ACADIA Pharmaceuticals Inc (ACAD) 2016 Q3 法說會逐字稿

Good day, ladies and gentlemen, and welcome to ACADIA Pharmaceuticals' third-quarter 2016 financial results conference call. My name is Suzanne 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, Suzanne. 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 for regulatory approval; the benefits or advantages to be derived from future approvals 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 candidates.

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've made with the launch of NUPLAZID. And second, I'll discuss the important advances we've 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 for pimavanserin.

Now let me turn to the launch. We've made great progress in our first full quarter with NUPLAZID on the market. We saw solid growth and 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 prior 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 to look at the foundational elements of the launch in these early days, we see a very compelling opportunity. We see steady rates of new patients starting, and continuing growth in the number of prescribing physicians and patients on NUPLAZID.

Let's take a look at some of these elements. On the access and reimbursement front, it's important, early in the launch, to have broad and easy access. We're 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 is consistent with what we observed in the clinical studies.

Now, 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 to date.

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 the 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, the 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're hearing from the medical community.

As we've 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 a drug. As you've 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 remainder 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're off to a good start. And over the coming quarters and years, we're 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 plans 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 study as an adjunctive treatment for 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've heard me say before, one of the complicating factors with the use of these drugs in Alzheimer's patients is that they've 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 its selective serotonin inverse agonist 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; or 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 but avoids activity in 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've 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 leadership roles at Baxalta and Baxter. We're delighted to have him as part of our team.

And with that, I'll 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'll 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 from 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 comps, 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 salesforce in April 2016, increased costs related to supporting 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'm pleased to report that to date, NUPLAZID performance and prescription growth are right on track with where we expected to be at this point in the launch. Of note, I'm especially pleased to report that we're 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, suggests that physicians who have prescribed 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 a complete remission of their hallucinations and delusions.

Operationally, we are pleased with our salesforce call activity. And importantly, we're 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're 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 a 30-day free trial of NUPLAZID, which they usually receive within 5 to 10 days after seeing a doctor.

Now turning to the prescriber mix. As you may recall, our pre-launch research estimated our prescriber mix to be a little more than 50% neurologist, around 30% psychiatrist, and around 20% in long-term care. What we've seen to date is that our prescriber mix is about two-thirds neurologist, around 10% to 15% psychiatrist, and around 20% in long-term care.

At this early stage, we're not surprised to see the higher proportion of neurologists, given that they have a higher density of PDP patients, and are generally a tier higher on our call lists than our psychiatrists. So far, our long-term care is on track with our pre-launch estimates. But I just want to remind everyone, it's 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. As a reminder, NUPLAZID is in a protected class for Medicare. As you'd expect, it's taking longer for the commercial segment of our business to make their formulary decisions; and, to date, NUPLAZID is now on 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, plans 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 the 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 executing on our broad development plans for pimavanserin. We are pursuing a number of additional indications with pimavanserin in areas of large medical need. 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 II, 12-week, randomized, double-blind, placebo-controlled study designed to examine the efficacy and safety of 34-milligram dose of pimavanserin compared to placebo in patients with AD psychosis. We enrolled 181 patients in this study.

The primary endpoint is psychosis as measured by the psychosis subscale, or to put it in other words, combined hallucinations and delusions domains of NPI-NH score at week six. We're also assessing secondary measures, including behavioral symptoms and sleep.

Additionally, we are assessing Mini Mental Status 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's 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 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.

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 anti-psychotics off-label. However, there are drawbacks with these therapies, including inadequate efficacy and significant side effects. The Catie-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. Preclinical and clinical data suggest that antagonism at 5-HT2A receptors may play a role in decreasing symptoms of agitation.

Involvement of serotonin system in a part of physiology 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 5-HT2A 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 design 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-milligram pimavanserin, 20-milligram 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 open-label safety extension study.

Let me know turn to schizophrenia. As many of you know, schizophrenia is a chronic, debilitating mental illness 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, lost of interest, emotional withdrawal, and cognitive disturbances.

As Steve mentioned earlier, current antipsychotics 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 background antipsychotic -- atypical antipsychotics -- could potentially aid 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 III 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 milligram of pimavanserin at baseline may be adjusted to 34 milligrams or 10 milligrams 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 a 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's an exciting time at ACADIA. Our commercial team continues to raise awareness and drive adoption of NUPLAZID. And we're pleased with the progress we've made, and look forward to continuing to build on this foundation.

At the same time, we've 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'd like to thank everyone at ACADIA for their hard work and dedication. All of us here remain deeply committed to, 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). Cory Kasimov, JPMorgan.

Thanks for all the detail today. It's good to see a nice start for NUPLAZID. A question for you on the commercial side, and then also one on the clinical side. Can you give any quantitative description of how many sample -- or just a rough estimation of how many samples are out in the field? I'm curious how much of the sales numbers in the third quarter are reflective of actual demand. Because I think people were thinking that this sampling program you had might depress numbers a little bit in the early stages of the launch. And then I have one clinical question.

Thanks, Cory. This is Steve. I'll -- let me give a really quick response, and Terry may want to fill in a little bit more detail. I just want to remind you, we have two types of sampling. One is the physical bottles that we have all experienced. We've all had our physicians give them to us for one thing or another. And then in addition to that for physicians that write scripts going through the hub, they have -- we make available to each patient a 30-day free trial.

So, very consciously, we have provided a lot of free drug in the form of samples in the system. And that will continue to be the case through these early days in the quarters with the launch.

So, Terry, I don't know if you want to add anything more that.

Sure, Steve. Cory, one of things that we really felt was important was that physicians have access to the drug in a variety of forms, and 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 the patient through the adjudication process. And we know 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 hand the sample out to both a patient going home with samples that's awaiting a 30-day free trial, or someone who is not going to get that 30-day free trial. In both cases, we make a concerted effort to make sure there are lots of opportunities for the physicians to sample out there. And although we haven't given numbers -- we have, as with any launch, really amped up the sampling in the marketplace during the launch period.

And just one -- I would echo everything Terry said -- just one quick annotation. I think it's a very important element of building the right foundation. We care about short-term targets and short-term indicators. We care a lot more about the long-term, and making certain that we're building the right foundation, and making certain that we don't have -- that we can minimize patients or physicians having any access issues with the drug is a very important part of laying the foundation.

Okay. All right, terrific. And then on the clinical side, I just wanted to ask about the recently started Phase III schizophrenia trial, and really how long that has been in the works. Because it seems the schizophrenia indication is something that you were always talking about; maybe figuring out, down the road, while prioritizing some other indications, such as AD agitation. If that was the case, I'm wondering what's changed there.

I'll start, and then Serge may want to jump in, as well. We have always been interested in schizophrenia -- our interest in schizophrenia has never waned. I think as everyone knows, it's a new management team, relatively speaking. And while the Company has had an interest in 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.

This has been in the works for literally almost a year now, to get to this point of starting the study. We've known this is what we're going to do for some time. We just haven't talked a lot about it for a variety of reasons, including competitive reasons. There are other people working in this space; and quite frankly, we don't see any reason to tell them exactly what we're going to be doing, since we will be competing for patients.

So I just want to underscore, we've had a very long-term interest in schizophrenia, primarily driven by -- not primarily -- almost entirely driven by the very significant unmet need which Serge described in his remarks.

Serge, I don't know if you have anything else to add to that.

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

Okay, great. Thanks (multiple speakers).

Cory, I'm sorry, this just reminds me of one other thing. I know that I've said this before; probably everyone on the phone has heard me say it. But there are certain advantages to being in a position where instead of trying to displace cheap generics, which we do have in schizophrenia, being in a position where -- and the mechanism of the drug just lends itself to this, so we find this very intriguing -- to be adjunct therapy, going on top of existing medication. So we don't need -- if we're successful here, we don't need to displace them if we show an additive benefit to those existing generic drugs.

Okay. That's a good point. I appreciate you taking the questions. Thanks.

Alan Carr, Needham & Company.

Thanks for taking my questions -- a couple of them. I wonder if you could give us an update on where things stand with Europe and that pediatric plan.

And actually to follow up on schizophrenia, a little bit of a different strategy maybe than the Phase II drug, going way back to I think 2006 or 2007, where you had a lower dose of the antipsychotic in combination with pimavanserin.

Can you talk a little bit more about that in terms of -- why do it this way? And also a little bit more also around why the three different dose of NUPLAZID. What's going to drive the titration -- is this going to be a titration where they start off at 20 and then you try to force them up? And if they don't tolerate, you'll lower it? What's the thinking behind that?

Alan, I'm going to ask Serge to respond to that question.

Yes, Alan. First, let me start with Europe. On our Q2 call in August, we announced that we would need to re-submit the proposed pediatric investigational plan. As you know, that's a requirement to have either [waiver] or agreed PIP plan with the Paediatric Committee of EMA before we can submit our PDP MAA.

We did submit our PIP in the third quarter, and we are waiting to hear back from the Paediatric Committee on our plan. Once we get our PIP approved, we can provide an update on the timing of our filing of the marketing authorization in Europe.

And in regards to the dose, our Phase II trial in schizophrenia indeed has a lower doses with antipsychotics that are used in that trial -- risperidone and haloperidol -- with the idea that a similar efficacy with improved side effect profile can be achieved in combination with pimavanserin. The approach we are taking in adjunctive therapies really to achieve the same potentiation of antipsychotic effect; but this time, in patients that are -- have inadequate response to currently used antipsychotic.

And the treatment regimen that we decided to pursue is the flexible dosing regimen. Rationale for that is, this is an all-comer study with almost all antipsychotics being eligible 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 is best.

It's not a forced titration; it is, on basis, everybody will start on 20 milligrams. But adjustment of dose in the first three weeks of treatment will be based on the efficacy seen in patients, as well as obviously tolerability profile.

So you are focusing on PANSS. Are there a lot of other secondary endpoints in here that you're going to be watching in this Phase III trial?

Yes. We have -- as it is usually done, we have a number of secondary measures. Obviously the key secondary measure is clinical global impression of severity. But in addition to that, there is a personal and social performance scale. We are measuring a number of other scales that are -- as a secondary measure in this study, as usually is done in these trials.

Any reason you would expect any impact on negative symptoms with this drug, or just positive?

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

Okay. And then I guess your plan here is 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 -- this ENHANCE-1 will have a pre-planned interim analysis for futility. And provided that that interim analysis suggests continuation of that trial, we will be then planning on starting the second trial in schizophrenia with the same indication.

Great. Thanks very much. I appreciate it.

Alan, this is Steve. I just wanted to add a couple of echoing comments to what Serge mentioned. When we did the previous study in adjunct therapy when added to Risperdal, we did see highly significant results, and they did translate in both positive and negative symptoms. So negative symptoms in schizophrenia is, as we've said before, is also an area of high interest to us. It's an area that has -- there's no drug approved to treat negative symptoms in schizophrenia. It's an area that has long, long been, if not the highest, one of the highest unmet needs in schizophrenia. And as I mentioned, it is an area that we continue to be very interested in.

When you look at the profile of pimavanserin, in addition to having shown a strong antipsychotic effect in two different -- very different population populations, in PDP psychotic patients and in schizophrenia -- we also see a profile that has strong potential in depression, as an antidepressant. And we've seen in the clinic a strong effect on nighttime sleep and daytime wakefulness, also areas that feed into the entire constellation of symptoms that schizophrenia patients have.

We need to do this 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'll just simply say, for now, that both the schizophrenia patients with an inadequate response to a single antipsychotic, and negative symptoms in schizophrenia, remain areas of very significant unmet need, and of interest to us.

All right, that's helpful. Thank you.

Ritu Baral, Cowen.

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

Ritu, I can't give you the exact number, but all I can tell you -- rollovers from clinical trials was 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 fill on prescription? Is the 30-day free drug -- is that covering the gap that's needed to get insurance authorization, or is it extending past that?

Terry is going to take that question, Ritu.

It turns out that the 30-day supply is ample time for most patients to get their claims adjudicated and a prescription sent, so we're very pleased with that to date.

What's your final (multiple speakers) -- I'm sorry. Go ahead.

I'm sorry, Ritu. I was just going to say, as we've said before, we do have a bridging program. We have done some bridging. But Terry's right; for the most part, 30 days has been sufficient. And of course we anticipate that, as we get on more commercial formularies, that the time to adjudication will shorten, and there will be even less need to bridge in the future.

What's your target time to fill? (multiple speakers) 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 variability with the donut hole? But also it looks like an increasing proportion of commercial patients over the next few quarters.

Todd is going to take that question, Ritu.

Ritu, as you know, we haven't guided specifically. Obviously, in Q3, we were in the mid-20s on our gross to net. The donut hole is the biggest driver of fluctuations from quarter to quarter. Everyone realizes that it's a calendar-year-based program, and it's individual to each patient based on the total portfolio of drugs they take.

Now, for most of our PDP patients, they're motor meds or generics that wouldn't create as big a donut hole liability as a drug priced in our range. And so we would expect that early in a calendar year, our percentage of donut hole would be higher than it would be later in the year as more patients progress through it.

The caveat on that is obviously we're early in launch. We've launched in the second half of the year, and so we still are getting our arms wrapped around what the specific amounts will be. But, certainly, the donut hole is the biggest driver of fluctuations quarter-over-quarter.

And as you've mentioned, as the commercial mix and the Medicare mix change over time, that will also affect it. But at this point, mid-20s this quarter, and we'll 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 the schizophrenia study, what is the receptor occupancy of the 20-milligram dose, the 10-milligram dose, in comparison to the 34-milligram dose? 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 on the escalation of doses. We certainly are close to full occupancy at the 20-milligram and above. Of course, this was a study done in very few patients, so one should take the results with some caution, in this respect.

But the point that we need to remember is that receptor occupancy, per se, 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 at 17-milligram equivalent -- or 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. That guided us that a starting dose at 20 milligrams is certainly the dose that is reasonable for this trial.

The second thing is that, as I said, we have patients here on different doses of atypical antipsychotic, and different atypical antipsychotic that will enter the trial. So allowing flexibility around 20-milligrams dose that we now that has antipsychotic potentiation is a reasonable approach that we thought we should take in the trial.

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

It is defined by essentially a constellation of criteria. One is the certain severity of the overall psychotic symptoms as measured on the total PANSS score; and then on the presence and severity of the particular specific positive symptoms that have to be at the moderate or higher severity present in order for patients to qualify; and, finally, on the overall global assessment of severity of psychotic symptoms. So it is not only one criteria. It is kind of a constellation of criterions that define these patients.

Understood. Thanks for taking all the questions.

Charles Duncan, Piper Jaffray.

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'm wondering if you can provide any additional (multiple speakers).

Yes, so Steve, any additional color on the main driver for the early out-of-the-box strength? You beat consensus pretty handily, yet 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 hate to repeat myself, but so many things so far about the launch have really been very consistent with what we expected. The payer reaction, very consistent with what we expected, but we knew the error bars were very wide. It could have been very different, but it's very consistent. Physician experience -- again, it's just something you just don't know. There's no way of knowing until you get the drug into these part of the populations. And it's early, but so far, very, very consistent.

I guess we're not surprised that we're not surprised, because so many things have been consistent with what we anticipated that we -- we did, in the quarter, come out ahead of our own plan a little bit. But it's very consistent.

And most importantly, it is just very consistent with the type of launch that we have expected based upon the market research we did, looking at a lot of other drug launches with paradigm-shifting potential, et cetera. And what we have expected is that we would establish a foundation and then build and build on it.

And I think that when we look 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 there's 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 it.

So, yes; we did come in above consensus estimates in the third quarter, as I mentioned. We also have observed what the Street is anticipating for the fourth quarter, and we think that that's consistent with our view of that.

And then as we roll into 2017 -- of course it's way, way -- it would be way, way premature for us to have any public view on that. But I think so far in the launch, we're seeing things are rolling out as we expected. And it feels like it's kind of as the Street has expected, at least from a ZIP Code type of perspective.

Okay. That's helpful. Well, great execution thus far. And it sounds like there wasn't any bolus of patients that were waiting for the drug or anything -- it's just new demand for a new drug.

We did have a little bit of what I would characterize as low-hanging fruit. We saw that early on. We saw a tiny bit of that in June. It got masked by all the free drug. And we saw some of that in July. But, by and large, again, it's been this -- the best way we can think to characterize it is a foundation that we're laying. We are doing a lot of sampling. We are doing things that have a negative impact on near-term revenues, but help build the foundation in the long run.

And of course, at the end of the day, that's what's most important to us, in terms of reaching the full potential of patients that could benefit from the drug, and of course for the benefit of our shareholders.

Okay, thank you. And then my two quick clinical questions for Serge. Just first of all, on the ENHANCE study, could you share with us any of the measures that you plan to take to ensure, call it, site -- clinical site or patient quality; or control for a placebo response, in terms of the -- over the course of the six-week study?

And then quickly for SERENE, what drove the decision to conduct the program in 100% of outpatient setting, which is really different than the ADA study in terms of this ADP? Is that caregiver input, different severity of patients? What really drove that strategy?

All right. Let me take one by one. In the schizophrenia study, we are applying all of the standard measures to reduce the placebo responses where and particularly measures for inter-rater reliability. So we are doing pretty much everything that current methodology in clinical trials and schizophrenia is standardly applying to this. Nothing specifically unusual. But if one of the things that we particularly believe is important for any clinical trial, and by implication in schizophrenia, is actually enrolling the right patients in the trial.

We do have -- and we will try to do that in all of our trials -- independent confirmation of the eligibility, particularly from the psychiatric diagnosis and criteria for -- there 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 significantly the quality and performance in the trial.

The second question, I'm sorry, it escapes my mind right now. I can't --.

Yes. Just quickly, the SERENE trial, what drove the decision to conduct the program in 100% outpatient setting, different from the ADA -- or different from the ADP study?

It is mostly the severity of illness that we are targeting, primarily moderate to severe patients. The patients that are already in the institutions may have much more advanced Alzheimer's disease. And it may be more difficult to evaluate properly the treatment effects. In this patient that they are outpatient, they can still be in the supportive care, but not receiving around-the-clock medical care. So as long as they are capable to actually do their visits at the sites as an outpatient, they are eligible for the trial.

Okay. Thanks for the added color. Great quarter.

Tazeen Ahmad, Bank of America.

Just a couple on the launch, if I might. In terms of your expectations, Steve, you've mentioned that what you're seeing in the metrics have been consistent, thus far, with what you would have expected before the launch. Why not think about issuing sales guidance if, so far, that the launch is going as you expected? Do you think that there could be -- you mentioned some low-hanging fruit. But do you think that 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, could 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 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 the last one first, regarding the EU pricing. Of course it's way premature for us to comment about how we would price NUPLAZID outside the United States. But I will just repeat what we've said before, that for these kinds of drugs -- because we're not in the orphan space, oncology space, et cetera -- it's not uncommon to see pricing outside of the US be dramatically lower than US; so greater than 50% discounted from the US price. It's not uncommon, if you look at some of the other CNS drugs, particularly neuropsychiatric drugs, for them to be in the 15% or 20% of the US price.

I have no idea if that's the ZIP Code we'll be in for NUPLAZID. We've obviously got a lot of advantages to the drug that we think should be reflected. But I just want to be clear that the pricing outside of the United States for these kinds of drugs is just very different.

I certainly appreciate the desire for us to give guidance. I just think, at this point, although to date things have been 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 at this stage.

There will come a time where that won't be the case. But today we think it's just premature for us to do that. And we're also somewhat comforted by what we see, as I mentioned, when we look at how the Street has looked at the fourth quarter and looking into 2017. It at least appears that we are, at least qualitatively, looking at this in a similar fashion in terms of launch dynamics and the potential to establish a foundation and grow and grow. Trust me; we look forward to a point in time where we can be more precise and be more quantitative, but it's just not now.

Okay. And then maybe just one question on the 30-day free trial. Are there instances where you are 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 if somebody should be given a renewal?

Terry is going to take that question, Ritu -- excuse me, Tazeen. Sorry.

The answer is yes. There are situations where the adjudication is taking longer. It's very important to us that the patient's therapy not be interrupted. And in those cases, we are granting bridges for those patients so that they can remain on therapy while the adjudication process takes place. It's the minority of 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 has happened a few times. As I said, it's in the minority of cases, but we have done it.

Okay. All right. Thank you, guys.

Jason Butler, JMP Securities.

Just first on the schizophrenia trial, I know we're some way away from results, but can you give us any kind of benchmark for what clinically relevant effects would be as an adjunctive therapy? When you look at the atypicals, you are seeing effect sizes in 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 a difference that we will see from placebo in the context of adjunctive therapy. It's probably not going to be of an effect size that we see in monotherapy, but fairly close to that and what we are looking at. And we're just -- in the assumption of our sample size, we assume a difference between placebo and active treatment of 6 points on PANSS as a meaningful difference. And that is what we expect to see at a minimum in our trial.

Okay, that's helpful. And then just wanted to ask about your comments on the mechanistic rationale for the potential lack of cognitive impact with NUPLAZID in Alzheimer's patients. Are you thinking that the drug has a greater impact on serotonin than other atypical antipsychotics, and that's what would drive 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 cause?

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 of [dopamine] transmission would be something that would, we believe, be beneficial in terms of the pimavanserin action.

Great. Thanks for taking the questions.

Paul Matteis, Leerink.

Congrats on the all progress. I have one commercial and one (multiple speakers) question. Thanks, Steve. First, on the commercial side, of the $5.3 million in sales, was there any change in inventory? And is that driving any of the effect we saw this quarter?

Hi, Paul, it's Todd. No, the inventory, in fact, was up there with -- to suggest any big load to the channel or those sort of thing you might see on drug launches -- are specialty pharmacies -- are not being incentivized in any way to load inventories. So this was very much patient-demand-driven results.

Okay. (multiple speakers)

Just to give a little bit more color there; because, one, it's a very simple molecule to make. And two, we're distributing exclusively through specialty pharmacies and specialty distributors. We just don't have the kind of inventory in the channel that you might expect if we were distributing through a typical wholesale type of distribution. Our inventory in the system just won't be at the same kind of levels as you would have elsewhere.

And I should mention, Paul, with us being on the sell-through revenue recognition model, we don't recognize revenue just when a specialty pharmacy buys the product from us. That is up on the balance sheet in our deferred revenue account.

Okay. That all makes a lot of sense. And then if I might just ask two quick clinical questions. My first one is on agitation. I'm wondering, with the ADP data -- so coming up so soon, why not wait until you see data from that study before starting a program in agitation, since agitation is a secondary endpoint in that trial? Do you expect to get useful information on the effect on agitation symptoms in the ADP trial?

Serge is going to answer that question, Paul.

The primary reason is that although it is a secondary outcome, the ADP trial did not specifically require any level of -- any threshold of agitation to qualify 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 patients that we will -- may see some effects of pimavanserin on agitation, because not all patients will have sufficient severity of symptoms to evaluate that.

We do not -- although that will be interesting and informative data from the trial in regard to AD agitation, as well as other behavioral symptoms that are measured by the Neuropsychiatric Inventory. Remember that measure of 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.

We did not consider that in whatever outcome of the ADP trial in regard to agitation merits decisive criterion for the start of the AD agitation trial. And we just -- and then that's the rationale why we did not wait for the results.

Okay. That makes a lot of sense, Serge. And then if I might 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 background therapy with an 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 patient's current therapy, or at least in some of the patients? Maybe you could just comment a little bit on what you think is going to be driving the additive benefit of pimavanserin in schizophrenia, in that context. Thanks.

Well, there is the direct modulation on the 5-HT2A, but there is also the indirect modulation of other neurotransmitter via 5-HT2A which actually -- some of the explanations for drugs that have both D2 and 5-HT2 action mechanism of action -- it's still there is a space for additional efficacy, because they are not really completely ameliorating symptoms of psychosis.

The logic here is that pimavanserin -- adding pimavanserin to the mix of the effects of atypical antipsychotic throughout different receptors and neurotransmitter systems is increasing the effects of true direct or indirect effects, not only on serotonin system but on the dopamine system and others.

So that's the -- I know it's probably not a very fully satisfactory explanation, but it's a lot of theory going on in there. And, of course, they are all hypothesis. We don't have an exact knowledge of the precise mechanism.

Sure. Fair enough. Well, thank you, Serge. Appreciate it.

Salveen Richter, Goldman Sachs.

Hi, Salveen. Are you there?

Yes, operator, why don't we try to circle back to Salveen? We can't hear if she's asking questions.

Bert Hazlett, BTIG.

Congratulations 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 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's psychosis patients? Or are they newly diagnosed patients that are just simply coming into the system? So are they getting switched from other atypicals, or are they brand-new Parkinson's psychosis patients? Or can you tell that at this point?

Just because we're running short of time, let me take a really quick stab at that, and then 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'd love to have a refined view of that, and we just don't. We don't have enough data at this early stage yet as we're ramping up. And of course we have more patients on therapy, week-to-week to month-to-month. We just don't 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? (multiple speakers) Yes, on switching versus newly diagnosed patients. I know this is not going to be a very satisfactory answer. We're getting both. It's just too fluid at this juncture for us to really comment on that, because it just -- we're seeing that move around a little bit. That's also the kind of thing we look forward to having a more refined view on in the future.

All right. Thanks for taking the questions.

Tazeen Ahmad, Bank of America.

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 is 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 this readout. Thanks.

Tazeen, again I'll take a quick stab. Serge may want to chime in. I would draw a little bit of a distinction between the -019 study that will read out by the end of the year and the studies that we are initiating.

The -019 study was really designed and executed as really a very exploratory study. We've talked about this in the past. Of course it's all in one center. And there are other things that are unique to that study that I think give us a certain lens to look through in terms of what -- the data we'll get from it.

I think it's highly likely that we'll achieve the objective in the study, and that is -- get enough information to have an informed view about what to do next. And in these early exploratory studies designed the way this one was, it may be that we have on one end of the spectrum a highly statistically significant result, a positive result. And it gives fairly good clarity when we pressure test it. We think that that is a believable result and gives us very good clarity to go forward.

On the other end of the spectrum, it's possible in these 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 then there's a whole lot of gray area in between. And in these early exploratory studies, you wind up in the gray area more often than not. So we just don't know. We're still blinded to the study results, so we're very eager to get the study results. But we think there's a very good likelihood -- doesn't always happen with the subjective endpoints in CNS -- but a very good likelihood that we'll get -- we'll achieve the objectives of the study, and get information that will tell us 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 III. You wouldn't be able to just file on this study results if it was highly statistically significant. Is that right?

It's always -- you hate to -- before you actually open the envelope in a study, you hate to say whether a study could or couldn't be registrational. But this one really was not designed to be a registrational study, nor executed to be a registrational study, so it's probably very unlikely.

Now, when we open the envelope, we will 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 did serve as the basis of a single study approval in PDP of course.

Okay. Thank you for that color, Steve.

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

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

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