Intra-Cellular Therapies Inc (ITCI) 2017 Q4 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Intra-Cellular Therapies Fourth Quarter and Full Year ended December 31, 2017 Financial Results Conference Call. (Operator Instructions) And as a reminder, today's conference call is being recorded.

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

Thank you, operator. Good morning and thank you all for joining us for today's conference call.

Our earnings press release providing a corporate update and details of the company's financial results for the fourth quarter and full year ended December 31, 2017, 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; Dr. Andrew Satlin, Executive Vice President and Chief Medical Officer; Dr. Kimberly Vanover, Senior Vice President of Clinical Development; Larry Hineline, Vice President and Chief Financial Officer; and Michael Halstead, Senior Vice President and General Counsel.

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 utilization of the company's product development candidate; our clinical and nonclinical plans; our plans to present or report additional data; the anticipated conduct and results of future clinical trials; plans regarding regulatory filings, future research and development, 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 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.

I will now turn the call over to Sharon.

Thanks, Juan. Good morning, everyone, and thank you for joining us for today's call.

Today, I am pleased to provide an overview of our achievements in 2017 and summarize our future plans for 2018 following, which Larry will review our financial results and then we will open the line for Q&A.

During 2017, we made important progress in the development of our lead product candidate, lumateperone as well as in the development of ITI-214, ITI-333 and additional programs.

We are encouraged by our prospects as we prepare our first new drug application or NDA and for the commercial launch of lumateperone, further advance our innovative R&D pipeline and continue to strengthen our leadership team.

Lumateperone is an advanced clinical development for the treatment of schizophrenia, bipolar depression and agitation associated with dementia including Alzheimer's disease.

Following guidance received from the FDA last year, we intend to submit our NDA for lumateperone for the treatment of schizophrenia by mid-2018.

Lumateperone has been granted fast track designation for the treatment of schizophrenia and we have a pre-NDA meeting scheduled with the FDA later this month.

With over 2,000 people exposed to lumateperone today, in 23 clinical trials, we believe our schizophrenia clinical development program provides strong evidence of the efficacy and favorable safety profile of lumateperone for the treatment of schizophrenia.

The schizophrenia efficacy program includes 2 positive randomized double-blind, placebo-controlled trials and supportive data from a third study, all 3 conducted in the United States.

Last year, we completed the first part of our open-label safety switching study in stable patients with schizophrenia and top line data, demonstrating the safety of lumateperone in a real-world setting were presented at the American College of Neuropsychopharmacology meeting held in December, 2017.

This study extends our understanding of the safety and effectiveness of lumateperone.

302 patients with stable symptoms of schizophrenia were switched from standard of care antipsychotic medications to 6 weeks of lumateperone administered orally once daily in the evening then switched back to standard of care.

Importantly, lumateperone is generally well tolerated from the first dose and unlike most antipsychotic requires no dose titration.

Consistent with and extending previous data from our studies in patients with acutely exacerbated schizophrenia, lumateperone exhibited a favorable safety profile in stable patients when switched from other antipsychotic medication.

Statistically significant improvements from standard of care were observed in body weight, cardiometabolic and endocrine parameters. These parameters worsened again when patients were switched back to standard of care medication.

Additionally, treatment with lumateperone was not associated with the motor or cardiovascular disturbances often associated with other antipsychotic medications. These data provide important dosing guidance to healthcare providers on the ease of switching to lumateperone.

In this study, symptoms of schizophrenia did not worsen upon switch to lumateperone. Rather, statistically significant improvement from baseline was observed in the positive and negative syndrome scale or PANSS mean total score.

In addition, greater improvements were observed in subgroups of patients with comorbid symptoms of depression and those with prominent negative symptoms.

Clinical conduct in our long-term open-label safety study is ongoing and is proceeding well.

We made substantial progress last year in furthering our lumateperone Phase III development program for the treatment of bipolar depression. This program consists of 2 monotherapy studies and 1 adjunctive study.

We anticipate top line results from the first monotherapy study, Study 401 conducted in the United States will be available in the second half of 2018 and the top line results from our global monotherapy study, study 404 will be available in 2019.

Subject to the outcomes of these trials, we expect to file an NDA for bipolar depression in the second half of 2019.

In connection with the global strategy of this program, we are expanding our adjunctive study, Study 402 to clinical sites outside the United States and we will provide timelines for this study after completing the expansion.

We are also developing lumateperone for the treatment of behavioral disturbances in patients with dementia, including Alzheimer's disease.

Agitation is highly prevalent and observed in over a half of patients with Alzheimer’s disease and represent a leading cause for institutionalization.

There are no approved treatments for agitation and aggression in this patient population.

Currently, medications are prescribed off-label to manage these behavioral symptoms but are limited by safety and tolerability concerns.

At low doses, lumateperone provides complete saturation of 5-HT2A receptors and also provides modest, but necessary D2 receptor occupancy.

We believe this unique pharmacology offers the potential for effective control of behavioral symptoms in neurodegenerative disorders.

Our Phase III clinical trial for the treatment of agitation in patients with Alzheimer's disease is ongoing.

We expect the outcome of the interim analysis for this trial will be available in the second half of 2018.

We plan to begin late stage studies in depressive disorders with lumateperone in 2018.

In 2017, we presented exciting discoveries demonstrating the molecular mechanism supporting lumateperone's potential as a rapid acting antidepressant.

Specifically, our data show that lumateperone enhances glutamatergic neurotransmission through both AMPA and NMDA channels in the prefrontal cortex by a dopamine D1 receptor activation and activates key proteins in the mTOR pathway.

These findings, in addition to the potent serotonin transporter inhibition, previously described with lumateperone and the robust improvements in depressive symptoms seen in patients with schizophrenia suggest the potential for lumateperone to exhibit potent and rapid antidepressant effects in patients suffering from a wide range of mood disorders, including comorbid depression, schizophrenia, bipolar depression, major depressive disorder and treatment resistant depression.

I would now like to discuss our phosphodiesterase 1 or PDE1 platform and our lead molecule in this platform, ITI-214.

PDE1 enzymes are highly active in a variety of neurologic and cardiovascular diseases and PDE1 inhibitors block this activity.

Parkinson's disease is characterized by reduced dopamine signaling.

Increased PDE1 activity is thought to contribute to the motor symptoms characteristic of Parkinson's disease by reducing the intracellular signaling initiated by dopamine.

Inhibitors of PDE1 restore this signaling. As a result, the use of ITI-214 may avoid the need for dopamine replacement therapy early in the course of disease and enhance its effect later in the disease, allowing for L-DOPA dose reductions delaying the onset of off periods and dyskinesia.

In preclinical models of Parkinson's disease, ITI-214 improved motor symptoms. The mechanism also supports its potential to address nonmotor symptoms prevalent in Parkinson's disease such as excessive daytime sleepiness and cognitive dysfunction.

We're also very excited about the ability of ITI-214 to prevent neural inflammation and act as a neural protectant in preclinical models.

In these models, ITI-214 prevents inflammatory processes and improves the survival of dopamine neurons in the brain. These data suggest that ITI-214 may have utility in modifying disease progression in Parkinson's disease and other neurodegenerative diseases with a strong neuroinflammatory component such as Alzheimer's disease.

Late last year, we initiated a Phase I/II randomized double-blind, placebo-controlled multiple rising dose clinical trial to evaluate ITI-214 in patients with Parkinson's disease.

In this trial, patients received ITI-214 oral doses once daily for 7 days.

The primary objective of this study is to evaluate the safety and tolerability of 214.

Secondary objectives are to evaluate the pharmacokinetic profile of 214 in this patient population and to explore its potential utility to control motor and nonmotor symptoms.

Plasma levels of inflammatory mediators will be assessed as potential biomarkers of neuroinflammation.

Clinical conduct of the third cohort is ongoing, following completion of the first and second cohorts with no safety concerns identified.

We anticipate top line results will be available in the second half of 2018 and will inform the design of future studies to evaluate 1 or more symptom domains.

In addition, the inhibition of PDE1 may represent a novel mechanism for the treatment of heart failure.

Preclinical data have shown the beneficial effect of PDE1 inhibition on cardiac function including increases in cardiac contractility and cardiac output and the potential for attenuation or reversal of cardiac remodeling.

Start-up activities for our randomized double-blind, placebo-controlled study of escalating single doses of ITI-214 in patients with systolic heart failure have commenced and we expect patient enrollment will begin this month.

Shifting to our other programs, we continue the preclinical development of our novel drug candidate ITI-333.

The United States is faced with an unparalleled substance abuse crisis and there is a pressing need to develop new drugs to treat opioid addiction and to provide safe, effective nonaddictive analgesics.

In response to this challenge, our team identified and characterized an exciting drug candidate ITI-333. 333 has 3 key modes of action. It acts as a partial agonist at mu opioid receptors and a 5-HT2A antagonist with interactions at D1 receptors.

In preclinical models, 333 has been shown to attenuate the behavioral effects mediated by morphine while exhibiting potent, naloxone-reversible analgesia. No safety concerns have been noted in animal models including a lack of effect on respiratory and GI function and ability to reverse morphine-induced reduction in GI motility.

We plan to develop 333 for the treatment of opioid and other substance use disorders, pain and mood disorders.

Finally, we ended the year with $464.3 million in cash and investments, which places us in a strong position to advance our development and commercial activities.

I will now turn the call over to Larry, who will review the financial results for the fourth quarter and year ending December 31, 2017.

Thanks, Sharon.

I will be reviewing our financial results for both the fourth quarter and year ending December 31, 2017 and provide an overview of our expectations for the use of our cash and investments.

The net loss for the fourth quarter of 2017 was $30.2 million compared with a net loss of $27.5 million for the fourth quarter of 2016.

Basic and diluted net loss was $0.56 per share for the fourth quarter of 2017, compared to a basic and diluted net loss of $0.64 per share for the same period in 2016.

For the full year of 2017, the net loss was $97.8 million, compared to a net loss of $116.4 million in 2016.

Basic and diluted net loss for the full year in 2017 was $2.12 per share compared to $2.69 per share in 2016.

Research and development expenses for the fourth quarter of 2017 were $26.9 million, compared to $21.2 million for the fourth quarter of 2016.

The $5.7 million increase is primarily due to higher clinical trial related costs.

Research and development expenses for the year ended 2017 were $79.4 million, compared to $93.8 million for 2016.

The decrease of $14.4 million is primarily due to lower clinical trials related cost and to a lesser degree, lower nonclinical and manufacturing cost.

These decreases in 2017 are offset in part by an increase of labor related cost.

General and administrative expenses for the fourth quarter of 2017 were $5.8 million, compared to $7.0 million for 2016.

The decrease of $1.2 million is due primarily to lower marketing and consulting cost and lower stock compensation expense.

General and administrative expenses for the year ended 2017 were $23.7 million, compared to $24.8 million for 2016.

The decrease of $1.1 million is primarily due to lower marketing and consulting cost offset in part by higher capital tax expense.

Cash, cash equivalents and investment securities totaled $464.3 million at December 31, 2017, compared to $384.1 million at December 31, 2016.

In October 2017, we raised gross proceeds of approximately $172.0 million with net proceeds of $162 million in a public offering of our common stock.

For 2018, subject to the timing of clinical trials, regulatory activities, manufacturing, precommercial and other activities, we expect to spend between $180 million and $200 million.

We expect that our existing cash, cash equivalents and investment securities will be used primarily to advance the lumateperone development program, including to fund clinical trials of lumateperone and bipolar depression, behavioral disturbances in patients with dementia, depressive disorders and other lumateperone clinical trials and related clinical and nonclinical activities.

To fund precommercial activities for lumateperone for the treatment of schizophrenia and bipolar disorder, and if lumateperone receives regulatory approval, initial commercialization efforts.

To fund precommercial activities for lumateperone for the treatment of behavioral disturbances and patients with dementia, including Alzheimer's disease, to fund preclinical and clinical development of the company's ITI-007 long-acting injectable program, and to fund nonclinical activities including the continuation of manufacturing activities in connection with the development of lumateperone.

Funds will also be used for other clinical and preclinical programs, including the company's phosphodiesterase PDE and ITI-333 development activities.

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

(Operator Instructions) And our first question comes from the line of Brian Abrahams with RBC Capital Markets.

So I guess, as you look towards -- my first question is, as you look towards the pre-NDA meeting, what level of detail do you expect to receive with respect to feedback coming out of that meeting. How likely is it, do you think that the agency would sort of directly endorse the potential to file based on the 2 positive studies that you have in hand? And when might we expect to, that the details of that meeting to be disclosed to the market? Then I had 1 quick follow-up.

I'm going to ask Andy Satlin, who many of you know and some of you don't. He joined us at the end of last year as our Chief Medical Officer and is heavily involved on our clinical programs and on our preparing our filing for our NDA. So Andy, do you want to take that question please?

Yes. Sure. Thanks, Sharon and thanks Brian, for the question. So the pre-NDA meeting is primarily to discuss the format and content of the NDA including things like how we've done analyses of the data and how we're presenting them in the full package. So we anticipate discussion around that but fairly limited to those types of questions.

Okay. Fair enough. And then just 1 quick follow-up on Luma. So you mentioned that the interim analysis -- there's going to be an interim analysis in the Alzheimer's agitation study in the back half of this year. Just wondering what we should be looking for? Or any sense as to what proportion of the patients this data will be from? Will this be primarily safety data? Or will we see any data from patients on the [CMAIC] endpoint? And from a smaller subgroup of patients, what should we be looking for on that efficacy endpoint? Are there any subdomains of CMAIC that we might start to discern a difference even with smaller patient numbers that we should be looking for?

I'm going to ask Kim to take that question, please.

So we have prespecified our interim analysis in this study in order to evaluate the assumptions regarding the variability of response and effect size. So we can stop the study. We can continue as planned or we can adjust the sample size. So we look forward to being able to execute this interim strategy later this year.

And our next question comes from the line of Jessica Fye with JPMorgan.

With respect to the planned bipolar filing, I think in the second half of 2019, do you expect that to include the adjunct study? Or would it be possible to just file on the 2 monotherapy studies?

Great. Kim, you want to take that?

Sure. So this is really part of our global strategy and as a reminder, we expanded our bipolar program and started our second monotherapy study to be conducted globally. So we were actually really encouraged by investigators outside the United States that in addition to seeing their monotherapy patients, that they also have an adjunctive therapy population and wanted to have a study to offer them. So we decided to expand the adjunctive study to sites globally and we're really pleased that our first monotherapy is on track to report out in the second half of this year, and we would expect to file subject to the outcome of our trials -- file our NDA for bipolar depression in the second half of '19. We'll be providing timelines for the adjunctive study after completing the expansion but certainly part of our overall strategy was to be able to have 2 out of 3 studies to take to the NDA.

I was just trying to clarify, do you need an adjunct study to file? Or is if the first 2 studies in monotherapy are positive, can you just file on those?

Yes, this is Sharon. Let me take that. Yes, you don't need an adjunctive study to file. We're looking for 2 positive studies.

And our next question comes from the line of Ritu Baral with Cowen and Company.

So as we do approach 401 bipolar depression data later this year, how should we think about what success looks like? Sharon, where do you see the unmet need here in efficacy versus safety? And what can a monotherapy study show us? Especially, potentially on the safety side versus standard of care?

Why don't I ask -- thanks Ritu, nice to hear your voice. I'm going to ask Kim to take that, please and then I may add some more color in the end.

So we're really encouraged by the safety profile of lumateperone that we've seen in our schizophrenia program. As you know that this is really, what we believe to be a very favorable safety profile and we had submitted for fast track designation, which was granted last year. We think this will translate very favorably to the bipolar population and this will really address an unmet need. As you may know that patients with bipolar disorder can be even more sensitive to high D2 receptor occupancy side effects than patients with schizophrenia and other antipsychotics have to lower their dose in order to be more tolerable in the patient population. With lumateperone, we have a relatively low striatal D2 receptor occupancy and have seen favorable tolerability in our programs. Sharon, do you want to add?

Well why don't we let Ritu ask and then I can follow-up.

So I guess are you expecting sort of a more robust effect size to emerge from this study because you don't have to down-titrate around side effects? Is that what we should be looking for? Is that fair?

I'll just start and say, I don't think we're -- so first, just to give everybody an overview, there are only a few approved therapies for the treatment of bipolar depression. Many of the antipsychotics are either approved or used off-label for the manic phase but there are only a few approved for the depressive phase. So -- and I don't think it's a matter of a better effect size, it's having -- of separating from placebo as well as having a favorable safety and tolerability profile.

In addition, as you know from our preclinical data, we've demonstrated that we have -- that the molecule in preclinical studies has shown an ability to be rapid acting, you know that we've in our schizophrenia studies demonstrated that those patients who came in with comorbid depression were very, very effectively treated for their depressive symptoms. So we are encouraged by all of those, Andy, did you want to add anything?

No. Just to confirm, these are registration trials. They are Phase III registration trials that we hope will gain the approval of this drug for this indication, and so it's the usual criteria that apply, we have to show efficacy, we have to demonstrate significant efficacy and we have to demonstrate safety in the program. But there is no implied comparison with other drugs, in these studies.

And a quick follow-up. On your depression study strategy. Sharon, you listed off a number of depressive states that might show benefit. What is the strategy for 2018? Are you thinking about like a Phase II all-comers study to tease out a signal in a subpopulation or is it worth doing separate Phase IIs in these different depressions?

We are right now planning a couple of studies in depressive disorders, and I think that we would rather wait to tell you about the exact details of these studies but you could expect them to be late stage studies and you might expect as well an earlier stage study testing out mechanisms. So you'll see a couple of things.

And our next question comes from the line of Charles Duncan with Piper Jaffray.

Luma is clearly becoming a pipeline and a product. Congrats on the progress. I had a couple of questions regarding that pre-NDA meeting, I heard the answer that Andy gave with regard to that. But I guess I'm kind of wondering if you might be looking to apply for an indication that may specifically address some of the differentiation that you see with lumateperone versus other antipsychotics? Could you give any color there?

Charles, this is Kim. For lumateperone, in our pre-NDA meeting, this is for the treatment of schizophrenia. But certainly as we put our package together for the NDA, and which is on track for mid this year, we will be looking to include our clinical data that really -- we believe supports the differentiated profile.

And that would be in the label. So hopefully be able to market to that. Let me ask you another question in terms of developing lumateperone kind of a follow-up to Ritu's. Is it possible to move not only into development for different forms of depression but also suicidality with that -- with the molecule?

I'll take that. Yes. It absolutely is possible to do that.

And then final question is regarding the future. You know it seems like you could be within a year, looking at a launch of Luma, my guesstimate. And so I'm wondering if you have an approved drug by say mid '19, will you be prepared to launch the drug? And if so, what are you thinking about in terms of the commercial infrastructure sizing or whatever?

This is Sharon. And yes, we are preparing for a launch for lumateperone for the treatment of schizophrenia. We believe that and we can effectively launch the drug for the treatment of schizophrenia to the psychiatry marketplace. As we go forward and file and hopefully receive approval for both bipolar and then agitation in patients with dementia, there, we will also focus on other markets such as primary care and the neurology marketplace as well. And so there, we might consider certain other arrangements. So I think that we are right now preparing the launch -- for the launch on our own.

Okay. As you move into those other indications, I'm not sure it's going to be your problem. My opinion. So congrats on the progress.

And our next question comes from the line of Paul Matteis with Leerink.

On the pre-NDA meeting, I'm wondering if you could just kind of contextualize how this meeting -- how the goals of this meeting and maybe the agenda are different than the meeting you had with the FDA a year ago. And maybe clarify within that, whether or not this meeting includes a review of some of the long-term safety data that you've been generating?

The meeting that was held previously was to go over the contents of the CMC parts of the application and that, as you know, was a successful meeting and we're not going to be addressing those things further. This meeting is to address the clinical sections of the NDA. But as I mentioned, it really is around content format, the way that we'll be presenting the data and not other questions regarding the actual data itself.

Yes. Let me just add to that. I think Paul is also commenting on other meetings we had that took into account when the FDA had certain questions of us or when we had questions of them regarding our clinical studies. So we've already had all of those meetings and correspondence et cetera. So I think the answer is, we've already had those, Paul, and now we're on to a different meeting.

Yes. Okay. That's helpful. And then I guess the bipolar data will start to come out with the review in schizophrenia ongoing. Are those at all intertwined? Like if you have a positive bipolar study, could that be a major amendment to a schizophrenia filing? Or vice versa, if the bipolar studies fail, could that also just kind of be considered in the overall view of the drug's profile?

Well, these are 2 different indications. So the schizophrenia NDA will be reviewed in its entirety with regard to the schizophrenia information and all safety information. The bipolar will be a separate filing and would be considered separately from the schizophrenia.

Okay. And then just 1 follow-up in the interim analysis for the agitation study, I guess when you think about the interim and then the full analysis. What were the basis of your powering assumptions? And what kind of effect size is clinically meaningful? How do you think about placebo effect?

This is really when you design the study and you have to make certain assumptions based on the variability and the effect size for your statistical power and in fact there is no approved product here. This is a real opportunity for us to meet an unmet need. So we've designed our clinical study in order to demonstrate efficacy. But in order to evaluate the assumptions that we made in the design of the study, we have prespecified this interim analysis that then will guide us to the completion of the study.

And our next question comes from the line of Sumant Kulkarni from Canaccord Genuity.

The first one is a very specific clarification on Lumateperone for Schizophrenia. If you look at the language in your 10-Q that you file last, it's -- one of the risk factors seems to suggest that you do need the long-term safety study data in hand for you to be able to file an NDA. Is that correct? Or do we need to wait just until approval to have that?

We believe that we have the safety data that we need towards the NDA filing.

The second -- it's a conceptual question on 214. Now that neurodegenerative diseases, Alzheimer’s, companies are looking at prodromal patients there. What is the potential to do that in a disease state like Parkinson's? And what would screening criteria be, perhaps, using nonmotor symptoms, if you were to go that route?

Is this question regarding 214?

214, yes.

So I think we're going to be getting the data from the Phase I/II trial in the second half of this year and we will use those data to design and to implement our next file as rapidly as possible. That will be a Phase II trial. At this point, we need the data from the Phase I/II in order to figure out what we're going to do.

And our next question comes from the line of Bill Tanner with Cantor Fitzgerald.

Sharon, could you just quickly remind us on the isoform selectivity of 214?

Sure. So it is a PDE1 inhibitor and it inhibits both or all A, B and C isoforms.

Okay. But no other -- none of the other, to any extent, of the other PDE?

Correct.

2,3,4,5 -- okay. And then just thinking about the Parkinson's study with 214, curious as to 7-days treatment, the sensitivity to the UPDRS to see a change. I know that obviously the study is being conducted for other purposes but there is that measurement and over 7-day treatment, what would you expect potentially the sensitivity of the scale I guess?

Either Andy or Kim.

I can respond. Thanks very much for the question. So you're right, primary objective of the study is safety and tolerability of 214 in this Parkinson's disease population. As we escalate the dose, we hope to see signals on some of these other measures that might suggest what direction to go in from an efficacy standpoint. And we will then use those signals if they are there to help design the next study.

Okay. That's helpful. And then just the last thing, where does its actually fit in, and Sharon, I know you had mentioned that you might be able to spare dopamine in the early stages, might enhance the effects of dopamine in the later stages. But just thinking where it fits in? If it looks like its dopamine sparing at the outset, the pharmacoeconomics of that, I'm assuming this is going to be priced quite differently than dopamine, so maybe just some thoughts there?

Right. So I think it's very early to be thinking of how this would be priced, but I do think that we could look at -- that we are looking at the different stages of the disease because we do think that on the dose sparing perspective, early on, it could prolong the amount of time where you don't need dopamine replacement. And then later in the course of the disease, you would need less dopamine replacement therapy. And again, it is in the preclinical models where we've shown really exciting data on the ability to be neuroprotective. So we -- it's early stages but we have, it's extremely exciting science here. And so we do -- if everything pans out, we do think that this could be used at all stages of disease and would be very, very important for this patient population and other patient populations who have -- with neurodegenerative diseases.

And I think there's a belief that continuous dopamine treatment could be disease modifying. So when you talk about the neuroprotection that you've seen in the preclinical studies, is that something that you might -- that you're referring to or might think that's a possibility?

Yes. Exactly, that and also as we've mentioned, there are effects on neuroinflammation that are beneficial -- potentially beneficial as well.

And our next question comes from the line of Robert Hazlett with BTIG.

You gave some nice color a bit earlier on the safety and potential tolerability of lumateperone and bipolar depression. As we head towards the data for agitation associated with dementias, would you expect the tolerability of lumateperone in those patients, to be similar to the good tolerability we saw in those patients with schizophrenia?

Yes. Thanks for the question, this is Kim. Yes, we do believe that the safety and tolerability of lumateperone that we've seen across our programs will translate favorably to the patient population with dementia and we'll be -- we're measuring that of course in our agitation and dementia study. So this is also our low-dose strategy that's really designed to hone in on the symptoms of agitation in the dementia patient population including Alzheimer's disease with a favorable safety profile.

Okay. Regarding the different, maybe dose forms of lumateperone, there has been some interesting indications developed for long-acting release forms. Just a quick one, is the LAR form of lumateperone still under consideration?

LAI?

Excuse me, LAI.

Yes, certainly.

And I would like to just add a little bit to what Kim said before and that is just to remind you that we have over 2,000 patients have received lumateperone to date with the same safety and tolerability profile. So we are very encouraged by the safety and tolerability profile of lumateperone in these patient populations.

Terrific. And just one more, the lumateperone program, there is a lot on going on in the U.S. could you just remind us Sharon, more broadly, the international strategy for the build out of lumateperone?

Sure. So we are putting together our strategy in Europe and rest of world. As you know, Europe is many countries and as you heard from us earlier this morning on our bipolar studies, we have expanded them globally. And so we are very enthused about the global marketplace.

Any timing there?

I think that -- we'll update you on timing in rest of world.

And our next question comes from the line of Matt Kaplan with Ladenburg Thalmann.

Just shifting gears a little bit in terms of looking at ITI-333 program. Can you give us some color there, with respect to your plans and potential timeline for 333?

Sure. This is Sharon and thanks for the question. And then I think, operator, I think this might be our -- all the time we have for calls. But or maybe one more if there is 1. But for 333, that's in preclinical development right now. We are presently planning on, if all goes well in the preclinical development that we would enter the clinic next year.

Okay. And any sense of indication yet that you're shooting for going towards first?

Yes, substance use disorder. We think there's utility in pain and mood disturbances as well but the first indication that we will be looking at or that we are looking at, I should say is substance use disorder.

And then shifting gears to 214. With respect to its neuroprotective properties, what are your plans for other neurodegenerative diseases, I guess beyond Parkinson's disease for that program? Or the PDE1 platform altogether?

Right. I think that what we want to do is first to see the data from the Parkinson's study. And that will really help inform as to the other indications that we pursue within the neurodegenerative populations. But this is a little bit too early, but we will know that later this year.

And then last question in terms of -- you gave a little bit more detail on your commercial preparation for lumateperone. Where are you in terms of building out your commercial infrastructure? And also what studies have you done in terms of preparing and analyzing the market and how to approach it? You're on your own, I guess in the -- for the specialist piece of it.

So, this is Sharon. We do have a -- we did late last year hire a head of Commercial Development who came to us from a large Pharma and has had experience in launching 2 antipsychotic drugs. I think we are building out the commercial organization and we are using different agencies to help us with this. And so it's been moving along. So I think you did ask another question in there but I didn't write it down, I forgot it.

Yes. In terms of the characteristics of the studies and preparation that you're doing in terms of analyzing the market?

Right. Right. So we have been doing all of the health economic outcome, surveys, we have been doing all of the normal precommercial activities of going into the -- into the doctors' offices in the community health centers et cetera, et cetera. So we have been doing all of the standard precommercial activities that you would expect to be done.

So with that information in hand that you've done, what do you -- can you give us a sense in terms of what the commercial organization will look like, a year from now? Assuming...

Well I don't mean to be facetious here but if my mother were still alive, she would say "does Macy's tell Gimbels?" And those of us old enough to understand that -- I think that we would prefer to, for the moment work on our NDA filing and keep silent on our commercial plans right now, other than to say we are working on all of the precommercial activities.

And our final question comes from the line of Jason Butler with JMP Securities.

It's Roy in for Jason. All my questions have been answered, thanks.

And that does conclude today's Q&A session. So I'd like to return the call to Miss. Sharon Mates for any closing remarks.

Ladies and gentlemen, this does conclude today's conference. You may all disconnect. Everyone, have a great day.