ACADIA Pharmaceuticals Inc. (ACAD) Q3 2016 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen and welcome to ACADIA Pharmaceuticals’ Third Quarter 2016 Financial Results Conference Call. My name is Susan, and I will be your coordinator for today. [Operator Instructions] I would now like to turn the presentation over to Lisa Barthelemy, Senior Director of Investor Relations at ACADIA. Please proceed.

Thank you, Suan. Good afternoon and welcome to ACADIA’s third quarter 2016 financial results conference call. This call is being recorded and an archived copy will be available on our website at www.acadia-pharm.com through November 21, 2016. Joining me on the call today from ACADIA are Steve Davis, our President and Chief Executive Officer; Dr. Serge Stankovic, our Executive Vice President and Head of Research and Development; Terry Moore, our Executive Vice President and Chief Commercial Officer; and Todd Young, our Executive Vice President and Chief Financial Officer. Before we proceed, I would first like to remind you that during our call today, we will be making a number of forward-looking statements, including statements regarding our strategy, including the timing, results or implications of clinical trials, other development efforts or regulatory approval; the benefits or advantages to be derived from future approval of and the commercial potential for our product candidates in each case, including NUPLAZID or pimavanserin; future commercial and financial results, and the future development and commercialization of our product candidate. During our call today, we may use words such as anticipate, believe, could, expect, intend, may, plan, potential, predict, project, should or the negative of those terms and similar expressions that convey uncertainty of future events or outcomes to identify these forward-looking statements. These forward-looking statements are based on current information, assumptions and expectations that are inherently 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 factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today’s date. ACADIA disclaims any obligation to update these forward-looking statements. I will now turn the call over to Steve Davis, our President and Chief Executive Officer.

Thank you, Lisa and good afternoon. Let me first take the opportunity to thank each of you for joining us on today’s conference call. Today, I will address a couple of areas in my prepared remarks. First, I will touch upon the strong progress we have made with the launch of NUPLAZID, and second, I will discuss the important advances we have made in executing on our broad development plans for pimavanserin in new indications. Following my remarks, Todd will discuss our financial results for the quarter, Terry will then lead a review of our key commercial activities and priorities for NUPLAZID, and Serge will go into more detail about our clinical development programs with pimavanserin. Now let me turn to the launch. We have made great progress in our first full quarter with NUPLAZID on the market. We saw solid growth in uptake of NUPLAZID and recorded $5.3 million in net revenue for the first full quarter of commercialization. We also saw very good reimbursement and access for NUPLAZID from public and private payers, and have had early success getting on formularies. NUPLAZID is now on virtually all Medicare formularies, and consistent with our expectations continues to be added to commercial formularies. Additionally, our sales specialists have made excellent inroads in broadening and deepening awareness of NUPLAZID and are getting good access to physicians, including neurologists and psychiatrists. Through our market research and feedback from our sales specialists we have received strong positive feedback from physicians, who have prescribed NUPLAZID and about their intent to prescribe in the future. Importantly, as we have received favorable feedback from physicians about NUPLAZIDconnect, our provider and patient support services center. In September we had a strong presence at the World Parkinson Congress with multiple poster presentations on NUPLAZID and booth exhibits for healthcare providers, patients and caregivers. In conjunction with the Congress, we sponsored the National Parkinson Foundation’s first Caregiver Summit. As we expect for a groundbreaking product in a first in class indication, the launch we are seeing is consistent with our view that NUPLAZID sales will grow steadily over many years, and that continues to be the focus of our business. As we pull back the lens and look at the foundational elements of the launch in these early days, we see a very compelling opportunity. We see steady rates with new patient startings and continuing growth in the number of prescribing physicians and patients on NUPLAZID. Let us take a look at some of these elements. On the access and reimbursement front, it is important early in the launch to have broad and easy access. We are seeing this. In fact what we see is consistent with our expectations based on the very significant body of work we did with payers in advance of the launch. Another key element of our foundation is that NUPLAZID appears to be performing as expected and consistent with what we observed in our pivotal study 020. The safety and tolerability profile was consistent with what we observed in the clinical studies, and on the efficacy front we are hearing from physicians that they are very pleased with the efficacy of NUPLAZID. They report a profile that lines up on all fronts with our clinical study observations. As we all know, this is not always the case when you get into broader populations. Of course, it is still relatively early in the launch, but we like what we see and hear today. Looking at yet another element of our foundation, and as Terry will note later on in the call, most of our assumptions regarding initial patient use, physician mix, payer coverage are all in line with what we expected and healthy. Finally looking through yet another lens, we review daily, weekly, monthly indicators and trends to assess the health of the launch. We look at things such as number of patient starts, number of patients on drug, number of physicians writing the drug, growth of the prescriber base, number of bottles shipped, the NRx and TRx penetration by physician segment et cetera. Importantly, when we look at these indicators we see a picture that is consistent with a healthy launch, and is consistent with the positive feedback we are hearing from the medical community. As we previously discussed, paradigm shifts require heavy lifting. They require repetition of message, diligence and physician experience, and they carry the potential for dramatic returns over the lifetime of the drug. As you have heard me say before, we want to be transparent about our goals and how we think about the business. When we look at the sell side revenue estimates for 2016, it seems like consensus estimates for the fourth quarter center in the high 8 million to low 9 million range, which is consistent with how we see the reminder of the year shaping up, and is consistent with our expectations regarding the early stage dynamics of the paradigm shift that NUPLAZID represents. So we are off to a good start and over the coming quarters and years we are confident that NUPLAZID will fundamentally change the way PD psychosis is treated. I'm going to move now to our pipeline. While our top priority of course is focused on the commercial launch of NUPLAZID, we are also excited to be executing on our lifecycle management science through a number of new studies across multiple indications, together with the completion later this year of our ongoing study in AD psychosis. Over the last couple of weeks, we have initiated two important clinical studies with pimavanserin. The SERENE study for Alzheimer’s disease agitation or AD agitation and the ENHANCE-1 study an adjunctive treatment of schizophrenia in patients with an inadequate response to current antipsychotic treatment. Each indication represents a sizable medical and commercial opportunity and is in an area, where new and improved therapies are greatly needed. Serge will go into more detail on these studies later in the call. So I will just briefly touch on each of these new programs. For AD agitation there is no drug approved by the FDA. Around 40% to 50% of patients diagnosed with Alzheimer's suffer from AD agitation. Today antipsychotics are frequently used off label to treat this condition, and as you have heard me say before, one of the complicating factors with the use of these drugs in Alzheimer's patients is that they have been shown to impair cognition. In other words, they make the primary symptom of Alzheimer's disease, cognitive impairment, worse. Pimavanserin of course works very differently than other antipsychotics with the selective serotonin inverse mechanism of action we believe pimavanserin has the potential to be an important new treatment option. For schizophrenia, the marketplace is different. Unlike PDP, where we are the only FDA approved drug, for AD psychosis or AD agitation where there are no therapies approved by the FDA, there are over 15 medicines approved today for schizophrenia. Despite this large number, drugs used to treat schizophrenia today just do not adequately address some very important symptoms of the disease, and they also carry significant side effects. They also tend to be fairly mechanistically similar. So with these drugs as a backdrop, studies show that approximately 30% of patients with schizophrenia have an inadequate response to their antipsychotic treatment. As a result, it is common clinical practice to prescribe two or more antipsychotics, despite the fact that these drugs all primarily target the dopaminergic pathway. Through its highly selective mechanism of action, pimavanserin targets 5-HT2A receptors that avoid activity of dopamine and other receptors commonly targeted by these antipsychotics. We believe adding pimavanserin to atypical antipsychotics may boost the antipsychotic effect, improve overall treatment response, and lessen the undesirable side effects associated with polypharmacy. As I noted previously, Serge will have additional comments on these important new studies and the potential benefits that pimavanserin may bring to patients suffering from Alzheimer's disease and schizophrenia. Before turning the call over to Todd to review our financial performance, let me make a brief introduction. Todd recently joined ACADIA as our Chief Financial Officer. He brings a wealth of financial and operational experience in the biopharmaceutical industry and held finance and leadership roles at Baxalta and Baxter. We are delighted to have him as part of our team, and with that I will the turn the call over to Todd.

Thank you Steve, and good afternoon everyone. I'd like to start off by saying how excited I am to have joined ACADIA and to be part of an organization making a meaningful difference in the lives of Parkinson's disease patients. Today I will highlight our third-quarter financial results starting with our product revenue for our first full quarter since launching NUPLAZID and I will wrap up by providing some insights into our outlook for the remainder of 2016. For the third quarter, we generated net product sales of $5.3 million with a gross to net percentage in the mid-20s. Our gross to net adjustments include fees paid to specialty pharmacies and specialty distributors, rebates and chargebacks associated with government programs, including our share of the donut hole for Medicare Part D patients, patient assistance to eligible privately insured patients and any product returns. I would like to mention that our gross to net adjustments can vary quarter-to-quarter primarily because our share of the donut hole for Medicare Part D patients will fluctuate each quarter. Please note that we recognize revenue when a specialty pharmacy dispenses NUPLAZID to a patient based on the fulfillment of a prescription, or when a specialty distributor sells NUPLAZID. This approach is frequently referred to as the sell through revenue recognition model, and is a common practice for companies launching their first product. Moving to the expense side of the P&L, total operating expenses for the third quarter of 2016 were $77.7 million. R&D expenses for the quarter increased to $25.8 million from $18.7 million in the third quarter of 2015. This increase was driven by increased clinical costs related to the launch of our AD agitation study and our schizophrenia study, plus preparation for the development of pimavanserin for additional indications. We also have increased personnel and related costs, including stock-based compensation expense associated with our expanded research and development organization. SG&A expenses increased to $50.5 million for the third quarter of 2016 from $20.3 million for the comparable quarter of 2015. This increase was driven by costs associated with the hiring of our specialty sales force in April 2016, increased costs related to support our commercial activities for NUPLAZID, and increased costs related to additional medical education programs. Turning now to our cash position. We ended the quarter with just under $589 million in cash and investment securities. For the third quarter, cash used in operations was approximately $50 million. We expect our cash used in operations to continue to increase in future quarters from investments to drive commercial growth and from our further development of pimavanserin for additional indications. Looking ahead, for the fourth quarter, we expect R&D expense to be in the mid-$30 million range and for SG&A expense to be in the high $50 million range. These amounts include expected stock-based compensation expense. With that I will now turn the call over to Terry, who will lead the discussion on the commercial launch of NUPLAZID.

Thanks Todd, and good afternoon everyone. As Steve has already mentioned, the launch is going very well, and I am pleased to report that today NUPLAZID performance and prescription growth are right on track with where we expect it to be at this point in the launch. Of note, I'm especially pleased to report that we are seeing steady adoption by physicians with consistent additions of new [writers] each week through the launch. Although it is still relatively early, our latest launch tracking survey as well as feedback from the field force suggest that physicians who are prescribing NUPLAZID are seeing results that are consistent with what we saw in our pivotal clinical trial including in some cases reports of patients who see the complete remission of their hallucinations and delusions. Operationally we are pleased with our sales force call activity, and importantly we are getting very good access to physicians. During the third quarter, our sales representatives met with over 13,000 healthcare professionals. In addition, our messages are resonating with physicians, and our most recent market research survey showed that NUPLAZID brand awareness among physicians continues to grow. In fact, unaided awareness of NUPLAZID went from 42% in June to 62% in September, and aided awareness increased from 66% to 76%. Among those aware of NUPLAZID 93% are aware of its attributes, and this is up from 73% in our previous market survey. We are also pleased with the overall performance of NUPLAZIDconnect in providing both provider and patient support. To date, the vast majority of patients through NUPLAZIDconnect are starting with their third day of free trial NUPLAZID, which they usually receive within 5 to 10 days after seeing the doctor. Now turning to the prescriber mix, as you may recall, our prelaunch research estimated our prescriber mix to be a little more than 15% neurologists, around 30% psychiatrists and around 20% long-term care. What we have seen to date is that our prescriber mix is about two thirds neurologists, around 10% to 15% psychiatrists, and around 20% in long-term care. At this early stage we are not surprised to see the higher proportion of neurologists given that they have a higher density of PDP patients, and are generally tiered higher on our call list than psychiatrists. So far our long-term-care is on track with our prelaunch estimate, but I just want to remind everyone it is early in the launch, and that may change. In terms of patient type, our latest survey indicates that a vast majority of patients who are prescribed NUPLAZID were experiencing disruptive symptoms. Switching gears to access and reimbursement, we are very pleased to report that NUPLAZID is now covered on virtually all Medicare Part D formularies, and as a reminder, NUPLAZID is in a protected class for Medicare. As you would expect, it is taking longer for the commercial segment of our business to make their formulary decisions and to date, NUPLAZID is now in formularies covering about 35% covered lives. The majority of plans covering NUPLAZID are requiring a prior authorization that simply confirms the PDP diagnosis. For those plans where a formal decision has not yet been made, banks are generally being adjudicated with prior authorization or a letter of medical necessity. As far as our payer mix, we are seeing that about three quarters of patients have Medicare Part D coverage, about 15% to 20% are covered under commercial plans, with the remainder of patients covered by VA, TRICARE, and Medicaid. Overall, we are making excellent progress in shifting healthcare providers from what has been a well established treatment paradigm of using antipsychotics off label to establishing NUPLAZID as the first choice, best choice for the treatment of hallucinations and delusions in Parkinson’s disease patients. We are confident the initial positive experiences reported by physicians will continue to accelerate prescribing of NUPLAZID for patients with Parkinson's disease psychosis and are very excited about the days ahead. And I will now turn the call over to Serge.

Thank you, Terry and good afternoon everyone. We have made significant progress in exhibiting on our broad development plans for pimavanserin. We are pursuing a number of additional indications with pimavanserin in areas of large medical needs. Last week, we announced the initiation of two important studies and plan to initiate two more by the end of the year. Before I review these new studies, let me discuss briefly our currently ongoing study with pimavanserin for Alzheimer’s disease psychosis. As we previously discussed, this is our first study in AD psychosis. It is being conducted through a single site with a large network of nursing homes in the London, England area. This is an exploratory Phase 2, 12-week randomized, double-blind, placebo-controlled study designed to examine the efficacy and safety of 34 mg dose of pimavanserin compared to placebo in patients with AD psychosis. We enrolled181 patients in this study. The primary endpoint is psychosis that is measured by the psychosis subscale or to put it in other words combined hallucinations and delusions domains of NPINH score at week 6. We are also accessing secondary measures including behavioral symptoms and sleep. Additionally, we are assessing Mini Mental State Exam over 12 weeks of treatment to evaluate the impact of pimavanserin on cognitive status compared to placebo. As previously stated, we plan to announce top line data from this study by the end of the year. Let me now turn to our new programs for pimavanserin, and let us start with AD agitation. Similar to AD psychosis, there is no drug approved by the FDA for AD agitation. AD agitation is a serious and common condition that is a major cause of distress for Alzheimer’s disease patients, their families and caregivers. Over 5 million people in the United States are living with Alzheimer’s disease and approximately half are diagnosed with this disease. Studies suggest that around 40% to 50% of patients diagnosed with Alzheimer's disease exhibit agitation as agitation is associated with more rapid cognitive decline, greater caregiver burden and earlier institutionalization. As this agitation in AD is characterized by verbal aggression, such as screaming, shouting; physical aggression, such as grabbing, pushing, hitting and excessive motor activities such as pacing and restlessness. With no FDA therapy for AD agitation, physicians often prescribe antipsychotics off label. However, there are drawbacks with these therapies including inadequate efficacy and significant side effects. The KD-AD study, Alzheimer’s disease study, has shown that antipsychotic treatments associated with worsening cognitive functioning at the magnitude equivalent to one additional year of disease progression. Pre-clinical and clinical data suggest that antagonism with 5HD2A receptors may play a role in decreasing symptoms of agitation. Involvement of serotonin system in the pathophysiology of agitation is further implicated by the off label use of trazodone, citalopram and other SSRIs in treatment of AD agitation. Given its novel mechanism of action as a selective serotonin inverse agonist, or SSIA, preferentially targeting 5HD2A receptors, we believe pimavanserin may confer efficacy in patients with AD agitation. In addition, pimavanserin overall favorable side effect profile may make it a promising therapy for AD agitation. Our SERENE study in AD agitation is a randomized, double-blind, placebo-controlled, multi-center outpatient study designed to examine the efficacy and safety of pimavanserin in approximately 430 patients. Study participants will be randomized to receive once daily oral doses of 34 mg pimavanserin, 20 mg pimavanserin or placebo for 12 weeks. The primary endpoint of the study is a reduction in total score on the Cohen-Mansfield Agitation Inventory. Following participation in SERENE patients will be eligible to enroll in off-label safety extension study. Let me now turn to schizophrenia. As many of you know, schizophrenia is a chronic, debilitating mentally and is characterized by thought disorder, emotional and cognitive dysfunction and behavioral disturbances. According to the National Institute of Mental Health, approximately 1% of the US population develops schizophrenia during their lifetime. These disturbances may include positive symptoms such as hallucinations, delusions and disorganized speech, as well as a range of negative symptoms including flat affect, loss of interest, emotional withdrawal and cognitive disturbances. As Steve mentioned earlier, current anti-psychotics used to treat schizophrenia have substantial limitations including severe side effects and inadequate response on the full range of symptoms of the disease. According to the American Psychiatric Association, about 10% to 30% of patients do not respond to antipsychotic treatment, or are what we call treatment resistant. Another 30% of patients have inadequate response to antipsychotic medications, meaning that they exhibit some improvement but continue to have psychotic symptoms. This is the population we are addressing in our study. Today we know that about 25% to 50% of patients with schizophrenia are treated with two or more antipsychotics. This polypharmacy has led to increased incidence of side effects and more complicated treatment regimens that can further contribute to poor compliance and subsequent relapse in patients with schizophrenia. Given pimavanserin’s highly selective pharmacological profile, and our past clinical experience with pimavanserin in schizophrenia, we believe adding pimavanserin to atypical antipsychotics could potentiate the antipsychotic effect, improve overall treatment response and lessen the undesirable side effects often associated with polypharmacy. Last week we announced we had initiated our Phase 3 schizophrenia study called ENHANCE-1. It is a six weeks randomized, double-blind, placebo controlled, multi-center, outpatient study designed to examine the efficacy and safety of adjunctive use of pimavanserin in patients with schizophrenia, who have an inadequate response to current antipsychotic treatment. Approximately 380 patients will be randomized to receive pimavanserin or placebo orally, once daily added to their ongoing antipsychotic in a flexible dosing regimen. The starting daily dose of 20 mg of pimavanserin at baseline maybe adjusted to 34 mg or 10 mg during the first three weeks of treatment. The primary endpoint of the study is the change from baseline to week six on the Positive and Negative Syndrome Scale or PANSS total score. Following participation in ENHANCE-1 patients will be eligible to enroll in 52-week open label extension study. In addition to these two recently launched studies, we plan to initiate two studies in additional indications by the end of the year. Let me now turn the call back over to Steve.

Thanks much, Serge. In summary, it is an exciting time at ACADIA. Our commercial team continues to raise awareness and drive adoption of NUPLAZID, and we are pleased with the progress we made and look forward to continuing to build on this foundation. At the same time, we have taken our development program to the next phase with the initiation of these two new studies in AD agitation and schizophrenia, and plan to commence two additional studies by the end of the year. Before turning the call over to the operator, I would like to thank everyone at ACADIA for their hard work and dedication. All of us here remain deeply committed and driven to improving the lives of people with CNS disorders. I will now turn the call over to the operator to commence the Q&A session.

[Operator Instructions] And your first question comes from the line of Cory Kasimov of JP Morgan. Your line is open.

Guys, thanks for taking my questions and thanks for all the detail today. It's good to see a nice start for NUPLAZID, I guess a question for you on the commercial side, and then also one on the clinical side, so can you give any quantitative description of how many sample or just a rough estimate of how many samples are out in the field. I guess I’m curious how much of the sales numbers in the third quarter reflective of actual demand, any people are thinking that the sampling program you had might depress the numbers a little bit in the early stage of the launch? And then I’ve one clinical question?

Yes, thanks, this is Steve. Let me give you really quick response and Terry may want to fill a little bit more detail. So, I just want to remind you a few type of sampling one is the physical bottles that we’ve all experienced, we’ve all had our physicians given to us bigger and other. And then in addition to that for physicians that write scripts going to the hub, they have, we make available to each patient a 30-day free trial. So very consciously we have provided a lot of pre-drug in form of samples in assistance and that will continue to be the case to these early days important to watch. Terry do you want to add anything more to that.

Cory, you think that we early felt that important was that physicians have access to the drug in advice forms so that they can get their patients on the drug immediately. We felt strongly that a 30-day free trial would be an ample amount to get patients through the adjudication process and we know that the majority of our prescriptions are going through our hub therefore, the majority of patients are having their 30-day supply accompany that. However, we also know that physicians are handing out samples in some cases they may have or can simply ask for both, the patient going home with samples that awaiting 30-day free trial or someone who is not going to get that 30-day free trial. In both cases we made a conservative effort to make sure that there is vast opportunity to the physicians to sample out there and although we haven’t given numbers, we’ve at launch really hands up to sampling in the marketplace during the launch period.

And just one – I’d echo what Terry said is one quick annotation. I think it’s a very important element of building the rack foundation. We care about short term target, the short term indicators, we care a lot more about the long term and making certain that we’re building the rack foundation and making certain that we don’t have – that we can minimize patients or physicians as mini accurate issues with the drug with the important part of line in that foundation.

Okay, alright, terrific. And then, on the clinical side, I just want to ask about the recently started phase III Schizophrenia trial and really how long that has been in the workforce, it’s seem like the Schizophrenia indication is something you’re always talking about maybe figuring out down the road or prioritizing some other indication such as AD agitation. So, if that was the case I’m wondering kind of what’s changed there?

Yes, I’ll start and then certainly maybe Serge wants to jump into that. We’ve always been – our interest in Schizophrenia has never veined. I think as everyone knows it’s a new management team relatively speaking and what the company has an interesting Schizophrenia, the original path that the company had laid out was a monotherapy maintenance approach which we think is very interesting but we think the approach that we’re taking now is a much more interesting approach and we did an awful lot of commercial analysis around this before choosing this. So, this has been in works for literally almost a year now to get to this point and starting the study, we’ve known what we’re going to do for some time, you can talk a lot about it for variety of reasons including some benefit reasons. There are other people working in the space and are frankly we don’t see any reason to tell them exactly what’s going to be good and so we’re competing probations. So, we’ve had a very long term interest in Schizophrenia primarily driven by, not primarily driven by the very significant unmet need which Serge described in his remarks. Serge if you have anything else to add in that.

Just to add that really pursuing Schizophrenia indication is a natural place for pimavanserin not only on the basis of all the clear medical needs and unmet need in Schizophrenia, but also on the basis of pharmacology of pimavanserin and the clinical data that we already have in pimavanserin naturally and to pursuing this indication.

Okay, great, thanks again.

Just remind you one thing, I know that I’ve said this before probably one has heard me say it, but there are certain advantages to being in a position where instead of trying to displace [indiscernible] which we do have in Schizophrenia being in a position where – and the mechanism the drug is limited stuff so we find this very intrigue to the edge of therapy going on heart of existing medication. So, we don’t need it for successful here, we don’t need to displace them if we show it as the benefit to those existing across.

Okay, it’s a good point, I appreciate you taking the questions, thanks.

And your next question comes from the line of Alan Carr, Needham & Company, your line is open.

Thanks for taking my questions. Couple of them, if you can give us an update on where things stand with the European pediatric plan? And then, actually the follow up on Schizophrenia little bit of a different strategy maybe then the phase II trial going way back to I think 2006 or 2007 where you had a lower dose of [indiscernible] in combination with pimavanserin. Can you talk a little bit more about that in terms of why do it this way and also little bit more also around why the three different doses NUPLAZID, what’s going to drive the – is it going to be a penetration where they start off at 20 and then you try to force them up and if they don’t tolerate your lower, what’s the thinking behind that? Thanks.

So Alan I’m going to ask Serge to respond to that question.

Yes, first let me start with European. On our Q2 call in August we announced that we would need to resubmit the propose to pediatric investigational plan as you know that’s the requirement to have either waiver or agreed plan with the pediatric community we may before we can submit our PDP MAA. We did submit our peep in the third quarter and we’re waiting to hear back from the pediatric community on our plan. Once we get of peep approved we can provide an update on the timing of our filing of the market and authorization in Europe. And in regard to those, our phase II trial in Schizophrenia and these had a lower doses with antipsychotic that are used in that trial risperidone and haloperidol with the idea that the similar efficacy would improve side effects profile can be achieved in combination with pimavanserin. The account we’re taking in adjunctive therapy is really to achieve the same potentiation of antipsychotic effect, but this time in patients that have inadequate response who currently use antipsychotic. And the regiment that we decided to pursue is the flexible dosing regimen, rationale for that is this is whole commerce study with almost all antipsychotics being editable for patients to be included in the trial and from that perspective it is allowing flexibility to investigators and physicians to adjust the dose to the need of patient in bed. So, it’s not a false preparation, it is on basis everybody will start from 20 milligram, but adjustment of those in the first three weeks of treatment will be based on the efficacy seen in patients as well as obviously thorough ability profile.

And so, you are focusing on points or there lot of other secondary endpoints in here that you’re going to be watching in this phase III trial?

Yes, we’ve as it is usually done we’ve a number of secondary measure however obviously, the key secondary measure is clinical global impression of severity. But in addition to that there is personal and social performance scale, we’re measuring a number of other scales that are – as a secondary measure in this study as usually done in this trial.

Anyways and you would expect any impact on negative symptoms with this drug or just positive?

Well, the patients that will be enrolled in this trial would have positive symptoms and in the context of positive the evolution of negative symptoms in the context of improvement of the overall psychotic symptoms is methodologically complex because of sort of specificity. But we absolutely expect on the basis of our prior experience and on the basis of mechanistic assumptions around pimavanserin that we will have a positive impact of negative symptoms and we’re definitely thinking of specifically addressing those symptoms in our development.

Okay. And then, I guess, your plan here is that if this is positive you just run another one in serial right after to confirm it?

The idea obviously is we need to learn from this trial and the idea being that we would be starting the trial, the trial will have, the enhanced ones will have preplan interim analysis for futility and provided that interim analysis suggest continuation of that trial will be then planning on starting the second trial in Schizophrenia with the same indication.

Great, thanks very much, I appreciate.

Hi Alan, actually I just wanted to add a couple of comments to what Serge mentioned. When we did the previous study in therapy – we did see that high significant results and they did translate in both positive and negative symptoms. So negative symptoms in Schizophrenia as we said is also an area according to us, it’s an area that has – it’s not approved to treat negative symptoms in Schizophrenia it’s a scenario that has long, long been – not the highest, but one of the highest unmet needs in Schizophrenia. And the missing area that we continue to be very interested in. When you look at the profile pimavanserin, in addition to having shown a strong antipsychotic effect in two very different patient populations and PDP psychotic patients and Schizophrenia, we also see a profile that has strong potential in depression and we’ve seen in the clinic a strong effect on [indiscernible] also areas that fit into the entire consolation of symptoms that Schizophrenia patients have. So we need to do the study that we’ve laid out but we will get a lot of very helpful and important information out of this study that I think will guide our further development of the molecule. And we’re safer now that both the Schizophrenia patients with inadequate response to single antipsychotic and negative symptoms in Schizophrenia remain areas of very significant unmet needs in winter course.

Alright that’s helpful, thank you.

And your next question comes from the line of Ritu Baral of Cowen, your line is open.

Hi guys, kind of graphs on the early start and future quarters. On the sales reported today, can you tell us what percentage of those sales were from patients to rolled over from clinical trials or were previously exposed to the drug versus new to drug patients?

Rita I can’t give you the exact number but what I can tell you, rolled over some clinical trials with a very, very small part of those sales, a very, very small part. We just didn’t have a lot of patients that rolled over onto commercial drug from ongoing clinical studies.

Okay, fair enough. And what are you observing as far as current time to sell on prescription, is the 30-day free drug, is that sort of covering the gap that’s need to get insurance authorization or is it sort of extending path?

Serge you can take that question.

It turns out that the three day supply is ample time for most patients to get their clients adjudicated and the prescription sent. So I am very pleased with that today.

As we said before, we do have a bridging program, we have done some bridging [Indiscernible] for the most part 30 days has been sufficient and of course we anticipate that as we get more commercial formularies that the time for adjudication will shorten and will be less need to bridge in future.

What's your target time to fill? Like would you affect it? All right, fair enough. And then, you mentioned that your gross to net may fluctuate for a number of factors. Can you bracket what the range could be given their ability with the [Indiscernible] but also it looks like an increasing proportion from the commercial patients over with the next few quarters?

So [Indiscernible] is going to take that question.

We do as you know we have guidance specifically obviously in Q3 we are in the mid 20's on our gross to net, but [Indiscernible] is the biggest driver of fluctuations from quarter-to-quarter, it realizes that it's a calendar year based program, it's individual to each patient based on the total portfolio of drugs they take. Now, for most of our PDP patients, there modern meds are generic that wouldn't create as big as [Indiscernible] liability as a drug price in our range and so we would expect that early in a calendar year our percentage of [Indiscernible] would be higher than it would be later in the year as more patience progress through it. The caveat on that is obviously were early loss, we've lost in the second half of the year and so we still are getting our arms wrapped around what this specific amounts will be, but certainly the [Indiscernible] is the biggest driver of fluctuations quarter-over-quarter. And as you mentioned as the commercial mix and the Medicare mix change overtime that will also affect it, but at this point mid 20s this quarter and you will see what happens here in Q4.

Got it and then a question for Serge, as we think about that 20 milligram dose in both the agitation study and Schizophrenia setting study, what is the receptor occupancy of the 20 milligram dose to 10 milligram dose in comparison to the 34 milligram dose, I guess why did you pick the 20 versus others?

There was only one small study done some years ago on the receptor occupancy and what we know that nearly complete occupancy is achieved fairly fast that we're on the escalation of dosage. So we certainly are closed to full occupancy at 20 milligram and above and will of course this was study done in very few patients, so one should take results with some caution in this respect. But the point that we need to remember is that receptor occupancy per say is not necessarily the only element when we take into consideration when thinking of the dose. What guided us mostly are two things, one is that 17 milligram equivalent of 17 milligram dose in the previous study clearly demonstrated enhancement of antipsychotic effect with risperidone and as Steve said both in positive and negative symptoms and the study was done in acute patients. So that guided us that the starting dose of 20 milligram is certainly the dose that is a reason for this trial. Second thing is that as I said we have patients here on different doses of atypical antipsychotic and different and atypical antipsychotic that will answer the trial, so allowing flexibility around 20 milligram dose that we know that has antipsychotic potentiation is a reason of all approach that we thought we should take in the trial.

Got it and then last question, how are you defining inadequate response or inadequate control in the schizophrenia study?

It is defined by essentially constellation of criteria, one is certain severity of the overall psychotic symptoms as measure on the thought of 10 score and then on the presence and severity of the particular specific positive symptoms that have to be the moderate or higher severity presence in order for patients to qualify. And finally, on the overall global assessment of severity of psychotic symptoms, so it's not only one criteria, it's kind of a constellation of criteria that define this patient.

Understood, thanks for taking all the questions.

Thank you.

Our next question is from the line of Charles Duncan of Piper Jaffray. Your line is open.

Thanks for taking the questions, one commercial and two brief clinical questions. First of all, on the commercial side, yes wow! Really nice quarter out of the box so congratulations on that. I am wondering if you can provide any additional, yes so Steve any additional color in the main driver for the early out of the box strength to guess, I mean you be consensus pretty handedly. Terry said that this is consistent with where you would have expected the drug to be, how do you see the next quarter turning out?

I would have to repeat myself, so many things so for about the launch has really been very consistent with what we expected. The payer reaction very consistent what we expected, but we knew that aero bars were very wide, it could have been very different, but it's very consistent. For this experience again which is something you just don't know, there is no one worth knowing until you get the drugs into the smaller populations and it's early, but so far, very, very consistent. So I think I guess we're not surprised because so many things have been consistent with what we anticipated that we did in the quarter come out ahead of our own plan a little bit. But it's very consistent and most importantly it's just very consistent with the type of launch that we have expected based upon the market research and looking a lot of other drug launches of risperidone shifting potential, etcetera. And what we have expected is that we would establish a foundation and build on it and I think what when we work at the street and how the street has thought about it, we try to be very transparent as much as we can, giving all of the subjective and dynamic observations that we have. I think it is a pretty good correlation as we said with how we're expecting this launch in the early days and how people on the street are expecting, so yes we did come in above consensus estimates in the third quarter as I mentioned. We also observe what the street is and just waiting for the fourth quarter. We think that's consistent with our view of that and then as we roll into 2017 it would be way, way premature for us to having the public view on that. But I think so far in the launch we are seeing things are rolling up as we expected and it feels like it's kind of a street has expected at least from a zip code type of perspective.

Okay, that's helpful. Well great execution thus far and its sound like there wasn't any like bogus of patient set or waiting for the drug or anything shifts new demand for a new drug?

Yes, we did have a little bit of what our characterized is -- we saw that early on in time – June you kind of got to match all the free drug and we saw some of that in July, but by and large again it's been kind of this, the best way we can characterize is that foundation that we’re lying, we are doing a lot of sampling. We are doing things that have a negative impact on newer term revenues, but built the foundation for the long run and of course at the end of the day that's what most important to us in terms of reaching the full potential of patients that can benefit from the drugs and of course benefit from our shareholders.

Okay, thank you. And then, my two clinical questions for Serge, just first of all on the enhanced study, could you share with us any of the measures that you plan to take to ensure call it clinical sight or patient quality or control for a foreseeable response in terms of over the course of this six week study? And then quickly for Serene, what drove the decision to conduct the program in a 100% of outpatient setting, which is really different than the ADA study in terms of this ADP, is that a care giver input, different severity patients what really drove that strategy?

I would take one by one, in the schizophrenia study, we are applying all of the standard measures to reduce the placebo response as where and particularly measures for inter radar reliability. So we are doing pretty much everything that current methodology in clinical trials and schizophrenia is sort of standardly applying to this. Nothing specifically unusual, but one of the things that we particularly believe is important for any clinical trial and by implication in schizophrenia is actually in drawing the right patients in the phase of trial. So we will try to do that in all of our trials independent confirmation of the eligibility particularly from the psychiatric diagnosis and criteria for that is not only relying on the investigator, but as well as the independent qualified interviewer that the patient is really the right patient for the trial. And that I think is the critical element that we hope will improve significance to the quality and performance in the trial. The second question I am sorry, it skipped my mind right now I can't…

Just quickly the Serene trial what drove the decision to conduct the program in 100% outpatient sitting different from the ADP study?

It is mostly the patient severity or illness that we are targeting primarily moderate to severe patients, the patients that are already in the institutions may have much more advanced Alzheimer disease. And it may be a more difficult to evaluate properly the treatment effects. So in this patient that they are outpatient they can still be in the supported care, but not receiving round the clock medical care. So as long as they are capable to be actually do their visits at the site as an outpatient they are eligible for the trials.

Okay thanks for the added color, great quarter.

Thank you, Charles.

Your next question comes from the line of Tazeen Ahmad from Bank of America, your line is open.

Hi, good afternoon. Thanks for taking my questions. Just a couple on the launch if I might, so in terms of your expectations Steve, you've mentioned that what you're seeing and the metrics have been consistent as far with what you would have expected before the launch. So why not think about issuing sales guidance so far that the launch is going as you expected, I mean do you think that there could be, you mentioned some low hanging fruit, but you think that would be meaningful enough to potentially have an impact at the beginning and then dissipate and then perhaps have an impact on what the future trajectory of the launch would be, it would just be a lot easier for us to be able to get a sense from you as to where you think the sales trends are going over the next couple of quarters. And then for PDP in Europe, do we just get a sense from you about what kind of pricing you would think would be reasonable to expect. Obviously, it would be lower than what you're getting here in the US but is it something that is more in the 20% to 30% discount range or is something more meaningful like 50% less than what we would expect to get here in the US. And then maybe one question after that on a free trial?

Yes. Thanks for the questions, Tazeen. Let me take your last one first, regarding the EU pricings. It's of course its way premature for us to comment about what how we would price the entire goods outside the United States. But I will just repeat what we said before that for these kinds of drugs because we're not in the orphan space, the oncology space, etcetera. It's not uncommon to see pricing outside of the US be dramatically lower than US. So, greater than 50% discounted from the US prices. Not uncommon if you look at some of the other CNS drugs, or even the psychiatric drugs for them to be the 15% or 20% of the US price. Now, I have no idea if that discount will be in for NUPLAZID. We've obviously got a lot of advantages to the drug that we think should be reflected. It's one of the cleared, the pricing outside of the United States for these kinds of drugs, it's just very different. I certainly appreciate the desire for us to give guidance. I just think at this point, although today, being said very consistent with our expectations. It is still very early. And the error-bars as we look further into the future are still very wide. And so, we just don’t think it would be appropriate or prudent to do that as we state. There will come a time where that won't be a haste. But today we think it's just premature for us to do that. And we're also somewhat confident by what we see, as I mention when we look at how this three has looked at the fourth quarter and looking into 2017. It appears that we are at least quantitated, we're looking at this in a similar fashion in terms of lost dynamics and into the tinsel to establish a foundation and grow and grow. So, trust me, we look forward to affording time where we can be more precise and be more quantitated that we just, it's just not now.

Okay. And then maybe just one question on the 30 day free trial. Are there instances where you're allowing patients to renew a 30 day free trial after they've already had one and if so what type of criteria are you using to determine that somebody should be given a renewal?

Yes. So, Terry is going to take that question, Tazeen.

So, the answer is yes, there are situations where the adjudication is taking longer. It's very important to us that the patients there be not be interrupted. In those cases we are granting bridges for those patients so that they can remain on therapy while the adjudication process stays place. So, it's the more new cases but we do that to make sure that therapy is not interrupted.

And have you had that happen, I guess you must have had that happen a few times already since you've launched.

Sure. It's happened a few times as I said, it's a minority of cases but we have done it.

Okay. All right, thank you guys.

Thank you.

Your next question comes from the line of Jason Butler with JMP Securities. Your line is open.

Hi, thanks for taking the questions. Just first on the schizophrenia trial, I know we're somewhere away from results. But can you give us any kind of benchmarks for what clinically relevant effects would be as an adjunctive therapy. I mean, when you look at the atypical, you're seeing effect sizes schizophrenia from 0.3 to let's say 0.6. Are you looking for any incremental benefit or do you need to see something that's in line with what we see as a monotherapy?

We certainly are want to see something that is clinically meaningful. And what we believe and what generally it seems that there is agreement is what we assume as difference that we will see from placebo in the context of adjunctive therapy. It's probably not going to be over effect size that we see in monotherapy but fairly close to that, that what we are looking at. And we're just, we're in the assumption of our sample size, we assume a difference placebo and active treatment of six points on pens as a meaningful difference. And that is what we expect to see as the minimum in our trial.

Okay, that's helpful. So, just wanted to ask what your comments on the mechanistic rationale for the potential lack of cognitive impact with when you place it in Alzheimer’s patients. Are you thinking that the drug has a greater impact on serotonin and other atypical and psychotics and that’s what would drive the potentially the lack of cognitive effects or is it the fact that you're not hitting the other targets like dopamine, that maybe is driving cognitive decline with those drugs that you wouldn’t course?

Now, obviously to some extent, commenting on this is always speculative, but it could be the latter what we believe and that is that the absence of direct effect or dopamine transmission would be something that would we believe be beneficial in terms of the pimavanserin action.

Great. Thanks for taking the questions.

Your next question comes from the line of Paul Matteis with Leerink. Your line is open.

Okay, great. Thank you, very much and congrats in all the progress.

Thanks, Paul.

A one commercial question. Thanks, Steve. First, on the commercial side, of the 5.5 million in sales, were there any change in inventory and is that driving any of the effect that you saw this quarter?

Hi Paul, it's Serge. Now, the inventory is not was up there with -- to suggest any big low in the channel or the sort of thing you might see on drug launches, or specialty pharmacies are not being, it's in the as soon as we way load inventory. So, this is very much pace and demands driven results.

Yes, okay.

It's just a give a little bit more color there. Because 1) it's a very simple molecule to make. And 2) we're distributing exclusively to specialty pharmacies and specialty distributors. We just don’t have the kind of inventory in the channel that you might expect if we're distributing through a typical wholesale type of distribution. So, our inventory is a system just won't get the same kind of levels that you would have elsewhere.

And to mention Paul, this has been on the self-driven revenue recognition model. We don’t recognize revenue just when as it starts with pharmacy by the product provost that is up on the balance sheet not at all revenue account.

Okay. That all makes a lot of sense. And then if I might just add two clinical questions. My first one is on agitation. I'm wondering with the ADPD that's so the coming up so soon, why not we introduce data from that study before starting a program in education, since education is secondary endpoint in that trial. You expect to get useful information on the effect on agitation symptoms in the ADP trial?

So, Serge can answer that question, Paul.

The primary reason is that although it is a secondary outcome, the ADP trail did not specifically require any level of any threshold low agitation to quality for that trial. And did not even require a minimum agitation to qualify for the trial. Therefore we don’t really there will be a subset of patient that we will may see some effects of pimavanserin non-agitation. Because not all patients will have sufficient severity of symptoms to evaluate that. So, we do not, although that will be a interesting and informative data from the trial in regard to adjudication as well as other behavioral symptoms that are measured by the neuropsychiatric inventory. Remember that measure about 12 different domains across behavioral or neuropsychiatric symptoms. The only really decisive information that we will have is on psychotic symptoms on hallucinations and delusions. So, we did not consider that in whatever outcome of the ADP trial in regard to agitation there is decisive criterion for the start of that AD agitation trail and we just and just refer now why we did not wait for the results.

Okay, that makes a lot of sense, Serge. And then if I may just ask one quick one on schizophrenia, I'm honestly a little bit confused of the mechanism in schizophrenia, because my understanding is that these patients will be on back on therapy within atypical antipsychotic which already modulates 5-HT2A. so, I'm wondering when you think about adding on pimavanserin, isn’t that receptor already saturated by the patients current therapy or at least in some of the patients, maybe you could just comment a little bit on what you can just going to be driving the and the benefit of pimavanserin in schizophrenia in that context. Thanks.

Well, there is the direct modulation on the 5-HT2A but the results of the indirect modulation of other neurotransmitter via 5-HT2A, and which actually some of the explanations for drugs that have both D2 and 5-HT2, action mechanism more action, it still there is a space for additional efficacy because they are not really completely familiarizing symptoms of psychosis. So, what the larger key here is that pimavanserin adding pimavanserin to the mix of the effects of atypical antipsychotic throughout different receptors in neurotransmitter systems is increasing the effects of through direct or indirect effect, not only on serotonin system but on dopamine system and others? So, that's I know it's probably not a very foolish distractory explanation but it's a lot of theory going in there and of course there are all hypothesis, we don’t have any exact knowledge of the precise mechanism.

Sure, fair enough. Well thank you, Serge, appreciate it.

Uh-huh.

Your next question comes from the line of Salveen Richter with Goldman Sachs. Your line is open.

Hi Salveen, are you there? Operator, why don’t we try to circle back to Salveen? We can't hear or if she's asking question.

Your next question comes from the line of Bert Hazlett with BTIG. Your line is open.

Thanks. Congratulation on all the progress. I have two quick questions. Is there any sense that the 30 day sample you're giving out, do you have any sense of whether or not there is that's taking longer than 30 days to get through? Meaning, is there any titration of the dosing going on. And then just a second one. As you think of the patients that are having experience with NUPLAZID, is there any way to tell whether this is part of the installed base, meaning these are long term Parkinson psychosis patients or are they newly diagnosed patients that are just simply coming into the system. So, are they getting switched from other atypical or are the brand new Parkinson psychosis patients, or can you tell that at this point?

Let me take just good running short of time. Let me take a really quick stab at that and Terry may want to jump in as well. In terms of refill rates, it's just way too early for us to have a feel for that. We love to have a fine view that we just don’t. So, we don’t have enough data at this early stage yet, as we're ramping up and then of course we have more patients on therapy, week-to-week and month-to-month. We still not have a good feel yet for the refill frequency and rates as they go month-to-month. And I'm sorry, your second question was?

Is it just.

Yes. On [indiscernible] patient. I know it's going to be very satisfactory and so it's just too fluid at this juncture for us to really comment on that because it's just that we were seeing that move around a little bit. So, that's also the kind of thing we look forward to having a more fine view on in future.

All right. Thanks for taking the questions.

Yes.

Your last question comes from the line of Tazeen Ahmad with Bank of America. Your line is open.

Okay, guys, thanks so much for taking a follow-up from me after a long call.

Sure, Tazeen.

But can I just ask one question on the ADP trial. Are you looking definitively to hit your primary endpoint in order to decide whether this indication has something worth pursuing or could it be the case that if you see directional trends that might encourage you to maybe redesign a different trial and keep looking at this indication. We're just trying to get a sense of whether it's all or nothing with the three out? Thanks.

So, Tazeen, I'll take again I'll take a quick stab, certainly when a challenge. I would have a little bit of distinction between the 019 Study that will read out about in the studies that we're initiating. The 019 Study is really designed and executed as really a very exploratory study. And we talked about this in the past, of course it's all one symptom and is there are other things that are unique to that study that I think give us a certain whims to look here in terms of what the data will give out. I think probably likely they will give will achieve the definite study and that is give enough information to have a full view about what to do next. And in these early exploratory studies designed and in the way this one was, it maybe that we have one in the spectrum a highly statistical significant results, positive results. And it gives fair with good clarity, when we pressure test it, we think that that is a believable result and gives a fairly good clarity to go forward. On the other in the spectrum, it's powerful when the studies that you get a result, you feel like it was a valid test of the mechanism, it wasn’t a failed study, there's no reason to go forward. And there's a whole lot of grey area in between and in these early explorative studies, you wind up in the grey area more often than not. So, we just don’t know, this we just gone onto the study results, so we're very eager to get this study results but we think there is a very good likelihood and always happens with these subjective endpoints and CNS that a very good likely that that will give, will achieve the objectives of the study, and get information which tells what to do next.

So, even if you do hit that say the assumption would be that you would have to move to a phase 3, you wouldn't be able to just file on this study result as it was highly statistically significant. Is that right?

Yes. I mean, it's always you hate the -- before you actually open the envelope and you hate to say whether there study could or couldn’t be registrational. But this would really was not designed to be registrations but when you're executed to be a registrational study. So, it's probably very unlikely. Now, when we open the envelope, we'll of course take a look at that but I think it's very unlikely that this would be a registrational study and just wasn’t designed and executed in the way that the 020 Study was that gives so is the basics of a single study approval in [phase 3], of course.

Okay. Thank you for that color, Steve.

Yes, you bet.

There are no further questions at this time. I'd turn the call back over to Mr. Davis.

Great. I know it's been a long call, so thanks to give for everyone for joining us today and for your continued support. We look forward to updating you in the future on our own progress.

This concludes today's conference call. You may now disconnect.