Intra-Cellular Therapies, Inc. (NASDAQ:ITCI) Q2 2016 Earnings Conference Call August 4, 2016 8:30 AM ET
Sharon Mates - Chairman, CEO
Kimberly Vanover - SVP Clinical Development
Larry Hineline - VP, CFO
Juan Sanchez - VP, Corporate Communications and IR
Adnan Butt - RBC Capital Markets
Bill Tanner - Guggenheim Securities
Leyi Wang - Leerink Partners
Robert Hazlett - Ladenburg Thalmann
Sarah Weber - Piper Jaffray
Good morning, ladies and gentlemen, and welcome to Intra-Cellular Therapies' Second Quarter 2016 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Later, there will be a question-and-answer session, and instructions will follow at that time. [Operator Instructions]. 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 quarter ended June 30, 2016, crossed the wire a short time ago. A press release is available on our Web site at intracellulartherapies.com.
Joining me on the call today are Dr. Sharon Mates, Chairman and Chief Executive Officer; Dr. Kimberly Vanover, Senior Vice President of Clinical Development; Larry Hineline, Vice President and Chief Financial Officer; Dr. Cedric O'Gorman, Vice President of Medical Affairs; 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 product candidates, the anticipated conduct and resource 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 made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements and the company disclaims any obligations to update such statements.
I will now turn the call over to Sharon.
Thanks, Juan. Good morning, everyone, and thank you for joining us for today's conference call. Today, I will provide an overview of the progress of our ongoing programs, including our Phase 3 studies for the treatment of schizophrenia, bipolar depression and agitation and dementia, including Alzheimer's disease as well as our other development plans. In her remarks, Kim will share more detail on these programs. Lastly, Larry will review our financial results and we will open the line for Q&A.
It has been a productive quarter. We have completed the enrollment of our second ITI-007 Phase 3 clinical trial in patients with schizophrenia. In this trial, we enrolled 696 patients. The completion of enrollment is a major milestone in our mission to advance ITI-007 as a new treatment option for patients suffering from mental illness. We expect top line data later this year.
ITI-007 is a first-in-class molecule which provides selective and simultaneous modulation of serotonin, dopamine and glutamate, the three neurotransmitter pathways implicated in severe mental illness. Unlike existing schizophrenia treatments, ITI-007’s dopamine receptor phosphoprotein modulation, or DPPM, acts as a presynaptic partial agonist and presynaptic antagonist at D2 receptors.
This mechanism, along with potent interactions at 5-HT2A receptors, serotonin transporters and D1 receptors with indirect glutamatergic modulation likely contributes to the efficacy of ITI-007 across a broad array of symptoms with improved psychosocial function and favorable tolerability.
According to the National Institute of Mental Health, over 1% of the world’s population suffers from schizophrenia and more than 2.5 million Americans suffer from the illness in any given year. There remains substantial unmet medical needs for the treatment of schizophrenia.
Existing treatments, while helpful for reducing the positive symptoms of schizophrenia, do not provide broad symptom control across other symptom domains and are limited by safety and tolerability issues, including motor and metabolic side effects, all of which lead to poor medication adherence.
Further, it has been demonstrated that poor adherence to antipsychotics is associated with higher risk of relapse, re-hospitalization and increased healthcare costs. We believe ITI-007 has the potential to advance the treatment of schizophrenia by providing broad symptom control with a reduced side effect burden, thereby allowing patients to stay on treatment and benefit from enhanced social functioning.
In addition, during the second quarter, we announced the advancement of ITI-007 into Phase 3 development for the treatment of agitation in patients with dementia, including Alzheimer's disease. It has been estimated that over 44 million people worldwide were living with dementia in 2013, including over 5 million patients with Alzheimer's disease in the United States and it is currently the fifth leading cause of death for people aged 65 and older. This number is expected to increase to 75.6 million people by 2030 and to 135.4 million people by 2050.
Studies have suggested that approximately 60% of patients with Alzheimer's disease experience agitation. While the diagnostic criteria for Alzheimer's disease typically focuses on the cognitive deficits, it is often the behavioral and psychiatric symptoms such as those associated with agitation that are most troublesome for caregivers, and lead to poor quality of life for patients, family members and caregivers.
According to the International Psychogeriatric Association, the definition of agitation includes excessive motor activity such as pacing and restlessness, verbal aggression such as screaming and shouting and physical aggression such as grabbing, pushing and hitting.
Furthermore, in addition to these hallmark deficits, patients with dementia also suffer from depression, sleep disorders, sundowning and psychosis, behavioral disturbances that when combined with other symptoms associated with agitation interfere with interpersonal relationships and other aspects of social functioning and/or ability to perform or participate in daily living activities, which can lead to early institutionalization.
We believe the unique pharmacology of ITI-007, which employs potent 5-HT2A antagonism, along with efficient modulation of dopamine and other neurotransmitter systems may translate into a safe and effective treatment for these patients.
In addition to meeting major milestones in our Phase 3 development programs for schizophrenia and agitation and dementia in the second quarter, we have continued to advance our other development programs.
Clinical conduct is ongoing in our Phase 3 bipolar depression program. This program consists of two Phase 3 clinical trials and includes patients with both bipolar I and bipolar II disorder. One trial evaluates ITI-007 as a monotherapy and the other trial evaluates ITI-007 as an adjunctive therapy with either lithium or valproate.
Bipolar disorder affects approximately 2.6% or 5.7 million adults in the U.S. according to the National Institute of Mental Health. Bipolar depression represents the most common clinical manifestation of bipolar disorder and is associated with a worse prognosis than bipolar mania.
There are few approved therapies for the treatment of bipolar depression. We believe ITI-007 has the potential to serve a broad patient population suffering from depressive episodes associated with bipolar I or bipolar II disorder as both a monotherapy and as an adjunctive therapy.
Within the ITI-007 portfolio we are also developing a long-acting injectable formulation to provide more treatment options to patients suffering from mental illness. Given the encouraging tolerability data to-date with ITI-007, we believe that a long-acting injectable option in particular may lend itself to being an important formulation choice for patients.
We also continue to advance our innovative phosphodiesterase or PDE platform. We believe that the lead compound in our PDE 1 portfolio ITI-214 is the first selective PDE type 1 inhibitor to be tested in humans. To-date, ITI-214 has been studied in four Phase 1 clinical trials and has been found to be safe and generally well tolerated in both healthy volunteers and patients with schizophrenia. We will provide more details of our plans later this year.
In the second quarter of 2016, we had a strong presence at scientific and medical conferences. We believe the positive data to-date and the high treatment completion rates seen in our clinical trials have the potential to translate to improved medication adherence and long-term benefits for patients.
We believe that patients, caregivers, clinicians and payors alike would recognize and appreciate such an advance in treatment. We are very enthusiastic about the positive response to our data by the scientific and medical community at these meetings.
Moving to our financials, we ended the quarter with $442.7 million in cash and investments placing us in a very strong financial position to advance our research and development programs. Shortly, Larry will provide further details on our financials.
I would now like to turn the call over to Kim.
Thanks, Sharon. I’m pleased to provide an overview of our second quarter achievements in the ITI-007 clinical programs for schizophrenia and for agitation in patients with dementia, including Alzheimer's disease.
Focusing on our schizophrenia program, we were pleased to announce the completion of enrollment in our second Phase 3 trial in patients with schizophrenia or 302 trial. This trial is a randomized, double-blind, placebo- and active-controlled clinical trial in patients with an acutely exacerbated episode of schizophrenia.
In this trial, 696 patients were randomized equally across four treatments; ITI-007 60 milligrams, ITI-007 20 milligrams, risperidone as an active control or placebo. Patients received study treatment orally once daily in the morning for six weeks. Clinical conduct is ongoing and includes an approximate one week screening period before randomization followed by the six-week study treatment period.
Prior to discharge from the in-patient portion of the study, patients are switched to a standard of care antipsychotic treatment plan for an in-patient stabilization period of up to five days. Patients are instructed to return for an outpatient safety follow-up visit approximately two weeks following the last dose of study treatment.
The study is being conducted in 13 clinical sites throughout the United States. The trial is evaluating the efficacy and safety of ITI-007 60 milligrams and 20 milligrams compared to placebo. The primary endpoint is changed from baseline versus placebo at six weeks on the Positive and Negative Syndrome Scale or PANSS total score. The PANSS is a well-validated, 30-item rating scale that measures the ability of a drug to reduce schizophrenia symptom severity.
The key secondary endpoint is changed from baseline at six weeks on the Clinical Global Impression scale for severity of illness or CGI-S that provides a clinician’s expert assessment of the patient’s overall symptom severity. Additional secondary endpoints and other measures, including safety and tolerability, which may highlight differentiating clinical features of ITI-007 are also being assessed. As Sharon mentioned, we expect top line data to be available later this year.
To-date, ITI-007 has demonstrated a statistically significant improvement versus placebo in the control of symptoms associated with schizophrenia. ITI-007 has also shown a safety and tolerability profile similar to placebo in two late-stage clinical studies.
These data as well as unique pharmacological findings from our ITI-007 Positron Emission Tomography or PET studies were highlighted at various scientific and medical conferences during the second quarter, including the Schizophrenia International Research Society meeting or SIRS, the American Psychiatric Association or APA, the Society of Biological Psychiatry or SOBP and the American Society of Clinical Psychopharmacology or ASCP.
Taken together, these data have demonstrated that ITI-007 reduced psychosis in patients with schizophrenia at relatively low levels of striatal D2 receptor occupancy, lower than the occupancy range required by most drugs currently approved for the treatment of schizophrenia. This substantiates the unique pharmacology of ITI-007 as well as its ability to provide broad efficacy with a favorable safety and tolerability profile.
In our first Phase 3 study, or 301, and our Phase 2 study 005 in schizophrenia, ITI-007 60 milligrams demonstrated antipsychotic efficacy as measured by change from baseline in the PANSS total score versus placebo at study endpoint. ITI-007 required no dose titration, showed early onset, and sustained efficacy for the four weeks of treatment.
In both trials, ITI-007 was well-tolerated with a safety profile similar to placebo. The most frequent treatment-emergent adverse events occurring in both studies and considered at least possibly related to ITI-007 were predominantly mild sedation and somnolence. In addition, ITI-007 demonstrated a motoric and metabolic profile similar to placebo.
Importantly, ITI-007 improved psychosocial function. In the 301 trial, ITI-007 60 milligrams was associated with statistically significant improvement compared to placebo on both the PANSS-derived Prosocial Factor and the Personal and Social Performance scale, or PSP, as early as four weeks.
In this trial, the 40-milligram dose of ITI-007 showed statistically significant improvement in CGI-S, the PANSS Positive Symptom subscale and the PANSS-derived Prosocial Factor indicating that both the 40 milligram and 60 milligram doses were pharmacologically active and provided clinic benefit.
In the 301 trial, there was a high treatment completion rate observed with ITI-007. ITI-007 60 milligrams demonstrated a statistically significant longer or better time to treatment discontinuation due to any reason compared to placebo, and a statistically significant longer or better time to treatment discontinuation due to lack of efficacy.
The number of patients who discontinued treatment in this trial due to an adverse event was low and the time to treatment discontinuation due to an adverse event was not statistically significantly different from placebo for either dose of ITI-007.
ITI-007 showed a motoric profile similar to placebo according to adverse event report or when objectively measured by the Simpson Angus Scale, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale.
These findings are important as many existing treatments for schizophrenia are associated with high rates of EPS, akathisia, Parkinsonism, tremor and restlessness. ITI-007 has shown efficacy and prosocial benefits in our schizophrenia studies to-date and has also demonstrated a metabolic profile similar to placebo as measured by metabolic parameters, including cholesterol, triglycerides, glucose and insulin.
In the treatment of schizophrenia, prescribers are often faced with the clinical dilemma of making a choice between treatments which are associated with cardiometabolic or motor side effects that can result in patients discontinuing their medication. We believe that the placebo-like safety and tolerability profile for ITI-007 underlies the high treatment completion rate since in our studies and may predict better medication adherence in clinical practice. We look forward to sharing data from our second Phase 3 clinical trial later this year.
Turning our attention to our low-dose strategy for ITI-007, in the second quarter we were pleased to announce the advancement of ITI-007 into Phase 3 development for the treatment of agitation in patients with dementia, including Alzheimer's disease or AD. The ITI-007 201 trial is a Phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with a clinical diagnosis of probable AD and clinically significant symptoms of agitation.
In this trial, approximately 360 patients are planned to be randomized to receive 9 milligrams of ITI-007 or placebo in a 1 to 1 ratio orally once daily for four weeks. The primary efficacy measure is the Cohen-Mansfield Agitation Inventory. This is the well-validated scale that measures the ability of a drug to reduce overall frequency of agitation symptoms, including aggressive behaviors.
The key secondary efficacy measure is a Clinical Global Impression scale for severity of illness. Other exploratory secondary endpoints include measures of other behavioral disturbances associated with dementia. Safety and tolerability are also assessed in the trial.
Currently, the FDA has not approved any drug to treat the behavioral symptoms of Alzheimer's disease. As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. Current antipsychotic drugs are associated with a number of side effects which can be problematic for elderly patients with Alzheimer's disease.
In addition, some antipsychotic drugs which are currently used off-label may exacerbate the cognitive disturbances associated with AD. There is a large unmet medical need for a safe and effective therapy to treat the behavioral symptoms in patients with Alzheimer's disease. We believe the favorable safety and tolerability profile of ITI-007 will translate well to this patient population.
The advancement of ITI-007 in development for the treatment of behavioral disturbances associated with dementia is one step forward to providing improved treatment options for these patients. We look forward to providing a further update on these and our other programs on our next call.
I will now turn the call over to Larry who will review the financial results for the second quarter.
Thanks, Kim. I will be reviewing our financial results for the second quarter ending June 30, 2016 and provide an overview of our expectations for the use of our cash and investments.
The net loss for the second quarter of 2016 was $30.8 million compared with a net loss of $21.5 million for the second quarter of 2015. Basic and diluted net loss was $0.71 per share for the second quarter of 2016 compared to a basic and diluted net loss of $0.61 per share for the same period in 2015.
Research and development expenses for the second quarter of 2016 were $25.3 million compared to $17.8 million for the second quarter of 2015. The increase is primarily due to cost associated with the second Phase 3 clinical development program for ITI-007 in schizophrenia and to a lesser extent the Phase 3 trials of ITI-007 to treat patients with bipolar depression.
General and administrative expenses for the second quarter of 2016 were $6.5 million compared to $4 million for the prior year period. The increase is primarily the result of higher stock-based compensation expense and to a lesser extent pre-commercialization activities and increased labor and related costs.
Cash and investments totaled $442.7 million at the end of the second quarter of 2016 compared to $475.2 million at year end 2015. We expect that existing cash and investments will be dedicated primarily to the ITI-007 development program, including to fund clinical trials of ITI-007 in schizophrenia, bipolar depression, behavioral disturbances and dementia, depressive disorders and related clinical and non-clinical activities to fund pre-commercial activities for ITI-007 for the treatment of schizophrenia.
And if ITI-007 receives regulatory approval, initial commercialization efforts to fund preclinical and clinical development of the company’s ITI-007 long-acting injectable program and to fund non-clinical activities, including the continuation of manufacturing activities in connection with the development of ITI-007. Funds will also be used for other clinical and preclinical programs, including the company’s PDE development activities.
With that, operator, could you please open the line for questions.
Thank you. [Operator Instructions]. Our first question is from Adnan Butt with RBC Capital Markets. You may begin.
Good morning and thanks for taking the question. I wanted to confirm – well, first, are you able to give better – I guess more tighter guidance on when Phase 3 data from the second study could be released? Could you rule out September? Could you say it’s more likely to be in October versus September?
Hi, Adnan. Thanks for the questions. I’ll take that one and I think as Kim mentioned in her talk that the study is six weeks on drugs and then a two-week follow up and we’ve said that we have – we finished enrolling in the end of June. So you count from that time six weeks plus two weeks, which gets you to the middle of August. And then you need to give us the time to clean the database and to lock it. And I think that we don’t want to give an exact estimate yet, because as you know in these clinical studies it’s not only Intra-Cellular looking at the data – we’re not looking at data, we’re looking at very blinded data at that point and we are cleaning – the CRO is cleaning the database and then they lock it. And then we get the tables and listings and it is – that portion of time is an imprecise one. So we choose not to give you an exact date because if we’re a couple of days early or a couple of days late from that quote exact date, we will be asked a million questions. So we choose not to give you an exact time. I think that everybody has done the counting and people are making their own speculation as to when the data will be gotten. It will be later this year is all we’re saying at this point.
Okay. Thanks. And just one more follow up. In terms of filing the NDA, where do you stand in terms of – on the carcinogenicity studies, if they are required, and any longer term safety data that might be needed for filing the NDA? Thanks.
Okay. So both of those are required. We have said that we will have – we expect to have all data necessary for filing at our filing time. And we’ve given you our filing times as well. Kim, do you want to add anything to that?
So they’re ongoing, right? Thanks.
Okay. Thank you.
Thank you. Our next question comes from Ritu Baral with Cowen & Company. You may begin.
Hi. This is Alex [ph] on for Ritu. Just a couple of questions on the Alzheimer's agitation study. Do you have an idea of what receptor binding is at the 9 milligram dose?
I’ll ask Kim to take that.
Hi, Alex. Thank you for the question. We do know from our healthy volunteers’ PET study at a dose of 10 milligrams that we see full cortical 5-HT2A receptor occupancy and about 10% striatal D2 receptor occupancy. And we know that the other pharmacology that comes along with the D2 occupancy, we have D1 receptor affinity and serotonin transporter affinity that comes along around the same dose range as D2. And so this is really the dose range that we’ve targeted having full 5-HT2A occupancy with just a little bit of D2 modulation that we think is really important to help control these behavioral symptoms in dementia, including Alzheimer's disease in this dose range. So the 9 milligram to 10 milligram dose, that’s really what we wanted to target for this Phase 3 study.
Okay, perfect. And then are you – do you know what sort of placebo assumptions you have for the CMAI primary endpoint on that study?
The placebo assumptions, I’m not sure I understand your question.
To just what effect would you expect to see on placebo?
So in all clinical trials, placebo does have some effect and we’ve designed our statistical analysis plan in order to account for the appropriate statistical powering to be able to separate from placebo with a clinically meaningful signal.
Okay. And have you released what the clinically meaningful signal would be on CMAI?
So I think that what we really do is we look at the clinically meaningful effect as we’ve seen – as Sharon and we have talked about before with the IPA definition of clinically meaningful agitation including aggressive behaviors. And so we really look for the clinical meaningfulness through what’s available in the literature.
Great. Thanks for taking the questions.
Thank you. Our next question is from Bill Tanner with Guggenheim Securities. You may begin.
Thanks for taking the questions. Maybe for Sharon or Kim, I guess, as it relates to the agitation study looking on clinical trials of 360 subjects, so just curious if somebody can comment on the appropriateness of that size? And not familiar with Cohen-Mansfield, so just trying to figure out if – you obviously must think that that’s an adequate number to discern if there’s an effect, but maybe just some comment on that. And then I had one follow up please.
I’ll ask Kim to take that question.
Thanks. So certainly we’ve spent some time looking at the Cohen-Mansfield Agitation Inventory scale and the statistical design going into this study and we believe we have the appropriate statistical power in order to detect a signal and we believe this is the appropriate scale to use for our study and for ITI-007 program.
Can you comment as to the power specifically?
I don’t have the details on that right off the top of my head.
Okay. And then, Sharon, the comment in your opening remarks on the PDE 1 inhibitor, you said it was generally well tolerated 214 and I’m just wondering if you can sort of qualify generally?
No. I think it’s the term of art used. They don’t read anything into that.
But your assessment is that it’s tolerated well enough to warrant going into additional testing, I guess?
Okay, all right. Thank you.
Thank you. Our next question is from Leyi Wang with Leerink Partners. You may begin.
Hi. Good morning. This is Leyi Wang on behalf of Seamus Fernandez, our senior analyst. First of all, Sharon, could you talk about the choice of 9 milligram dose in the agitation study? What guided such a specific dosing level for this patient population? And also on the agitation study, the efficacy endpoint is four weeks but how much safety follow up is likely to be required? And then lastly, what does the competitive landscape look like to you now on the agitation and what are the limitations for this study? Thank you.
Okay. Thanks, Leyi. Since you asked me to take it, I’ll start. Luckily Kim is writing down your questions because I was not. So the first question I think was on the specific dose selection and I do think Kim did mention that we choose the 9 milligram dose because – so what we wanted to do was have full saturation of 5-HT2A and a little bit of D2 activity. If you look at what’s used off-label right now like the use of some of the atypical antipsychotics that’s what they’re trying to do. They’re trying to get a little bit of D2 activity and 5-HT2A activity but they can’t do that, because they either – compounds either first saturate the dopamine receptor and then 5-HT2A or they also have a lot of off-target receptor activity. We know that by 10 milligrams we have fully saturated 5-HT2A and we think that a little bit of D2 activity that’s really important for the agitation is optimal in the dosing that we’ve selected. I don’t know, Kim, do you want to add anything to that?
The only thing that I would add is we had a previous Phase 2 study in patients with primary insomnia where we looked at doses 1 milligram to 10 milligrams in that patient population and we saw statistically significant increases in total sleep time, decreases in wake after sleep onset and increases in the deeper slow-wave sleep especially early in the night, and with no cognitive impairments next day. So this is really – we know that these low doses get into the brain and we’ve shown the target engagement in our PET study as well and are having a pharmacodynamic effect consistent with improving sleep. And then we had our earlier safety study in the healthy geriatric subjects and in a cohort of patients with dementia where we looked at the safety of the 9 milligram dose. So we’re really excited to be taking this forward into the Phase 3 study.
And just to add to that, the dose range we did in that sleep maintenance insomnia study was 1 milligram, 5 milligram and 10 milligrams and 1 milligram where it’s presumably primarily a 5-HT2A antagonist did improve sleep maintenance. But then as you got 5 milligrams, the improvement was greater and 10 milligrams where we have about a 10% D2 occupancy was the greatest magnitude of effect that we saw. So that went into our selection for using 10 milligrams or 9-milligram dose. The second question was on competition and I think that first of all as you know and as we said in our earlier remarks that there are many patients with Alzheimer's disease and of that patient population, about 50% to 60% of them have agitation and these behavioral disturbances associated with dementia. So we think the population is very large and there are several companies looking to develop treatments in this arena. So far there are no approved products for these indications in this patient population. And lastly is I think on our – I didn’t quite get the whole question but I think it was something about our duration of our study and I think that – we do think that the selection of a four-week study was appropriate for this patient population.
And just to real quickly follow up. So I think my question on the term and duration is more on the safety follow up, how long after the follow up is likely to be required to show safety? And then just another quick follow up on sort of the competitive landscape in the agitation side. Could you comment on what are the limitations of the eventual cross-talk assumptions analysts are likely to try to do from ACADIA’s exploration of neurovascular in a presumed similar dimension population. Thank you.
All right. So in terms of the safety duration as with all of our programs, we will follow the ICH guidelines and the FDA guidelines for the duration of treatment for our safety database.
And then in terms of – I’m not sure I really got your question. If we would comment, I think there are – your question was something on ACADIA and I think we’re not commenting on other company profiles. I don’t believe that ACADIA at present has a study in this patient population. So I can’t comment on something they don’t have yet. So I don’t have a comment there.
Okay, great. Thank you.
Thank you. Our next question is from Bert Hazlett with Ladenburg Thalmann. You may begin.
Thanks. Thanks for taking the question. A couple of kind of off the [indiscernible] questions. Could you describe the manufacturing readiness for 007? What’s being done? What’s been done? What’s still on the critical path there? And then could you remind us what’s owed to Bristol with the program in terms of milestones or royalties? I have one or two more. Thanks.
Okay. So our manufacturing has been going well and we are certainly on track with all of our manufacturing activities. I don’t say we wouldn’t necessarily comment specifically other than that we’re on track. So I think that’s all we will say. There have not been any hiccups on the manufacturing. And then on your asking about the – what’s owed to Bristol? I think what we’ve said is that we would owe in the single digits and that we do have upfront fees to pay to Bristol that are up to an aggregate of $14.7 million and the total remaining payment are up to a total of $12 million.
Did you ask another question?
Thank you for that. And then just in terms of the other Phase 3s with regard to agitation and dementia and then bipolar depression. Thank you for the initial color on those. Maybe I missed it but was there any guidance given with regard to timing of the completion of either of those studies?
I think we do have something up on clinical trials. I think that for the bipolar we’re anticipating the end of next year finishing enrolling and I think for the dementia it was about two years from where we started, which was the end of June. So I think you should estimate about two years from that start time.
Okay. Thank you. And then just with regard to the pipeline and the thoughts between the investment and the PDE program versus the long-acting injectable for 007 and maybe the 131 metabolite. How do you think about the investment in those opportunities? And is the 131 metabolite for mood disorders still under consideration?
So on the PDE program we will update you later this year on that. We do anticipate going back into the clinic with the PDE 1. We have spent the year really evaluating; there are many indications for PDE 1 inhibitors just like for 007. And so we have really taken the time to go through each of these indications. And before we choose one in this CNS, we have also been exploring some non-CNS indications and we are still exploring the non-CNS indications and we’ll also update you on that front later this year. What was the next question? On the LAI and 131, so any of the metabolite programs we’ll also update you on later this year. And the long-acting injectable is currently in preclinical development and we would expect to be able to enter the clinic late next year.
Okay. Thank you very much. Congratulations on the progress. We look forward to the data later this year.
So do we. Thank you.
Thank you. [Operator Instructions]. Our next question is from Charles Duncan with Piper Jaffray. You may begin.
Good morning. This is Sarah on for Charles. I have two quick questions on the schizophrenia program and then one on the behavioral disturbances. So for schizophrenia, assuming the second trial looks adequate to support an NDA filing next year, what sales force build out and manufacturing activities are planned for the second half of this year? And then can we expect any further analyses on that new data set or the combined Phase 3 data sets at any clinical meetings in the next six to nine months?
Hi, Sarah. Thanks for the questions. You have a bunch of questions there, so let me start with the easiest one and that is as we said a little earlier, the manufacturing is ongoing. There is nothing unusual here. So it’s ongoing. I think your others questions, I’ll ask Kim to address.
Hi. Yes, certainly we will be preparing new data when we have the second trial report out later this year. We will be preparing presentations at scientific and medical conferences. And then certainly we would have a plan subsequently in order to do some combined analyses and continue to present these data as we move forward.
And then just one on the behavioral disturbances trial. For that plan to interim, can you just remind me when that’s going to happen? And then what the possible outcomes could be? Is it just around increasing sample size if need be or could there be other adjustments on dosing or anything else?
Right. So as we’ve said, the interim analysis would be planned in order to make adjustments to the sample size. These are routine type of analyses that are done in the course of the trials that are all preplanned. And there’s no other additional information that we have at this time.
Thank you. I would now like to turn the call back over to Dr. Sharon Mates for closing remarks.
Thank you, operator, and thank you all for joining the call. In summary, 2016 continues to be an exciting year as we advance our programs and move closer to announcing top line results from our second Phase 3 schizophrenia trial.
Based on the unique pharmacology of ITI-007 and the positive clinical data we have generated to-date, we feel confident that ITI-007 will benefit patients who suffer from a broad range of central nervous system disorders. These patients remain underserved by existing medications.
We are committed to bringing innovative treatments that address the broad range of symptoms to treat patients suffering from neuropsychiatric and neurologic diseases without the safety and tolerability issues associated with many of the current therapies.
We look forward to speaking to you again soon to report on the progress of our programs. Operator, you may now disconnect the call.
Ladies and gentlemen, this concludes today’s conference. Thanks for you participation and have a wonderful day.
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