPLYTA to even more adults with schizophrenia.

As you heard from Sharon earlier, we are also looking forward with great anticipation to our potential label expansion in bipolar depression later this year and are well into our commercial planning for this exciting opportunity. Today, there are only a few approved treatment options for this underserved patient population. We expect the introduction of lumateperone to be a welcome addition to this market because it has demonstrated robust improvement in depressive symptoms and a favorable safety and tolerability profile and has the potential to be approved for the broadest range of patients. We plan to make the appropriate additions to our sales force in advance of the bipolar depression PDUFA target action date, and we will be prepared on day 1 to seize this opportunity.

We are proud of the strong commercial execution of the team and our successful launch of CAPLYTA. We continue to be very pleased by the CAPLYTA growth trajectory, and our team will be ready to expand our commercial efforts to help even more adults with schizophrenia and patients with bipolar depression going forward.

I will now turn the call over to our Chief Financial Officer, Larry Hineline.

Thank you, Mark. I will review our financial results for the fourth quarter and for the year ending December 31, 2020. In the fourth quarter, we recorded net product revenue of CAPLYTA of $12.4 million compared to $7.4 million in the third quarter. No net product revenues were reported in the same period of 2019.

Research and development expenses in the fourth quarter of 2020 were $14.3 million compared to $19.1 million for the same period in 2019. This decrease is due primarily to a decrease in manufacturing expense and a decrease of lumateperone clinical and nonclinical expenses.

Selling, general and administrative expenses totaled $58.3 million for the fourth quarter. This is compared to $22.8 million for the same period in the prior year. This increase is primarily due to an increase in sales-related labor expenses and commercialization expenses.

Net loss in the fourth quarter was $60.7 million compared to a net loss of $40.6 million for the same period in 2019.

For the year, total revenues were $22.8 million and CAPLYTA net revenues were $22.5 million. No net product revenues were reported in 2019. Research and development expenses for the year ended 2020 were $65.8 million compared to $89.1 million for 2019.

Selling, general and administrative expenses for the year ended 2020 were $186.4 million compared to $64.9 million for 2019. Selling expenses for 2020 were $132.5 million as compared to precommercialization expenses of $32.5 million in 2019. General and administrative expenses for the year were $53.9 million as compared to $32.4 million for 2019.

Net loss for the year ended 2020 was $227 million or a loss of $3.23 per share compared to a net loss of $147.7 million or $2.68 per share for 2019.

Cash, cash equivalents, restricted cash and investment securities totaled $658.8 million at December 31, 2020.

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

(Operator Instructions) Our first question comes from Umer Raffat with Evercore.

This is Bo for Umer, 2 if I may. First is, could you give us some color on the data package for the bipolar depression sNDA? And particularly, we are curious to know whether there is any updated drug-drug interaction study of the UGT inhibitor such as valproate co-administered with lumateperone. And maybe a follow-up question for Mark is on the commercial. Could you give us some updated thoughts on the duration of treatment? And you mentioned the continued prescription rate in your prepared remarks, which is comparable for Latuda and Vraylar. Should we then think about the duration of treatment is also similar to these antipsychotics?

Thanks, Bo, for the question. I'll start. This is Sharon, and then I will ask Suresh if he'd like to add anything. So you've asked us for some color on our data package. So yes, we have submitted our sNDAs for the treatment of bipolar depression. And yes, there is updated information on the UGT's interaction. And in our studies, we have not seen interaction, and we think this is great news. And so we have submitted all of our data, and of course, this will be part of our label discussions.

Suresh, would you like to add anything on that?

No. Nothing further to add that, in fact, that we did submit the information to the FDA.

Yes. And then I think the second part -- so I hope that answers the first part of your question. And then the second part of the question is -- you directed towards Mark. So Mark, would you like to take that, please?

Yes, sure. Thanks, Sharon, and good morning, Bo. Thanks for your question about duration of therapy. And yes, this has been a very encouraging part of the launch thus far with CAPLYTA. And what I would say, it is still too early to do sort of your classical compliance and persistency curves. We'll need several more months to be able to do that. However, what we are tracking very closely as an interim metric is the TRx to NRx ratio.

And when we do that for CAPLYTA, and we compare that to other recently launched oral antipsychotics at the same time in their launch, we find that CAPLYTA is actually outpacing those antipsychotics in terms of the refill rate and in terms of the TRx to NRx ratio. And we find that very encouraging and consistent with the hypothesis that we had that the safety and tolerability profile for CAPLYTA would be received well by patients and allow them to stay on their therapy. So it's something we'll continue to watch. And as we get more information around compliance and persistency curves, we'll share that information with you as well.

Our next question will come from Charles Duncan with Cantor Fitzgerald.

Sharon and team, congrats on a great quarter and the pipeline expansion. I had a question on commercial and then one on the pipeline. Quickly on commercial. Regarding -- the traction you're getting with prescribers looks good. But I'm wondering if, for this year, your goal is to focus on new prescribers for deepening the use or prescription of lumateperone or CAPLYTA within a prescriber's base. And then I'll come back and ask a pipeline question.

Mark, do you want to take that?

Yes, sure. Thanks, Charles. And what I would say is we have been pleased overall when we look at both the breadth and the depth of prescribing that supports the growth trajectory that we've seen on CAPLYTA thus far in launch. The answer to your question is we will continue to look to both extend the breadth of prescribers. But also those who have already tried CAPLYTA, we will be seeking to increase their depth of prescribing as well.

And one of the things that is very encouraging to us is the really favorable feedback that we get on the experience that both patients and physicians have been having with CAPLYTA early on in the launch. As you know, early on in the launch, you want them to have a very positive experience with the medicine, and when they do, then they're more likely to increase their depth of prescribing, and that's something that we'll build upon that success that we had in 2020 as we go throughout 2021 as well.

That makes sense. On the pipeline, just quickly, it's a 2-part question, I apologize for that. One is on bipolar. I just -- I'm trying to work out the timing, and it seems like the recent press release was very likely driven by the acceptance of filing. So could I assume time lines if an sNDA takes only roughly 6 to 10 months that, that could -- PDUFA date could be in the third quarter? And then as a follow-up to that, in terms of pipeline expansion, the DRP, the 1284 program looks very interesting to me. And I'm just kind of wondering if you could provide a little more color on the target product profile for a deuterated or an ODT form of lumateperone. And what is it that you'd really like to achieve for that particular patient population, the elderly patient population?

Okay. So you asked a bunch of questions. I'll start with the bipolar timing. I can then either start -- either go on to the 1284 question, or maybe both Suresh and I will take that one because I'm not sure I wrote down the entire question. But on the bipolar timing, on our press release, what we announced was that we submitted recently. So I think that -- and we have guided to expect a standard review, which is a 10-month review. So you can work out the numbers and see where that takes you, okay? So that's on the bipolar timing.

On our ODT, it is -- 1284, as you know, is a new molecular entity. And we believe it is well suited to study in the elderly population based on its pharmacologic characteristics. In our recently completed Phase I program, we did find that 1284 was rapidly absorbed into the systemic circulation, was metabolically stable and resulted in high systemic exposure. In these studies, we didn't report -- there were no serious adverse events in either group. And in the elderly cohort, the reported adverse events were infrequent, with the most common adverse event being transient dry mouth.

Suresh, do you want to add to that at all about 1284?

Yes. In terms of the safety profile, you're correct, there is in that -- that was safe and well tolerated. There was no adverse -- serious adverse events. And in fact, the elderly population had infrequent -- common adverse events were mainly transient dry mouth. And we are also -- the orally disintegrating, it allows for use in elderly population. We are pursuing indications in the elderly population. And we are mainly looking at behavioral disturbances in patients with dementia, treatment of dementia-related psychosis and treatment of certain depressive disorders in the elderly.

Our next question will come from Brian Abrahams with RBC Capital Markets.

This is Leo on for Brian. I guess I was curious about thinking ahead to the commercial performance in 2021. How are you thinking about adjusting your hybrid strategy or a potential shift in the pandemic towards a greater reopening to try to drive a greater sales inflection in CAPLYTA? And then sort of as a follow-up to that, as you look ahead to the bipolar launch and you've been interacting with prescribers, what's the sort of physician interest on the ground for the bipolar launch? And do these physicians care equally for the same factors as in schizophrenia, like the low AE profile? Or might they be interested more in other aspects such as the ease of dosing or the efficacy?

Leo, great questions. I'll ask Mark. Would you like to address them, please?

Yes. Sure, Leo. Thanks for your questions. And yes, what I would say about our commercialization model is we feel very good at this stage about the hybrid model that we have in place. And again, the hybrid model means that our -- both our sales representatives as well as our speakers who do our promotional talks about CAPLYTA are equipped to do that either in an in-person environment, which is what they've always traditionally done over the years, or because of what's happened with COVID to pivot to a virtual environment if they can't access physicians in an in-person manner. Now we would always prefer the interaction to be in-person. There's no substitute for that. But our representatives and speakers have become very adept at delivering their presentations in a virtual environment through Zoom, telephone, other mechanisms like that.

And so what I would say is we're actually -- I would say we're optimized for -- regardless of the environment that transpires with COVID. So COVID continues to be with us. It continues to impact patient care, and our representatives are operating very effectively. There's reasons for optimism that the COVID cases are beginning to come down, and we'll begin to see the market open back up. Physician offices become more accessible, clinics becoming more accessible, et cetera. And when they do, our representatives and our speakers will pivot back to in-person engagements. But we do believe that there will be a permanent change in the commercialization model where we will supplement those in-person engagements with active digital engagement both by the representatives as well as through our other digital marketing initiatives. So we think we're poised and we're well placed to make that transition back to a post-COVID world, if you would, and be very effective in doing that.

The second part of your question around bipolar, from a commercial perspective, prior to an approval, our sales force, speakers, et cetera, do not engage on bipolar depression at all as it would be off-label. So I can't really comment on any feedback that we're getting in the field on bipolar depression. I can say in the market research that we do physicians recognize that some of the dynamics that exist in the schizophrenia marketplace where you have limitations of the current antipsychotics because of side effects and the cycling of those patients through other antipsychotics also exist in bipolar depression.

And we believe that the favorable safety and tolerability profile that was seen in our bipolar clinical trials pretty much replicates what we saw in schizophrenia, and that safety and tolerability profile has been very well received by physicians in the marketplace for schizophrenia, and we would expect that to continue once we get the indication for bipolar depression as well. So I hope that answers your 2 questions. If there's anything that I can clarify, just let me know.

Our next question will come from Ashwani Verma with Bank of America.

So I had 2. For the ITI-333, which we are pursuing for opioid use disorder, is that similar to the target product profile of VIVITROL, which is for opioid dependence? Or are you using a slightly different approach? That's one. And as far as the LAI, are there any specific attributes to the molecule that make it easier, difficult to formulate, in this kind of a formulation? You're aiming for a 1-month dosing, so is that driven by luma's profile or also factors in the competitive landscape?

Great. Great. So I'll take that, and ITI-333 is a very different molecule from VIVITROL. First of all, it is a new opioid partial agonist with very low intrinsic activity. It does not have substance -- any substance use associated with it at all. It is also a 5-HT2A antagonist. So it is a totally different mechanism of action from VIVITROL, so no comparison there.

In terms of the LAI, yes, there are some characteristics. We have several formulations of our LAI, and that's because it wasn't -- this was not an easy molecule to formulate for an LAI. It took a lot of development, but we do believe that we have -- as I said, we have several formulations. However, we do think that the formulation that we're testing is an optimal formulation, and it is administered subcutaneously. So we think that is an advantage. Patients have expressed a choice for a subcutaneous over an IM injection.

If you asked another part of the question, I can't remember it. So maybe -- does that answer your question? First -- the first formulation is that we're testing it as a 1-month formulation, and then we will go from there to other durations.

Our next question comes from Jessica Fye with JPMorgan.

This is Daniel Wolle for Jessica Fye. Two questions for me. One, while we understand that you haven't provided guidance for 2021 revenue, how comfortable are you with consensus numbers? And two, regarding 1284, how does the PK profile compare with that of lumateperone? Besides rapidly developing, are there any other properties that makes it amenable to treat the indications that you are currently interested in dementia and others?

Right. So thank you, Daniel. Earlier this year, we did say that we were comfortable with consensus numbers, which are 110 -- about $110 million, and we remain comfortable with those numbers. So that's your first question. We anticipate a strong build over the course of the year and particularly in the second half of the year when, as Mark stated, we anticipate COVID disruptions to be improving markedly. So we are comfortable and we are comfortable with our numbers.

Moving to 1284. I think that we've said that we do believe that there -- that both the molecule and the formulation of 1284 has some advantages to it for use in -- especially, in particular, in elderly patients because it's rapidly absorbed into the systemic circulation. It's metabolically very stable and it results in high systemic exposure.

Our next question will come from Sumant Kulkarni with Canaccord.

My first one is actually a very specific one on 1284. Could you frame how dosing may have looked like relative to regular lumateperone in Phase I data that you've generated so far? And then more specifically going forward, was it the low dose that was used in the prior trial in older patients? And the second part of that is, is it fair to assume that you'll be using a 505(b)(2) pathway for this new molecular entity?

Sumant, that's a lot of questions. So in dosing relative to Phase I, we did a single ascending dose study. So we did test to dose this in a single ascending dose study and then in a multiple ascending dose study as well, where it was dosed once-a-day for 7 days. I think as far as the regulatory pathway, this is a new molecular entity. We will have discussions with the appropriate regulatory authorities on that regulatory pathway as we move forward. And we'll let you know as soon as we know.

Got it. And then just on the dosing in a Phase II or Phase III trial relative to the low dose of lumateperone that was used in the elderly patients in the prior trials?

Can you wait till we put it on clinicaltrials.gov, please, what our dosing strategy is going to be? I think we'll do that soon. I would rather -- I'm always uncomfortable of saying what we're going to do until we do it. So you know that from us. We're very conservative, and we will publish it on clinicaltrials.gov as we go forward into Phase II studies on these different indications, which may be the same or may differ in the indication. The dose may differ depending on the indication, and we'll let you know.

Our next question will come from Bert Hazlett with BTIG.

So I just have another question on 1284, 2 actually. First of all, you talked about it stabilizing lumateperone. Does it alter -- specifically alter the formulation persistence or behavior of any of the metabolites of lumateperone? And then secondly, could you remind us of the IP that you expect for lumateperone? How long do you expect exclusivity?

Let me -- can you state the first part of your question again? I missed it.

Yes. Lumateperone has a number of metabolites, as you're well aware. I'm just wondering whether the deuterated version alters the formulation persistence or any of the behavior of any of the metabolites of luma. And then again, the IP, how long are you expecting exclusivity for lumateperone?

For lumateperone or for 1284? Well, I can tell you both. So there are no new metabolites in 1284, and we qualify all metabolites. And again, as we go forward, we can describe the metabolite profile for you. We do have robust patent profile for both lumateperone and 1284. So I think that if you're asking 1284 is into the 2040s. And lumateperone is very solid into the mid- to late 2030s.

Our next question will come from Graig Suvannavejh with Goldman Sachs.

Congrats on the quarter. I've got 2, please. One, I know it's early days, but I'm curious about your MDD program, and I know you're expected to initiate studies 501 and 502. I was wondering if you could just help us think about what that clinical Phase III trial program overall is going to look like in terms of expected time lines if we were to start thinking about perhaps adding revenue. Just trying to get a sense of what the time lines look like here. And how does the 403 study, if it all, fit in supporting that registrational program? And then my second question is maybe more on the financials and looking at 2021. I was wondering if you could provide a view on what the quarterly progression of OpEx spend will look like with respect to R&D and SG&A.

Yes. So our adjunctive studies, 501 and 502, are studies looking at major depressive disorder as adjunctive to standard of care. And as we said, there are 2 studies. Clinical conduct will begin this year. And I think you should expect 2 years for enrollment and readout of these studies. That is what is typical for these kinds of studies. They are conducted globally, including the U.S. And we will post them on clinicaltrials.gov as we start each of these studies.

Then I think you asked -- before you get to the financials, I think the easy one on the financials is we are not giving quarterly guidance on our projections. And maybe, if Larry has anything to add, he can add to that. But...

I think it's -- yes, we're not going to give quarterly -- we can't give quarterly guidance, but I think it's safe to say that, from the R&D perspective, we will see expenses increase over last year's expenses, 2020's expenses, and I would see them increasing quarter-to-quarter. So no particular guidance, but certainly see an incline as we go through 2021.

And Sharon, just to ask if you could comment on how the 403 study sits in the context of what you're trying to do to expand the opportunity for lumateperone.

Right. So it is an expansion, I'm glad you came back to that. It is an expansion of the opportunity for lumateperone. It is not part of the adjunctive studies in MDD. The study 403 is looking at both bipolar and major depressive disorder in patients with mixed features. So before we go further into that, maybe I'll ask Suresh, can you please define for the audience what mixed features are, both in major depressive disorder and bipolar disorder. And then I'll come back and talk about what we think the opportunity is again, okay?

Yes. Thank you. We have -- mix features is a condition that's specified within the DSM-5 for both major depressive disorder and also bipolar disorder. Patients with MDD with mixed features have severity of illness, increased severity of illness. They also have high rate of suicide ideation, high rates of suicide and also the high rates of recurrence of episodes. And also, there is higher comorbidities and these are difficult-to-treat patients. And if these patients are not followed and treated, patients with MDD have a potential to be diagnosed with bipolar disorder later on.

Now coming to the patients with mixed features in the bipolar depression, they also are having the same features, mainly having some symptoms of (technical difficulty) symptoms of mania or hypomania and have full episodes of depression. And about 1/3 of the patients in both populations, both in MDD and in bipolar depression have mixed features. Since these patients are difficult to treat, and right now, at this time, there is no specific medication to treat these conditions, this is a study we are following, the 403, which was amended to include these patients. And this is a fully powered study as a registration study. And it's been conducted to -- once the studies are done, we will speak to the FDA on the next steps regarding this.

So just to follow-up on that, we think this is a large unmet medical need. About 1/3 of patients in MDD and about 1/3 of patients in bipolar disorder exhibit these features. So -- and these patients, as Suresh said, are more difficult to treat, have more comorbidities and have increased rates of suicide and suicidal ideation. So we think that these are important patient populations within each of these domains, and there are no approved drugs to treat these patients. So they keep cycling through all available alternatives until -- that are -- and it's all, of course, off-label until hopefully you stumble on something that is helping the patients.

So we think that with 1/3 of each patient population, that this is a huge unmet medical need and that we will look at the results of Study 403 and go to the FDA with these results and discuss the path forward for the indication. So we're very excited about that as adding this to our label for lumateperone.

I think operator, we might have time for one more question if there's a last question.

Yes, we do have a follow-up question from Umer Raffat with Evercore.

I have a couple, if I may, Sharon. One, theoretically, given everything we know about the aniline metabolite formation and how it blended itself more to that formation in nonhuman models than in human, is there any sort of mechanistic reason to expect why the deuteration would change that, just given everything we've known from the past? And then secondly, as you're thinking about MDD studies going forward and indication expansions, would there be a consideration for possibly promoting the 1284 for those indications and not CAPLYTA?

Yes. So first of all, you can't improve on nothing. So as you know, in human beings, as you said, this -- those anilines are seen in species that are not humans and so you can't improve it on a lack of seeing something. So 1284 is -- does not have aniline formation, neither did lumateperone in humans. So that is not a question.

And the question about other indications for 1284, we are very pleased and comfortable with lumateperone in the present indications that we are studying. We are very excited about the studies that we have mentioned to you with 1284. We will -- as we go forward, we'll keep you apprised of any other indications that we decide to go into with 1284. But for the moment, what we're launching with and the path we're going down right now is the stated pathway that we told you about the lumateperone and the stated pathway that we've told you about for 1284. So stay tuned.

And by the way, just since Evercore is still on, I hope I answered both questions in the beginning about the UGTs. Yes, we're very comfortable. We've had -- we've conducted all of our studies. We've submitted all the information to the FDA. So that kind of dovetails with your questions.

Okay, then. I want to -- I think we're over our time. I want to just thank everybody for participating on the call and thank you for all of your questions. They were very good questions, and we look forward to keeping you apprised. It's a very, very busy year for Intra-Cellular, and we look forward to updating you as we go forward with all of our programs. Thanks very much. And operator, you can now disconnect.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.