Neurocrine Biosciences, Inc. (NBIX) Earnings Call Transcript & Summary

Welcome back to the William Blair Biotech Focus Conference 2021. Thanks for joining us. My name is Myles Minter. I'm a senior biotech analyst here at the firm covering neurosciences among other areas. Just before we get started for today's panel and neuropsychiatry updates, just have to refer listeners to disclosures on williamblair.com for various forward-looking statements that each company may be or may not be making in this chat. Additionally, there is a link to a Q&A feature at the bottom of your screen. I'm already seeing a couple of pop-up, but feel free to type in your questions at the bottom there, and we'll do our best to get those answered around the panel. But with that, it's my pleasure to welcome the panel members. Today we have representatives from Neurocrine, Praxis Precision Medicines, VistaGen and Aptinyx. I will not go through the introductions. Rather I'll have them introduce themselves and give a brief 1-minute spill on the exciting things that are happening at each respective company. So on my screen, I'll probably start clockwise so that would start with Kyle at Neurocrine.

Great. Thanks, Myles, and thanks to William Blair for the opportunity to be part of the panel this morning. Just a little about myself and Neurocrine, and then I'll hand it off to the rest of the panelists here. As mentioned, my name is Kyle Gano. I head up the business development and strategy group here at the company. I've been at Neurocrine for about 20 years and had a very typical biotech experience over that timeframe, wearing multiple hats and working in different functional areas over that timeframe. But in terms of the company itself, we're nearing our 30-year anniversary, believe it or not. We have had the opportunity to bring a couple of products to the market ourselves and share in the commercialization of products of one of our collaborators. So if you want to keep the scorecard, we've got 4 commercial products currently, 2 in the hands of AbbVie in women's health and 2 that we commercialized ourselves in neurology and psychiatry, that being INGREZZA and ONGENTYS, the latter we launched in Q3 of last year. In terms of exciting things we're working on this year, we do have a big data readout later this year in our INGREZZA program. In this case, we're developing valbenazine, which is the generic name of INGREZZA for pre-associated with Huntington's disease that we'll read out in the Phase III later this year. Looking across the pipeline just in terms of key milestones for us this year, we're looking at by the end of the year having 5 pivotal programs ongoing and 8 mid- to late-stage programs in terms of new studies that we'll be starting. So really excited about expanding the pipeline this year. That's all about execution of those studies that are nearing Phase II and getting those studies up and running and giving us a shot to report on data next year. So I think I'll pause there, and let us get into the discussion. I know the other panelists need to have their time for intros as well.

Thanks, Kyle. I'll turn it over to Marcio.

Thank you so much, Myles, and thanks, Kai, for the great introduction there and congrats to Neurocrine for 30th year. It's kind of important, and appreciate the opportunity from William Blair team to discuss today. So I'm Marcio Souza. I'm the CEO of Praxis. We are focusing entirely, I would say, in CNS and psychiatry, a very comprehensive pipeline. I'm sure we're going to be able to touch on some of the programs today. In terms of the company, we were founded about 6 years ago, and we IPO-ed last year. So a little bit younger than some of the companies here today, but very excited on participating on this revolution in terms of CNS and bringing new drugs to patients. The foundation of the company is by translating the original ideas in terms of genetics of epilepsy to a number of CNS conditions, including a more general like movement disorders and psychiatry and, more specifically, developmental encephalopathies and genetic epilepsies in general. We have a number of readouts in the next 18 months. It's a very, I would say, catalyst rich from our perspective with our lead program that we are investigating for both a major depressive disorder and PTSD and most recently announced for essential tremor as well. We're going to have proof-of-concept readouts coming up for perimenopausal depression for 114 before the end of the year. And then early next year for what's the biggest expected milestone for that program is the 2 studies in monotherapy and adjunctive therapy for major depression disorder. One of them has been run as registrational. The area of study, we're very excited about that and expecting a milestone. And then many other milestones for each one of the programs that we have, including our movement disorder programs and our cephalgia program for 562. So I'll pause there. As well we're excited to share this stage with the other companies today.

Thanks. Over to Shawn at VistaGen.

Myles, thanks for the opportunity to speak today. Gentlemen, it's a pleasure to be with you. Myles, your team is doing a fantastic job in terms of raising awareness about mental health, mental illness across the board and where the current standard of care falls woefully short of what we think patients need. So kudos to you and your team, and keep up the good work. Calls like this are very important. We are focused entirely on going beyond that current standard of care for anxiety and depression disorder. So we have 3 candidates in the pipeline. All are clinical-stage. The most advanced just started our Phase III program for social anxiety disorder, that's PH94B, extremely unique pharmacology with rapid onset potential, exceptional safety profile to date in all the clinical studies that we've seen and potential across multiple different market segments in the anxiety arena. And same thing with PH10, we're looking for a stand-alone potential in MDD, again, with rapid onset potential, an exceptional safety profile and multiple plays within the depression arena. And we also have AV-101 which is an oral prodrug NMDA receptor antagonist for MDD and several neurological disorders. That's earlier in development, and we're going forward with that in combination with probenecid. So it's a very exciting time for the company. As you well know, we're well funded. A lot of catalysts over the next 24 months and perhaps the largest of which in less than 12 months from now, the readout of the first Phase III of PH94B in social anxiety disorder. This is -- it's an extremely exciting program in an area where we've just seen skyrocketing prevalence. And the need is dramatic. Even pre-COVID, the need was staggering. So excited about that and look forward to keeping the market up to speed on our progress. We have a lot of activity in the clinic and in the regulatory arena and maybe even on the partnering side.

Right. And last but not least, Norbert at Aptinyx.

Thank you. So Myles, first of all, many thanks for inviting us to attend this panel. It's a real pleasure and privilege to be among the other panelists. And I listened to the introductions, and it's very clear that CNS is looking much, much more promising now than it has been in a long, long time with a number of very differentiated programs in development in neuropsychiatry, but also in neurodegeneration. And that, of course, would be terrific because as we all mentioned and know, the unmet need is enormous. The therapeutic choices today are very limited. And it's great that you actually raised attention to that with William Blair because I think we need to all have more awareness of it. Briefly on Aptinyx, we started the company just about 5 years ago. It is a company that's spun out of our predecessor company, Naurex. We are a clinical-stage company entirely focused on CNS. Our technology is NMDA receptor based and, in particular, and that differentiates us, I believe, preclinically and clinically, NMDA receptor modulators that can be positive allosteric modulators at higher doses or negative allosteric modulators that has shown a really differentiated profile for efficacy as well as for safety. We are fortunate currently to have 3 of our compounds, our own proprietary compounds, designed to synthesize profile by Aptinyx, around which we have extensive intellectual property, 3 of those compounds in 4 indications: one compound NYX-2925 is in 2 chronic pain conditions, one being fibromyalgia, the other being diabetic peripheral neuropathy, painful DPN actually. They both are based on earlier exploratory studies that informed and derisked the currently ongoing Phase IIb studies. Our current assumption is that those studies will both read out in the first half of 2022. That will be a catalytic milestone for the company. We have a program in neuropsychiatry with our second compound, NYX-783 in PTSD. We recently, just a few months ago, disclosed the data of our exploratory signal-finding study in PTSD patients. I was very satisfied and pleased with our results. We, just at the end of April, had a very productive Type C meeting with FDA to finalize our clinical development program going forward. And we'll be kicking off a Phase IIb study in the fourth quarter of this year as well as the second Phase IIb study in PTSD with 783 in the first quarter of next year. And then the third compound, NYX-458, is in neurology in dementia or cognitive impairment in Parkinson's patients as well as patients with Lewy body dementia. That kicked off again after we parked in COVID-19 times where we wouldn't be able to do Parkinson's studies, of course. It kicked off again in the first quarter of this year and is a signal-finding exploratory study that we anticipate to read out in the second half of 2022. So just like the other speakers, a number of truly exciting programs, near term, midterm readouts, and I believe with the profile of efficacy and safety that suggests and offers that we might indeed be on our path to find truly innovative therapeutic choices that address some of the unmet needs that exist today, both from an efficacy, safety as well as abuse liability point of view with existing therapies. So with that, again, thanks for having us on the panel. Okay?

Yes. Thanks for the introductions, everyone. One of the things that's absolutely fascinated me in neuropsychiatry is that specific mechanisms of actions of drugs can have broad implications for multiple indications. So it leads me to my first sort of top-level question for the panelists here is that when you've got a neuropsychiatry asset with a particular mechanism that could have such broad implications, how do you decide what indications to initially chase versus which ones to expand into? And does that have implications for potential business development relationships you can do down the line? Maybe we can start with Kyle, considering your portfolio is largely in-licensed from Takeda.

Yes. So we've got a number of programs that span neurology and psychiatry in the portfolio. And I think that where we stand on that is -- and I hate to use this phrase, because a lot of us use it in the industry. The concept and the value to appreciate a pipeline within a program. Because there does -- it does make your investment in all the development work going from discovery to the clinic worthwhile if you have the opportunity to study a mechanism, a hypothesis in multiple disorders versus one program, one disease. Those are a lot of bets and a lot of dollars that each of us have to think about if that was the situation that we had for all of our pipeline programs. That being said, where do you go in terms of indication selection? For Neurocrine, it probably goes along the lines of 2 routes. One is, first and foremost, is there a genetically validated disease state that is attached to the target that you're pursuing for a given program? If there is, that gives you perhaps greater confidence than relying on an animal model disease in psychiatry, which we know is fraught with a lot of hair and challenges there in and of itself. So you start there, is there a genetically validated disease state attached to the target, and what do you do to move that floor as quickly as you can. Beyond that, if that's not there, then you're looking at, are there other opportunities that you've seen out in the literature by other companies that might take that mechanism in the disease state that you're looking at? Is there directional data that's been out there by others. And your molecule solves a problem that, that molecule did not have in order to take it forward. So I think those are areas that we lean on more often than not. Beyond that, of course, if you've got a target that you're working on, you try to lean on the translational medicine piece and have that guide you elsewhere as you think about science. So by that, I mean if you look at rodent and non-rodent species. Non-rodent, you are thinking about monkey. Can you look at target engagement? Do you have that going from rodent to non-rodent to man? Do you have things like target occupancy data along the way? And then lastly, are you moving biomarkers relevant to disease you're interested in, in those different species that give you confidence in moving in a particular disease state. So those are the things that we think about when we've got a program that could potentially be taken in multiple disease states. And you see bits and pieces of those pathways play out in our pipeline, whether it's in epilepsy or in disease states in psychiatry.

Marcio, do you want to comment on that?

Yes. Like it's largely similar to what Kyle said, where I think for us at Praxis is a little bit different at the beginning because we're -- the validation on genetics, I just mentioned, it's kind of a premise for any program in the company. So it's like a fundamental filter. So we don't recheck that since no program would exist without the check to begin with. One thing for us now that it's quite important is to have uncorrelated biology. So the example, for example, that I could cite is or I can give to you is like Parkinson's and our essential tremor for 944. While there is a physiology that is similar, right, it's like the more fundamental biology and validation, cross-validation of different pathways, understanding that the brains -- those are networks, right? We always talk about this like a very specific mechanism. But this imbalance are actually creating, as Norbert eloquently said at the introduction, there is so much to be explored on these networks. So always looking for how can we impact them and, at the same time, derisk the program. So the 114, for example, going to MDD, that would be an obvious place to go to anxiety, for example, but we chose to go to PTSD in that case, since we believe it's more complementary, but at the same time, differentiating the biology. And where some of the models are all fear-sanctioned or fear-producing, so we can have better like ideas at least from the animal model to the bigger model like us that we intend to treat. But that's a little bit how we look. And I would say the overarching thematic is the business, right? Is there an unmet need out there. It starts and ends with the patient. If the markets are ready, like if the patients don't need an additional therapy, if we're talking about like minor increments, we don't have an interest on that. We're really looking to fulfill large unmet needs. Luckily enough for us and luckily enough for these patients, unfortunately, CNS is full of unmet needs. So we didn't really have to hyper-prioritize at this point, but we're looking for best in class for each one of the programs we're developing.

And then, Shawn, yes, with the Pherin class, like obviously, you've gone into social anxiety disorder, and that [indiscernible] indications are neglected in some way, but particularly SAD. So maybe you can explain the rationale there. And we've also got numerous questions in for VistaGen about potential business development deals and if we can expect something like that in the near term.

Sure. I'll address that part when you say that's okay. But no, I think as the others have said, look, mechanism overlap in neuropsych is certainly prevalent. And we're certainly -- as others have noted, we're well informed by targets that have a higher probability of success in specific disorders. So that still plays very heavily into any decision. The unmet need, as Marcio said, of course, you have to consider that. But the other part is really you have to take a look at what's going on across our industry, right? Although no one size fits all, certainly, it has to be taken into consideration in what's occurring across pharma, what else is in play, how we differentiate it not only from the current standard of care, but from what else is in motion to ideally become part of the new treatment paradigm for these indications. So for us, it was very important in SAD and across all of the other anxiety disorders. We're focused on adjustment disorder and procedural anxiety, postpartum anxiety, panic. These are all indications where we know there just isn't really -- there aren't good options today. Rapid onset is very important across all of these neuropsych indications, whether it's depression disorders or anxiety disorders. People want to know quicker than today's medicines allow them to know whether they're going to be a winner. And if not, then you have to move to the next alternative. So that's key for us. That was key with the pharmacology related to the compounds we acquired using the nose as a portal to achieve phenomenal neuropsych benefits is indeed novel. So it takes some time to focus on whether or not there's true differentiation. And at the end of the day, you don't want the underlying condition to be overwhelmed by the side effects and the safety profile of the meds. So we don't want to be a benzo in an anxiety arena, where we're impairing functionality in any way. We don't want to create potential for addiction. So we look at whether or not there's any binding to opiate, nicotine, dopamine receptors, whether there's GABA potentiation, things that are clearly triggers over decades now of use in the space. We know what works, and we have a pretty good idea of what doesn't work in terms of the current treatment paradigm. So it's our job as CEOs on these panels to figure out how to move the ball way ahead down the field. And I think fortunately for us and others here, you're either in the end zone already like Kyle or in the red zone. So hopefully, that's the way that we continue to proceed as a space, because as each of us does better, all of us do better, no question about it.

And then maybe on to Norbert, you've sort of approached it as an NMDA receptor modulator platform, but developing individual assets for indications within that platform. Can you talk about that rationale rather than just producing one asset and trying to leverage that for multiple indications?

Yes. So I've mentioned -- you just mentioned that the NMDA receptor is our target. There are decades of research in academic labs as well as in industry labs to show that the NMDA receptor plays a pivotal role in normal brain biology. That includes mood. It includes cognition. It includes memory, learning. Very well established that it is plasticity changes that ultimately depend on NMDA receptor activity to be induced. And of course, that offers a wide variety of therapeutic indications that are known to be associated with a dysregulation of the NMDA receptor. Why are we in PTSD? Well, it starts with the fact that there has not been a new therapy approved in PTSD in more than 20 years. The currently approved therapies are both SSRIs. I believe that they help symptomatically to address maybe areas of depression. But the question really is what triggers PTSD, right? And PTSD clearly is the inability of someone, who experiences a dramatic event, to extinguish the fear that they become conditioned to and to consolidate that fear extension so that they can actually live normal lives like those of us who actually can experience a trauma and overcome the traumatic experience and normalize thereafter. And so, there is a really important data set we have generated preclinically in looking at models of fear extinction. And while I agree with Kyle that preclinical models can only be so predictive of a human condition, in particular in an area as complex as CNS, what we see is consistently that NYX-783 accelerates fear extinction and facilitates the consolidation of that fear extinction. It's also known that in PTSD, there is a hypofunction of NMDA receptor activity in the prefrontal cortex. So we have enough biology to believe that the approach we are taking by activating the NMDA receptor with 783 in a positive allosteric manner should actually facilitate and help in the way I just described. And the study that I mentioned earlier that we did in PTSD patients turned out to actually show us, number one, the compound is indeed active in making a clear change in improving CAPS-5 as the major readout, but also in the areas of the -- of heads, the depression score -- sorry, the anxiety score. And what we saw in the study is, again, a superb safety profile and onset of activity readily within 4 weeks. And so the -- I think the earlier comment that we need to have more rapidly acting therapies is really essential next to efficacy to begin with and safety. And I think that will offer a transformative change. I am very encouraged by those results. We, of course, are proceeding into the next phase of development. We have other choices like substance use disorder, but in particular before, because of our fear extinction data, I think 783 is particularly well suited to be tested in a PTSD paradigm like we are currently doing. So that's the rationale. But it is truly the platform that has many, many more applications. You just have to have the discipline to hone in on what is most relevant from an unmet need point of view and where you have the very best data for your compound.

No, that's fair enough. I want to touch on trial design and endpoint, because it's one thing to have an active compound, it's another thing to actually prove that [indiscernible], which is obviously what the regulators are looking at. So my overarching question is that the FDA seems to be pretty lenient in terms of adaptive trial designs, randomized withdrawals, enriching patient populations. But they also come out and state that they want that trial to be representative of the ultimate patient population that you're going to be treating. So where is that balance struck? How sort of valid are the endpoints we use in neuropsychiatry to actually conferring patient benefit? And what are the key considerations in designing those trials to make sure you strike that right balance of giving the drug the best chance to show a positive outcome, but also in the correct patient population that we can actually use that evidence to inform on prescribing? Maybe I can start with Marcio on that one, and we can go around the panel.

Well, I would say it's probably a multifaceted answer there, right, Myles. There are well-established ways to develop some of these indications. Like I'll use like depression, like decades of experience, many guidelines, our expectations from the agents and extrapolations from the agency. And then disease that, like Norbert just mentioned, PTSD, we're both interested on this indication that there are very little that was developed. There's about 7% of the U.S. population suffering from this. So the expectation that you're going to cover the entire spectrum of the condition is just unreasonable. And I think the agents understand that. So how do you select? Number one is kind of a little bit of a cliche, but controlling the controllables. Making sure that placebo is in check. Like I would imagine all of us agree that if you're going to run a placebo-controlled trial, the first thing you want to make sure that the analysis is not going to overcome whatever is happening there. And that requires to be reasonably homogeneous, the population that requires to be -- since some of these end points are what one could call not so objective, right? They are based on sometimes on questionnaires, on impressions from clinicians or from patients that you get the best possible patients on those trials. And I think the FDA, at least on our interactions, care a lot about that, get the right patient with the right diagnosis in the trial. The way we are doing this and I understand others in this call are doing as well is by using systems like SAFR, by partnering with Mass General, having like 2 psychiatrists looking into the severity and the diagnose before the patient gets into the trial. That creates more consistency that's reduced the noise. Whatever placebo response is going to be the place response, not an inflated one, because you got the wrong patients in the trial. And what is reasonable to extrapolate and what is not reasonable. And that's always a discussion upfront with the agency. And at the end, ones who are proposing a label, right? The label proposal is always on the sponsor side. And sometimes we forget that. So we are proposing, for example, 114 from the very beginning, treatment of unmet results of major depressive disorder. And to do that, the FDA gave us very clear advice. Like, for example, we must run the trial for a minimum of 28 days. So we know what is necessary there. But they also said, just to illustrate as my last point on this, that we could pick the pivotal studies to be on either adjunctive or monotherapy. And we decided to go on monotherapy because that's the cleanest way to show the signal in our view. Others chosen a different path, right? So it is a choice. So there is a lot of, I would say, leeway. I don't believe they are lenient. I actually believe that they understand the condition and they partner very well with the companies in order to like understanding the unmet needs to help those patients out there.

And then maybe to Shawn, like you've got the PALISADE trial up and running now. And that struck me as interesting, considering that's actually a laboratory sort of setting public speaking challenge. So I'm wondering how those sort of FDA interactions went to sort of set that as the primary test and then use the label with scale. It's the primary endpoint there. But like how do you think that, that controls for the trial success rate, I guess, and versus how your Pherin drugs could actually be used in the real world setting?

Well, first, back to the original comment -- question, the agency, I think you -- I've talked about this back in the early days of '19 when there were the ADCOMS around esketamine. So we started to see a really wonderful sea change at the -- at least at DOPP as to the fact that, look, these new generation drugs have different pharmacology associated with them that the old school treatment and development paradigms don't necessarily fit. And in that case, as you remember, 1 of the 2 pivotal studies was a randomized withdrawal study. So that hadn't been done in that division before that. What we saw in a very favorable interactions with the agency was an awareness that the pharmacology of PH94B is fundamentally different from the 3 antidepressants that are approved in SAD. And this is an acute treatment scenario, whereas we're looking to deal with the acute treatment of anxiety in adults with social anxiety disorder, which is a profound fear of evaluation, judgment, humiliation, in often very predictable settings. And so like a rescue inhaler for asthma or a migraine drug upfront of a migraine episode, we see PH94B fitting into that slot right upfront what are often, again, very predictable triggers. So having a 12-week study, like was the case with the antidepressants, in a real world setting just wasn't a fit for an acute treatment modality like we have here. So using the subjective units of distress scale, which is well established in a public speaking challenge, which is well established as a way of provoking fear and anxiety in a laboratory setting. At the end of the day, FDA is not abandoning its focus on needing solid science and medicine to drive the regulatory decisions. They never will do that, nor does anyone want them to. But what I do think there's a shift is towards trying to find the most simplified way possible to assess the efficacy and safety and tolerability of a particular drug and that pharmacology comes into play and the study design follows. So when it was clear the way that PH94B works in Phase II, we saw highly stat sig outcome, within 10 to 15 minutes, a very rapid onset of anxiolytic effects. So it was clear that, that was done in a laboratory setting, that public speaking can be -- commonly provoke fear in the laboratory setting. So they wanted the same trigger in the same setting across the same type of environment throughout the course of the study. And so that allowed us to lean into the Liebowitz study, which was a 3-site study in Phase II that had both public speaking and social interaction. And again, in the effort to make the most simplified way possible to assess the benefits of the drug, just public speaking was required, not both social interaction and public speaking. So again, having this interactive relationship with the agency often, sometimes fast-track, creates that. But more really, it's -- the needs out there are always quite clear to the FDA. There's no mystery to the agency about what the world needs. In fact, we saw the drug safety communication on benzos come out in September of last year. So no surprise there that the use of benzos is skyrocketing. Even pre-COVID, it was pretty high, 92 million scripts. Not all of that's for anxiety, but still they see those kinds of things. And we have a benzo epidemic on our hand that very well could have played into this. But fundamentally, the key was what is the most simplified way to assess the potential efficacy and safety of this drug in a controlled environment, and that's what we got to, so.

And Norbert, you very recently just had some FDA interactions on the PTSD program. So can you give us an update there and your thoughts on the language provided there?

Yes. So maybe I'll start with following up on a comment that Marcio made, namely that in CNS, maybe depend on subjective data points. I think placebo -- control of placebo response is a really critical element. Because I do believe that we have a lot of compounds that show excellent efficacy. They just can't get over the hurdle of separating adequately enough on placebo. And therefore, a real focus has to be on placebo control. That requires proper training of the sites. It requires proper training of the raters. It requires that you look at your relationship with a patient not as a therapeutic relationship, but you look at it as a research relationship. And every word you choose to actually say has an impact on whether or not you involve or don't involve a placebo response. So I think it really has uniquely different requirements from other indications where the readouts are much, much more straightforward, right? On our PTSD study, we actually, because it was an exploratory study, applied the sequential parallel comparison design to try to minimize or reduce placebo response. It actually did not quite give us the results that we were hoping for, looking for. And so we, of course, then focused very much on what did the data say in Stage 1 of that study, which is very much a traditional active event against placebo-controlled. And there 783 did very, very well. That, of course, is the design of our next study. It's an active against placebo, double-blinded, randomized study. It will be along the lines of what a registration study would need to look like. It will be monotherapy. Marcio mentioned that as well for his study. It will be a 10-week duration of daily therapy. We are looking at 2 different doses. We even go as far as having 2 separate studies, 2 arm studies versus one 3-arm study to minimize variants and placebo response. And the discussion, as I mentioned, we had with the agency at the end of April, was a very positive discussion that now has a very clear path that we actually laid out for what we want to do next. And as I mentioned earlier, the first of those 2 studies, the 50-milligram dose is going to kick off in the fourth quarter, followed by the second 2-arm study in the first quarter of 2022. With all those, I would say, really important areas of paying attention to minimizing and controlling placebo response as much as possible to give the drug the very best chance to really show what it can do. And that, I think, is the focus we all have on this panel.

I think, Kyle, I'm particularly interested in luvadaxistat, and we had some data on negative symptoms of schizophrenia, but it seems like you were able to do some sort of signal on cognition. I think when we look at trials of cognitive symptoms in schizophrenia, they use an endpoint called the matrix, which is kind of constantly evolving and may have less regulatory validation here. So how do you think about pursuing indications like that? What are your sort of talks with the FDA about that endpoint selection sort of involve? And how do you get comfortable about designing a trial for those sort of hard-to-treat indications?

Yes. Let me just start by continuing a little bit on the discussion that's already been had here just as a transition. I think our experience at Neurocrine over the years is that we've been given no shortcuts from the FDA on any of our programs over time. We've always had to do things the hard way. And most of it stems from the fact that we continuously, for whatever reason, like to support programs in disease states that have no validated endpoint. So it often takes us over the span of several Phase II trials to optimize or fully develop the endpoint or a patient-reported outcome and then put that in an interventional study and show that it works. And until we get there, what we've noticed over the years is that the agency isn't terribly interactive with us. They give us some direction, but they want to see that data. And once they've had that data in hand, then it's -- everything changes. And for our women's health program that's partnered with AbbVie, we had to conduct 6 Phase II studies, and that's painful for a lot of small companies to live through that. And I think one of the takeaways from that before I continue here is that I think as leaders of companies, we have to continuously be good stewards of the challenges of the neuroscience and appropriately set expectations for those in the field that this is a long process. There's no shortcuts here. It's very rare of the case that we're going to have an oncology path where there's one study that we do with a nice biomarker and we're going to be on the market in 2 years. That's just very unusual. You've looked at the Amgen case with their KRAS program for their oncology indication. I think from clinic to NDA approval is just a couple of years. And you just don't see that in neuroscience. So I think setting expectations is an appropriate thing for us all to think about being in this field. But going back to the example here on our programs over time, so 6 Phase II trials for women's health program, we had to develop a PRO. And finally, we got that to a good spot. And like I said, overnight, it changed in terms of our interactions with the FDA as we moved into Phase III. Obviously, that helped us get a partner in AbbVie in 2010. If you fast forward to our INGREZZA program, which is a program that's indicated for tardive dyskinesia, we had to conduct 4 Phase II trials before we optimized the endpoint there. An interesting thing that we had to deal with there was, I think, Norbert, you touched on this is placebo effect. We relied a lot on clinical site raters to help us with the subject of endpoint, and they were psychiatrists. And they're not used to applying a movement disorder endpoint. And we just couldn't get that to work for us. So what we ended up doing is filming all the subjects at baseline and during the key time points of the pivotal trial, Phase II in this case. And we lost a lot of fidelity in this case by using video for the endpoint versus having it be an in-person interaction. So all those videos were brought back to central raters, and they were completely randomized. They were just all mixed up. And the investigators or, let's say, the reviewers had no idea what patient was what when they came in to get their assessment. And what we saw was basically 0 placebo effect here. We took all that placebo effect that we're seeing at the sites and we eliminated it. And of course, there wasn't that much from a movement disorder perspective in the minds of the patient, much by way of a placebo fact. And that was a game changer for us. We got a really nice result at the end of Phase II and then our subsequent pivotal trial. And that led to breakthrough designation by the FDA and a pathway to market. So these can be very long, circuitous tasks where there's ups and downs as you learn in Phase II. It does make it very easy to confirm in Phase III. So the things that we think about generally when we think about our programs now, endpoints, is it -- do we have one? Is it validated or not? What are we going to have to do in Phase II? So I think that reads on your question on CIAS. We worry about placebo response, of course, and that's usually a topic of discussion when it comes in when we talk about trial design. But it doesn't just stop there in the endpoints in the trial design. I think when we get positive data, the things that we need to start worrying about then is how much do we disclose. Because if you put a lot of positive data out there and you're, for lack of a better word, pumping that data, that's your future placebo effect. So we have to be mindful of that in psychiatry in particular on how much we disclose moving forward. It's not just a competitive issue, it's a placebo effect that we worry about moving forward. And anything we can do to help us win in Phase III, we're going to be mindful of that. So those are the things we think about for CIAS now with luvadaxistat in our DAAO inhibitor. And you're right, we didn't get the outcome that we wanted on the negative symptoms, but we did see a very strong signal on the endpoints commonly studied for the cognitive impairment associated with schizophrenia. We had 2 endpoints that we used here to examine that. And for us, again, over our time, we haven't gotten any breaks. It's just been something that we appreciate that is our burden that we have to work with. And instead of trying to take any shortcuts by moving into Phase III or try to shortcut a typical development path, what we're going to do is we're going to take the same molecule that we've developed here in the negative symptoms and basically just replicate the study that we just conducted in the negative symptoms, but flip the order of the endpoints. It's unfortunate that Takeda, when they had this asset, went with the negative symptoms because they know -- we know it was a very debatable question of whether they pursued CIAS or the negative symptoms for that. Probably would have been the same for us. Not a clear pathway for CIAS, as you mentioned. Negative symptoms, there have been more companies that have pressure-tested that unfortunately failed as well. But we're going to replicate that study and use the endpoints that we used in the Phase II and see if we can replicate that signal. And then we'll be off for the remainder of the development program. But we're not going to ask too much of the next study. I think that's a key to everything that we have to do here as well is don't ask the study to answer too many questions. Keep it really simple, try to get to the main one you want. If you can win there, that gives you another day to look at the program and see where you want to take it. So I'll take a pause there and see if there's any further questions on that, Myles.

Yes. I think that's great. We are pushing up on time. I did want to mention that the placebo response is clearly important. I mean we've seen some really well conducted trials in schizophrenia by like Karuna and recently Cerevel that have shown historically minimal rates. And then we've seen recent waterfall data that seems to be historically high, like, and that's just clearly impacted that demonstrated effect size of agents. But maybe the last question, I have to ask it, and it's more focused on the neurology side. But with the recent approval of Aduhelm, do we have any predictions for how the agency is going to react in the neuropsychiatry space and how the division of neurosciences is going to perceive new drug applications? Are they going to be more or less flexible? Maybe just an opinion here. I'll start with Marcio and pass it around.

I believe the FDA is very strong. I believe that agency has withstand many difficulties and challenges before and continue to be like the steward of, like, health and drug and other things for the country. I can say our recent interactions, despite COVID, despite the fact that we're put under pressure, their systems were put under pressure, they've been incredibly responsive, incredibly professional. Incredibly, to be honest, they know exactly. I think Kyle mentioned that and Norbert mentioned that. There is no cutting corners here, especially in the areas we are. And they've been very clear with us on what is necessary and what's not necessary. I think it's as positive as it's ever been. There are isolated events, and I believe they are like that. They are not a reflection of the agency or the industry, some fortunate, some unfortunate, but it's part of the course. We're going to continue to help these patients, that's what we're here for, under the guidance and auspice of great agents that we have in this country and should be really proud of it.

Well said. Any other comments from the panel before we wrap it up?

I think I would just echo what Marcio just said [indiscernible].

I think the sentiment seems to shift a bit with the approval by Biogen. I do balance that with what I've seen with Acadia out there, for example, in DRP. It seems like at least publicly that, that didn't turn out as a positive outcome with them, and they have a positive study. So I think that there are things that make you think in the back of your mind of what's going on. But I think the bottom line is that I think we all assume that we just don't take anything for granted and we always try to put forth our best attempt to getting the data that the agency would like and desire. I think that if we keep doing the right thing there, that ultimately logic minds will prevail and everyone will succeed here.

Myles, I guess, I'd only add that, look, none of us does anything really without some FDA interaction upfront of any of those important investments in people and cash resources. But it does matter when there's a tremendous need for a drug in a disease, it's extremely serious. And I think you could still somewhat point to the esketamine example. I think that was a -- maybe there's an example there of the threshold for approval, being adjusted when it sees drugs that fill a tremendous void. But that's -- that can't be a presumption when you're making development decisions and regulatory decisions. Again, it's always got to be based on strong science in medicine and sound regulatory activities. And you don't -- the past is not always prologue, but I'm encouraged by the way the FDA and the team is putting time and resources into really wanting to understand the way that these new generation drugs in CNS work, how they're differentiated and maybe past treatment paradigms and development paradigms don't perfectly fit. And that interaction is critical as we go forward to make sure that the development pathway fits the drug's potential.

All right. Well said. Super exciting programs going on at all 4 companies here and real leaders in the neuropsych space. So I applaud your efforts, and it's great to see you all flying the flag there. So with that, I'll close panel, and enjoy the rest of the conference. Thanks, everyone.

Thank you, Myles.

Thank you.

Thank you. Bye-bye.