All right. Good morning, everybody, and thank you so much for joining us for Acadia's inaugural R&D Day. Welcome to the people in the room here at our hotel. Welcome to everybody online. We're delighted that you took time today to join us. Today marks an exciting milestone for the company as we open the curtain on the innovation engine driving our future. We're here to share meaningful insights into our pipeline programs, programs that we believe have the potential to deliver transformational growth for Acadia in the years ahead. Before we dive into the future, I'll begin with a brief overview of our current commercial businesses, the successes we've achieved to date, and our overarching strategy. Let me be clear, the primary focus of today is forward-looking.
Accordingly, as noted on our great slide here, these forward-looking statements are based on current information that are inherently subject to change and involve several risks and uncertainties that may cause our results to differ. These factors and other risks associated with our businesses can be found in our SEC filings. Today, we're here to talk about what's next, what's possible, and why we're so energized by the opportunities ahead. With that, let me turn to the first slide. I do want to take a moment just to ground us on where Acadia stands today, how we're positioned to drive near-term value for our shareholders. At our core, Acadia exists to advance care for patients with underserved neurological and rare diseases. That mission guides everything we do.
As we look to our future, our growth strategy, or the how, is anchored in these four key pillars: precision medicine, data innovation, globalization, and patient empowerment. We begin today's discussion from a position of strength. Acadia really is an exciting place. We have two successful, growing brands, each profitable on a standalone basis. For the first time in our history, we expect these brands to generate more than $1 billion in combined revenue this year, which is a remarkable milestone. Both of our commercial brands share a powerful commonality. They were first to market in their respective indications, addressing high unmet needs, and they remain the only approved therapies in those spaces. With NUPLAZID, we recently achieved a significant set of legal milestones with two favorable patent litigation rulings.
In 2025, with a strong focus on growing our market share, we anticipate net sales in the range of $650 million-$690 million, representing 7%-13% year-over-year growth. Turning to DAYBUE, we're looking to drive incremental growth with new patient starts in the U.S., as well as expanding globally with an anticipated EMA approval in the first quarter of 2026. In 2025, we expect DAYBUE to generate net sales between $380 million and $405 million, reflecting 9%-16% growth. You'll see from today that we're excited about every program in our pipeline, but we also understand that the time horizons in this room matter to this audience. That's why Liz and our team will deep dive into our two later-stage assets with top-line readouts in 2025 and 2026.
The first is our COMPASS- PWS phase III study evaluating ACP-101 in Prader-Willi syndrome-related hyperphagia, with results expected soon. The second is our phase II study of ACP-204 in Alzheimer's disease psychosis, with top-line data expected by mid-2026. We are equally excited about the earlier-stage programs we'll be discussing today. These are highly differentiated assets with the potential to deliver meaningful impact for patients in critically underserved populations. They represent bold science and big opportunity, and we believe they're an essential part of Acadia's future. With strong growing brands, meaningful upcoming data readouts, a solid financial position underpinned by positive cash flow, and a healthy balance sheet, we're also well-positioned to pursue strategic business development opportunities that can further enhance our growth trajectory.
Of course, the focus of today is how we will build on our strong commercial franchises with the new wave of innovation in each of these two core franchises. Let me walk you through our strategy for doing just that. You'll see here within each franchise, we have a core pipeline coming behind each launched brand to build on our current commercial strength and capabilities. Today, Liz and our team will talk you through five of these assets in seven new indications, with a focus on why we believe these molecules hit our high bar of unmet medical need, the opportunity to be first in class or best in class, and the ability for Acadia to develop them and commercially successfully launch them. That's just the start of building Acadia to become a biotech powerhouse.
Looking ahead, we see opportunities to drive our BD focus to expand into adjacent rare disease categories that you see here. These areas, we believe, our internal capabilities align with our rigorous scientific approach, and we can make a real difference. Now let's turn to where these programs can take Acadia and why we believe our future is so bright. As you look at where Acadia is today and where we aspire to go, it's clear we're building from a position of strength. Our current commercial portfolio, consisting of NUPLAZID and DAYBUE, is expected to generate, as I've just said, over $1 billion in revenue this year, a milestone that puts us in a select group of biotech companies. We anticipate over time that their total peak sales could reach between $1.5 billion and $2 billion combined.
When we look at the five pipeline molecules we're going to be discussing today, we will be entering larger markets. They have high unmet need and relatively little competition today. With that favorable backdrop, we estimate that their combined peak sales potential on a risk-adjusted basis represents an incremental $2.5 billion. Now, when we look at the full peak sales potential of the assets we're going to discuss today, so the five assets, if each molecule were to successfully make it to market, we see them having the potential to reach up to $12 billion combined, with at least three of them capable of achieving well over $2 billion in peak sales. Now, let me be clear, this is not guidance.
As we all know, drug development carries inherent risks, clinical, regulatory, commercial, and not every one of these programs will succeed, although I sincerely hope they do. The purpose of sharing these figures is to give you a sense of the magnitude of the market opportunity we see in our pipeline. We believe the potential embedded in our current clinical programs is significantly undervalued by the market today. We understand it's our responsibility to build the case, to deliver the data, to execute with discipline, and to unlock that potential value. We are deeply grateful for your continued support as we pursue this mission. Your belief in our vision enables us to push boundaries, take bold steps, and stay committed to the patients who are counting on us.
With that, let me turn it to Liz to take us deeper into the science and the strategy that will shape Acadia's next chapter. Liz?
Thank you, Catherine. I am delighted to second Catherine's warm welcome to our first R&D Day. I'm Liz Thompson, and I lead the R&D team here at Acadia. As a scientist and a drug developer, I have found meaning and light in my career by having the great privilege to be part of the journey of many patients and their families. When I joined Acadia last year, what drew me was the fundamental resonance with the mission here. Acadians are motivated by the everyday moments that unaffected families can take for granted. Whether that's being able to talk with an aging parent without the fear or suspicion from their delusions, or look mom in the eye, or share a laugh with a sibling, we know that these moments matter, and we wake up every day trying to enable more of them.
Coupled with this deep sense of purpose was the opportunity to be part of charting the next chapter of an organization with a strong foundation. We'll touch fairly lightly on our current marketed medicines today, but you will hear a great deal about how they underpin our growth and diversification strategy for the future. Now, to give you some context, you can see our pipeline here. Throughout the day, we look to give you additional insight into molecules in the pipeline, and in particular, to spend time on programs beyond the later-stage ACP-101 and ACP-204. Of course, you will hear about them as well. We'll be talking about a number of patient populations, including Prader-Willi syndrome, Alzheimer's disease psychosis, Lewy body dementia psychosis, essential tremor, major depressive disorder, tardive dyskinesia, and Huntington's disease.
In line with our increasing approach to pipeline risk diversification, you'll see a mix of more established and more novel biology. In line with the focus that Catherine mentioned on data innovation and precision medicine, you'll also hear a bit about how we're using biomarkers to aid in our development efforts. By the end of the time you're spending with us today, I hope you'll come away with an appreciation of how Acadia is advancing care for underserved neurological and rare diseases. We have an active pipeline, and it's gathering momentum over the next few years. This includes nine disclosed programs, of which eight are expected to be clinical stage by the end of the year, and multiple undisclosed programs. We have seven phase II or phase III studies anticipated to start between now and the end of 2026.
On top of that, we anticipate five study readouts from phase II or phase III trials between now and the end of 2027. We are accelerating our potential to bring solutions forward to patients, and we'll be delivering on that commitment with this team, portfolio, and pipeline. Here is our agenda for the day. You have just heard Catherine's welcome and introduction, and you are now getting close to the end of my opening section. Throughout the rest of the day, we will be specifically highlighting pipeline assets, including ACP-204, ACP-211, ACP-711, ACP-271, and ACP-101. We will also be providing an overview on DAYBUE. Towards the end of the day, I will be covering diseases including rare epilepsies, our potential expansion areas in rare disease, and giving you an overview of our future-looking R&D strategy. Throughout the day, we are going to have several short breaks for questions.
The first of these is going to be after ACP-211. The second will be after ACP-271 into tardive dyskinesia, and the final is going to be at the end of the day. Please hold your questions until those times. I should also note that we anticipate that each Q&A section is going to be short, with only time for a few questions. For those items we can't get to today, please contact Al Kildani, our Head of Investor Relations, and he's going to help you get answers to those additional questions. Now, without any further ado, let's move on with the day.
Our journey through the pipeline today is going to be an exploration of adjacencies, showing you how Acadia's journey has been one of carefully building from areas of success or experience to new frontiers as we've expanded within neurological diseases and how we plan to continue that approach in the future, now applying our sharp commercial insight to every program we consider. Today, we'll start with programs that build upon our proud legacy in neuropsych with ACP-204 and ACP-211. The first up here is ACP-204, our new 5-HT2A inverse agonist, which has been built upon learnings from pimavanserin in both molecule and program design. ACP-204 is a molecule with what we believe to be improved properties, reduced likelihood of QT prolongation, greater achievable exposures, and faster time to steady state, which we hope together can lead to greater efficacy.
We have selected our clinical spaces and designed programs within those spaces to increase our likelihood of technical and regulatory success, again, grounded in what we have learned with pimavanserin. You will hear about how we have done that in both Alzheimer's disease psychosis and Lewy body dementia psychosis. With that, I am pleased to introduce Dr. Sanjeev Pahak. Dr. Pathak is our Head of Clinical Development here at Acadia. He is a psychiatrist and a neuroscientist with nearly 20 years in the industry, following more than a decade in academic medicine. He has contributed to the development and registration of numerous medicines, currently serving patients living with schizophrenia, bipolar disorder and bipolar mania, and major depressive disorder. I am delighted to have him here to share with you more of our insights into ACP-204. Sanjeev?
Thank you, Liz. As Liz noted, I'm a neuroscientist and a pediatric and adult psychiatrist, and I head clinical development at Acadia. Today, it is my great pleasure to talk about ACP-204, a novel and highly selective 5-HT2A receptor inverse agonist that we are developing for the treatment of Alzheimer's and Lewy body dementia-associated psychosis. Firstly, there's a tremendous unmet need for Alzheimer's disease psychosis and Lewy body dementia psychosis, as there are no approved therapies. Importantly, off-label therapies that we clinicians prescribe, sometimes in desperation, could be potentially ineffective. Moreover, these off-label therapies carry significant side effect burden, such as worsening of cognition that is severely debilitating for those living with dementia. These can aggravate motor function and cause sedation, resulting in falls. The patients and caregivers deserve a treatment that works, is convenient to administer, and devoid of these adverse effects.
We think that ACP-204 has the potential to deliver efficacy and an experience that is devoid of these troublesome side effects. Now, let's look at the prevalence of the patient population that we are trying to help on the next slide. Psychosis in the context of Alzheimer's disease, Lewy body dementia, as well as Parkinson's disease, is highly prevalent with approximately 3 million people living with these symptoms that ACP-204, alongside NUPLAZID, could help. This includes approximately 30% of the population with Alzheimer's disease, approximately 50%-75% of the population with Lewy body dementia. This is in addition to the patient population with Parkinson's disease that NUPLAZID is approved for, where approximately 50% experience psychosis. Alzheimer's involves amyloid and tau-based pathology in the brain. Lewy body dementia involves alpha-synuclein-based pathology and includes two subpopulations of Parkinson's disease dementia and dementia with Lewy bodies.
While the proteinopathies may be different in these disorders, similar brain networks are implicated in psychosis in these disorders, and ACP-204 is believed to normalize these brain networks by modulation of serotonin signaling. The high prevalence, the high unmet need motivates us to work really hard to serve this community. Therefore, at Acadia, we have been working for a long time to serve the patient community living with psychosis associated with neurodegenerative conditions in the context of the pimavanserin program and now with the ACP-204 program. There, we have learned a great deal about what would make a good molecule, as well as considerations for what we would like to achieve. Let's look at this on the next slide. On the left, you see the structural differences between pimavanserin and ACP-204.
These differences are to minimize or eliminate the QT prolongation and improve upon the well-characterized and favorable safety profile of NUPLAZID. This is very relevant for a frail and elderly population. Additionally, the lack of a QT signal enables us to investigate higher doses and achieve higher blood exposures. Data from pimavanserin tell us that this has the potential for greater efficacy, and I'll speak more about it on subsequent slides. We also want to achieve a faster onset of action, and that is possible with ACP-204. We also want to have a program that robustly characterizes efficacy and safety and meets regulatory requirements. Now, let's look further into the potential of a QT signal on the next slide, or lack of a QT signal on the next slide. Shown here are concentration QTc change graphs.
Here you see why we believe there may be no risk of QTc prolongation, even with the higher doses. Pimavanserin is shown in the graph on the left, and the ACP-204 is shown in the graph on the right. The green arrow on the left reflects roughly the concentrations of the marketed dose of pimavanserin. As shown here, the QT change is not clinically significant. However, if the concentration is roughly twice as high as the marketed dose of NUPLAZID, as shown with arrows in red, there is a risk of increasing QTc beyond the threshold of 10. This finding limited the dose of pimavanserin to the therapeutic dose of 34 mg. On the right, we have the ACP-204 graph with a similar plot. The slope of this graph is flat or ever so slightly negative.
You will note that even at double the therapeutic exposures depicted as a vertical green arrow on the far right, there is no increase in QTc. This enables dosing flexibility with room for higher doses, room for higher concentrations to achieve stronger efficacy. Overall, as I have noted before, the ACP-204 program builds upon what we learned from pimavanserin. Recall that Acadia previously ran a randomized placebo-controlled trial in nursing home patients with Alzheimer's disease psychosis. Results from that trial are shown here. On the left, pimavanserin met its primary endpoint versus placebo at week six. In the middle, at the same time point, you can see a number of responder analyses suggesting meaningful separation between pimavanserin and placebo at various levels of improvement.
While the data package was deemed not sufficient for approval by FDA, it gave us confidence in the relevance of 5-HT2A mechanism of action, especially in the context of potentially better efficacy and potentially faster efficacy. In regard to Lewy body dementia, we had observed very favorable signal in this population with pimavanserin in the context of dementia-related psychosis randomized withdrawal study. In this study, the Lewy body dementia population was a subgroup. While the sample size was small for the subgroup, we observed very few relapses with pimavanserin and substantially higher relapses on placebo. This further strengthens our conviction in the 5-HT2A mechanism of action. Another key lesson from pimavanserin is that higher blood levels can achieve higher efficacy. Shown here is an exposure response curve with concentration on the X-axis and efficacy on the Y-axis.
In looking at the data, pimavanserin demonstrates positive exposure response, suggesting that higher blood levels yield more efficacy. There are two lines, one showing Alzheimer's disease psychosis and one showing Lewy body dementia psychosis. You can see here that as the concentration increases towards the right on the X-axis, the efficacy improves, as shown by a decrease on the Y-axis. This is true in both diseases. Importantly, the vertical line represents the median exposure yielded by the currently marketed dose of NUPLAZID, suggesting that additional exposure could yield some additional efficacy. Now, let's look at how ACP-204 concentrations compared with pimavanserin. This is a concentration line time curve. In this figure, the concentrations of ACP-204, 60 mg, and pimavanserin, 34 mg, are plotted with time in days on the X-axis and drug levels on the Y-axis.
Note that the 60 mg dose of ACP-204 represents the higher dose currently under clinical exploration. Pimavanserin concentrations are depicted by the dark blue line, and the ACP-204 is shown in light blue. The concentrations are modeled for the elderly population. The concentrations achieved with 60 mg dose of ACP-204 is much higher relative to the marketed dose of pimavanserin, and the concentration reaches a steady state faster at approximately six days versus roughly 15 days with pimavanserin. We believe that it has the potential to lead to stronger and faster efficacy for ACP-204. We are also exploring a lower dose of ACP-204, 30 mg, which would achieve concentrations similar to pimavanserin's marketed dose, but would do so more quickly. After measuring blood concentrations, we also wanted to estimate the brain concentrations to obtain on the variable informing the potential for efficacy.
Shown here are concentration time graphs depicting drug concentrations in the CSF of non-human primates. As these are in non-human primates, these data would more readily translate to human CSF levels. Our findings show that ACP-204 results in five times higher CSF levels relative to pimavanserin. When the plasma levels are equivalent, this finding would also suggest that ACP-204 has potential for stronger efficacy. Next, we'll look at information that supports that ACP-204 can be conveniently dosed. We have learned in our phase I clinical trials that ACP-204 can be dosed with or without food. The graph on the right shows exposures when given with food, as seen in gray, or without food, as seen in dark blue. As you can see, the lines are on top of each other, demonstrating it can be given with or without food.
We also observe a half-life of around 20 hours, which means it can be taken once a day. Importantly, it can be conveniently taken with the usual medicines prescribed for neurodegenerative conditions like Alzheimer's disease and Lewy body dementia. Now, let's look at safety and tolerability. Like pimavanserin, ACP-204 is dopamine-sparing that lends itself to having favorable tolerability and safety profile compared with dopamine-blocking atypical antipsychotics. While dopamine-blocking antipsychotics are associated with cognitive side effects and dopamine blockade specifically exacerbates movement disorders, in clinical studies, data demonstrated that pimavanserin did not impact motor function nor cognitive function. The table on the left shows the ratio of 5-HT2A and D2. The higher numbers mean low or negligible D2 activity. We see that neither pimavanserin nor ACP-204 show D2 activity with ratios in the thousands. As the number for ratios goes down, the D2 activity goes up.
As a result, we believe that ACP-204 will not contribute to motor side effects, nor is it likely to have cognitive deteriorating side effects that are seen with dopamine-blocking agents. So far, our clinical trial data support this belief. The forest plot on the right-hand side shows pimavanserin data plotted against data from second-generation dopamine-blocking antipsychotics. The vertical line of zero represents a level where the drug would be similar to placebo. What we see is that for all of the dopamine-blocking agents, the point estimates are on the right, and the confidence interval does not cross zero when all the antipsychotics are put together, which demonstrates cognitive side effects with these agents. In comparison, pimavanserin's point estimate is on the left-hand side with the confidence interval crossing zero. That means it is a medicine without cognitive side effects.
We expect a similar profile from ACP-204 since it is also dopamine-sparing. Next, you will hear from Ms. Helen Metzger and Ms. Meryl Comer, who are caregivers, and Dr. Jeff Cummings, an internationally renowned expert, about how much new and better treatments are needed.
Alzheimer's disease is a progressive neurodegenerative disorder of the brain. It is characterized by the accumulation of two toxic proteins in the brain. One is called amyloid that accumulates into plaques, and one is called tau that accumulates into neurofibrillary tangles. These pathologies then kill the cells and produce atrophy or shrinkage of the brain. Alzheimer's disease and psychosis is the presence of hallucinations or delusions in an individual with a diagnosis of Alzheimer's disease. Hallucinations are seeing things that are not there.
They might see a dog in the room, or they might see other people, or they might see children in the back seat of the car that are not really there. Delusions are false beliefs. They're beliefs usually around people stealing things from them, feelings of abandonment, that they believe that their children intend to force them out of the house. They have feelings sometimes of having no money, of impoverishment, delusions of impoverishment. In some cases, there are delusions of infidelity, that their spouse is having an affair with someone. Of course, the point is that these are all extremely painful experiences, both for the patient and for the care partner. My survival strategy, as painful as it was, was to play into his reality.
For example, at night, and that's when there's much more confusion, if he claimed that strange creatures had invaded our bedroom, I would capture them in a pillowcase, run down the steps, open the door, slam the door, and only then could I calm my husband down enough to get him back into bed. When he began to ask who I was and why was I sleeping in his bed, I had to move to another room. I put up a camera to monitor because night was day and he was up and moving all the time. It was exhausting, and it was terrifying, which is why, quite frankly, I didn't speak about it. I swallowed it. Lewy body disease is another neurodegenerative disease of the brain, and it differs from Alzheimer's disease in that the protein that accumulates in the cell is called alpha-synuclein.
We had amyloid and tau protein in Alzheimer's disease. Now we have alpha-synuclein accumulating in the cell in Lewy body dementia. The aggregates of the protein are called Lewy bodies. That is the pathology that occurs. That protein then kills the cell. There is atrophy and the emergence of a very extravagant set of neuropsychiatric symptoms in this disorder. Hallucinations are one of the core features of Lewy body dementia. Again, these are usually fully formed visual hallucinations of animals or people, but they can also be misinterpretations of flashing lights or other things that occur in the visual environment. Having had three family members who have gone through the arc of Lewy body dementia and had all the symptoms of the psychosis along the way, I know the impact personally, and I know the broad spectrum of the symptoms and how they affect.
I watched my mother be decimated by my father saying, "I don't recognize who you are, and I don't like you." Telling other family members, "Well, you know, we're divorced." That was heart-wrenching to my mother. I just ran under crisis management, and by the time my father passed away, responding to his needs in the care home, making sure the physicians were on board, trying to mitigate his symptoms, I nearly collapsed from both physical and emotional exhaustion. With my sister, it was unique. She asked me at the very beginning of her journey, "Will you walk this path with me?" I told her all the way through to the end, no hesitation.
Halfway through her journey, as I watched her suffer more with this disease, I was at my office one day, and I just stopped cold and said, "If I don't get professional help, I can't do this because I was projecting her death. I know what this disease looks like. I know every bit of it physically and emotionally." I stopped at Helen, "Stay in the present." With my dear brother, he wanted to live in denial, as many families do. They don't want to know how desperate this can become. He stayed in the dark until it was so obvious he couldn't. We just held on and supported him as best we could.
To all the families out there that I work with, and there have been over 100 caregivers throughout this country that I have cared for and supported, I have seen and heard more stories that literally will break your heart. We desperately need solutions to this psychosis. There are no approved treatments for the psychosis of Alzheimer's disease or the psychosis of Lewy body dementia. We really need these treatments. These are very distressing symptoms, both to the patient and to the caregiver.
What I would hope for is a medication that is very efficacious, that would have a marked effect on reducing delusions and hallucinations, a medication that was very safe to use in older populations, particularly, for example, no impact on gait as an adverse, something that would not exacerbate the Parkinsonism of Lewy body dementia, because we know that's a common problem with using conventional or atypical antipsychotics. We want something that is very convenient for the patient to take. Once-a-day dosing, for example, would be terrific.
Throughout my journey as a treating physician and a drug development scientist, I'm deeply moved each time I witness or hear the challenges faced by caregivers of individuals with Alzheimer's or Lewy body dementia. I'm sure you all felt the same. We all heard that there is tremendous unmet need. With this unmet need in mind, I will go into details about our Alzheimer's clinical trial. This is a global, double-blind, placebo-controlled, parallel group, randomized control trial evaluating two doses, 60 mg and 30 mg. The primary endpoint is SAPS- H+D, which assesses hallucinations and delusions in this population. We have a master protocol for three studies that will run in a seamless fashion. phase II is currently ongoing, and the sites will begin enrolling once phase II is completed.
We have a different design for Lewy body dementia psychosis, which is on the next slide. Our Lewy body dementia program, once again, includes a global, double-blind, randomized placebo-controlled study where we are testing two doses, 60 mg and 30 mg versus placebo. We are enrolling patients with Parkinson's disease dementia and patients with dementia with Lewy bodies because these populations share the common alpha-synuclein pathology. The primary endpoint is SAPS Lewy body dementia psychosis at six weeks, which assesses psychosis or hallucinations and delusions in this population. Please note, this is the endpoint that is identical to the primary endpoint for the pivotal study with pimavanserin for Parkinson's disease psychosis or PDP. Now, I would like to underscore some key innovations that we have introduced into this program. As I mentioned, we are running a seamless phase II/III trial in Alzheimer's disease to accelerate development.
Specifically, sites can commence enrolling in the phase III studies once phase II enrollment is complete. Importantly, though the phase II and phase III studies are statistically separate and can be analyzed and reported separately, we are also using state-of-the-art biomarkers for both programs. This allows us to enroll patients with a confirmed diagnosis of Alzheimer's disease consistent with the latest biomarker-based diagnostic criteria for this disease state. For the Lewy body dementia program, the biomarkers will enable us to inform similarities or differences between Parkinson's disease dementia and dementia with Lewy bodies and support and inform the phase III population and enrichment strategies. Overall, this will give us greater confidence in the population and in efficacy of ACP-204. Lastly, we are also working with TREND Community, a digital health analytics company, to enable faster recruitment.
In the end, I would like to reiterate the key takeaways for ACP-204. Alzheimer's and Lewy body dementia-related psychoses are severe, highly debilitating illnesses, and there are no approved treatments. The off-label treatments are potentially ineffective and carry significant adverse effects. ACP-204 could change that. ACP-204 is a highly selective, potent inverse agonist of 5-HT2A receptors, and is believed to normalize dysregulation in brain networks implicated in psychosis. It has shown that it is not associated with QT prolongation, enabling exploration of higher doses and a wider dose range, and has the potential for stronger efficacy in both Alzheimer's and Lewy body dementia-related psychosis. Finally, the program incorporates innovations that enable collection of meaningful information to strengthen phase III. Thank you for your attention. Now, I will hand the mic back to Dr. Liz Thompson.
Thanks, Sanjeev. In the next section, we'll be sharing information on ACP-211. We first disclosed this program earlier this year. Our vision for ACP-211 is an oral agent with the potential of ketamine-like efficacy with an improved patient experience, specifically including minimal in-office monitoring requirements. In this section of the presentation, we're going to share some of the data that make us believe in that potential.
This section should also give you some understanding of our drug development philosophy, in particular, some insight into how we define the criteria by which a molecule earns its right to stay in our pipeline, and how we design our experiments to enable disciplined decision-making around those criteria. Dr. Dragana Bugarski Kirola is a psychiatrist and neurologist who has been working in the field for almost 30 years. Most of her academic research and clinical work has been focused on neurophysiology and sleep, schizophrenia, autism, dementia, and affective disorders. Dragana has authored more than 40 papers in high-impact journals, and she's a vice president within our clinical development organization. I am delighted to welcome her up to join us. Dragana?
Thank you, Liz. Hello. As you heard, my name is Dragana Bugarski Kirola, and I'm the vice president of clinical development at Acadia.
Today, I'd like to share some information about our program in major depressive disorder and treatment-resistant depression. I will tell you a little bit about what ACP-211 is, how it compares to the other compounds in its class, and most importantly, why we are excited about it. There are depressive episodes in life, but not every episode of low mood is a major depressive disorder. Major depressive disorder is a pervasive feeling of sadness and loss of interest that lasts for more than two weeks and is accompanied by disturbances in sleep, appetite, energy, and concentration. Low self-worth and hopelessness can oftentimes lead to lameness to hurt oneself. The symptoms have to be so severe that they impact everyday functioning.
Current treatments for major depressive disorder can be limited by the extent and the onset of efficacy or show quick antidepressant effect, but require clinic administration and protracted clinical monitoring due to serious side effects such as dissociation and sedation. To illustrate my point, I will give an example of a former patient of mine, a young 30-year-old mother of two small children. She was walking with them one day down the street when she suddenly left them on a sidewalk and jumped in front of a moving truck. It was just by sheer skill of that truck driver that she survived unharmed. Her husband reported that she was not sleeping, that she was not responding, and she sat in front of me, severely depressed and completely mute.
In order to get her treatment she needed, I had to convince her to stay voluntarily in the psychiatric unit with other chronically ill psychiatric patients and be separated from her children for months. This is because the treatment required a combination of antidepressants that would be given intravenously and would only have an impact after several weeks, during which she would remain symptomatic and in high risk of suicide. As a doctor, I want to have better options for patients like her. She should not have to choose between getting treatment and staying with her kids, being surrounded by her family members as opposed to being with psychiatric patients, which is why I'm excited about this program. ACP-211 is designed as oral therapy with potential for ketamine-like efficacy and targeting minimally required in clinic monitoring.
Approximately 21 million of the adults in the United States are diagnosed with major depressive disorder. Of those, only 9 million are getting treated. Of those, 3 million are deemed treatment-resistant. To put things into perspective, the state of Florida has 21 million people. Imagine all of Florida being depressed. Imagine that of 21 million people, less than half are getting treated for it. This is why major depressive disorder is the second highest cause of disability of all the diseases and why the economic burden is so high. Both ketamine and esketamine have efficacy in depression, but with significant side effects. Ketamine is a mix of two isomers, the R1 and the S1. RS ketamine shows a rapid reduction of depressive symptoms within two to four hours when given intravenously in low subanesthetic doses.
As many of you know, esketamine or SPRAVATO has been recently approved for treatment-resistant depression. Now, the dissociative anesthetic properties of ketamine and esketamine, namely dissociation and sedation, occur even at low doses shortly after administration. Sedation is observed in SPRAVATO studies, and it can be severe. By that, I mean that people cannot get up from a chair or they may be found unresponsive. The other side effect is dissociation. Low-grade dissociation has no impact. People may actually report that they are seeing their surroundings a little bit more clearly. More profound dissociation can lead to feelings of derealization, feelings of being detached from oneself, depersonalization, or even identity confusion. This is why protracted clinical monitoring for several hours is needed.
Clearly, a new therapy would ideally have the rapid and robust antidepressant effect of ketamine or SPRAVATO with minimal potential for sedation and dissociation, which brings me to ACP-211, a selectively deuterated form of R-norketamine with potential to have that ketamine efficacy and with lower sedation or dissociation. Let me explain. The causes of depression are not well understood, but it has been proposed that impaired glutamatergic signaling may play a significant role in it. In a healthy state, you can see that synaptic activity is enabled through rich connectivity of short and long branches of glutamatergic neuron. In depression, there is a decrease in the density and loss of synaptic connectivity that affects the brain's ability to regulate mood. Antidepressant treatments like ketamine or ACP-211 increase density again and promote neuroplasticity, which is involved in mood regulation.
Now, this process is actually mediated by the inhibition at the NMDA receptor and by the activation and increased expression of AMPA receptors. Both of these are on the glutamatergic synapse. This is, for those of you biologists, a very simplified version of glutamatergic synapse. In a healthy brain, there is a balance between activation and inhibition, between glutamate and between GABA, gamma-aminobutyric acid, or the inhibitory neurotransmitter. In depression, there is clearly an imbalance that's leading to decreased synaptic connectivity favoring inhibition, which can be seen clinically, like in my patient, for example. Ketamine binds to the NMDA receptor, preventing its inhibition, but this may not be the only mode or the only way to mediate antidepressant response. Additional mechanisms such as AMPA activation, the amplification of AMPA pathway, may play a significant role.
Thus, what I'm trying to tell you is that compounds like ACP-211 that have lower affinity for NMDA receptor inhibition can still be clinically effective. What happens over here is that glutamate activates the AMPA receptor that leads to the increased release of the brain-derived neurotrophic factor, which is involved in neuroplasticity, promotes neuroplasticity. That process activates the tyrosine kinase receptor, which influences signaling downstream and eventually restores the functioning of the synapse. In conclusion for this slide, ACP-211, as you can see over here, uses similar pathways as ketamine to deliver antidepressant efficacy or activity, but because of its propensity to lower affinity for NMDA receptor, its propensity for sedation and dissociation is much, much lower. All right. In animal models, as you can see, ACP-211 has actually shown comparable efficacy to ketamine. What do I mean by that?
ACP-211, when given up to the animals 24 hours prior to testing, significantly decreases the immobility time, which is a measure of antidepressant activity, a behavioral despair model. Not only that, it actually the animals resume swimming, which means that their motivation is restored. Their survival instinct is restored. As you know, lack of motivation is one of the key symptoms of depression. The other model that we use over here is a decreased preference for sucrose, which is considered as a sign or evidence for anhedonia, loss of the ability to feel pleasure. In this model, restored sucrose consumption would actually be indicative of antidepressant activity.
As you can see over here, again, when animals are treated 24 hours prior to test with ACP-211, there is a significant jump, significant increase in sucrose consumption that's sustained all the way till the end in stressed animals, but not in non-stressed animals. Again, this shows that the animals show recovered ability to feel pleasure, and that is the evidence for antidepressant potential of ACP-211. Now, the second feature of our target product profile is superior safety or no sedation and minimal dissociation. As you can see over here, ACP-211 actually shows less motor impairment than ketamine in animal models, specifically rotating rod test. Here shown are animals treated with vehicle, and they're able to resist from falling off of the rotating rod for about three minutes. There are no bars for animals pre-treated with ketamine because they fall immediately down from the rotating rod.
The animals pre-treated with three different doses of ACP-211 show comparable latency to falling off from the rotating rod as the vehicle, meaning no impairment, no motor impairment, technically no sedation if you really want to translate it into humans. Let's see how the humans react. ACP-211 has been tested in healthy volunteers because they are more sensitive to the side effects of medications than patients who have been tried on a variety of different drugs. As you can see over here in the graphs, this is a concentration over time of ACP-211 from the single ascending dose study where doses from 30 mg all the way to 900 mg were tested. A couple of points over here. First, the peak concentration happens within two to four hours after dosing. Second, the peak concentration is dose-dependent.
The higher the dose, the higher the peak, and remember, the higher the risk for side effects, sedation, and dissociation. The third point is at the end of day one, there is nothing in the system, no ACP-211, so there is no accumulation. From the safety point of view, the data to date, or the profile to date, seems very reassuring, as you can see from the data from healthy volunteer study. No impairment of consciousness, no sedation. Dissociation was seen only with the highest doses and was mild and transient. There was some impact on the heart rate and on blood pressure where the dizziness was associated with orthostasis and again, mild and transient. These data really support our next step, which is to proceed testing ACP-211 in patients.
As I said, our next step is really the next stage trial is designed to inform our ability to meet our target product profile on sedation and on dissociation. This is a pretty typical proof of concept study. The design is illustrated over here below, but it will be in patients with inadequate response to antidepressant treatment. What I want to highlight is that the stopping criteria and monitoring for rates of sedation and dissociation are embedded in the study design. The start of the study is planned for the last quarter of this year. In summary, these are the key takeaways. Major depressive disorder is a serious mental disorder that affects 21 million people in this country alone.
Currently approved treatments, as you can see, are limited by the efficacy and the onset, either the onset of efficacy or simply the efficacy or inefficiency, or show rapid improvement, but with serious side effects such as dissociation and sedation. ACP-211 is an orally administered, selectively deuterated form of R-norketamine. As you can see from my presentation, data from animal models support ketamine-like efficacy, but also very benign profile, no sedation. Finally, when we looked at the healthy volunteer study, they allow us to go high with the doses with minimal dissociation and no sedation. The phase II MDD study is going to evaluate efficacy and safety, specifically ruling out unacceptable rates of dissociation and sedation, as Liz has alluded to. Finally, I want to close with two points. The first is that my patient was not the only young depressed mother.
There are many others out there that could benefit from rapid improvement that can be compatible with living their daily lives, not staying in the hospitals for days, weeks, or months. Second, ACP-211 exemplifies the opportunity to pave the way to new, much better treatment I think we all deserve. Thank you so much for your attention.
Thank you so much, Dragana. Now we have just a few minutes for questions, and we can take two or three of the most burning questions that you have regarding ACP-204 or ACP-711. Al is walking around with a mic.
Thanks, Al. Ritu Baral from TD Cowen. I'm going to stick with 211. Your deuterated norketamine. Can you talk to how you believe that the deuterated R-norketamine could be different from the IV R-ketamine that was previously investigated? Like what sort of PK and PD dynamics may give it an advantage versus that drug that failed. Also, can you talk to, in that phase II that you're starting in Q4, can you talk to your definition of MDD with inadequate response versus the TRD definition that is used in SPRAVATO development? Thanks.
Okay. I'll make a couple of comments, and then I'll invite Ragna to add in a little bit. I think that we see 211 as having a unique profile in a number of ways. Certainly, the convenience of an oral administration, I think, is a positive compared with some of the other agents that have been investigated in the space. I think that also the data we have to date, and obviously that's preclinical in phase I, so we're going to learn more about this as it goes through later stage clinical, but the data we have to date is supportive of seeing the potential for strong onset of efficacy with no sedation and low dissociation, which I think would be a pretty impactful profile if we're able to demonstrate that in phase II. Thus far, data are supportive in that direction.
Dragana, would you like to comment? Actually, I am sorry, I forgot what the second half of the question was. Oh, the definition of MDD. Would you like to comment a little bit more on how we're defining patient populations?
Yeah. Thank you for the question. I think this is a very typical question, as many of you know. There's not a real consensus among the scientific community when it comes to the TRD. FDA has their own, and then community has their own, and also for the inadequate response. For the inadequate response, we actually do have the questionnaire that we're going to use retrospectively for two or more failed studies, and that also in the context of the percentage of the response. For the TRD, the FDA actually does request at least minimal response, less than 25% or 30%. We will use this retrospectively, but within one episode, the ongoing depressive episode. Those are the criteria for the clinical trials, and there will be a randomization also based on those criteria as much as we can.
Yeah. This phase II data, of course, is going to help us inform what we would go forward with and if we're going to.
For the indication, yes.
Thanks. Brian Abrahams, RBC. Maybe shifting to 204. In addition to the differences that you discussed, I believe that 204 also has some differences in preference for 5-HT2A versus 2C as compared to pimavanserin. And I know it can be tough to predict the impact of some of these subtle differences in receptor profile, but I'm curious if you have any sense as to how this could potentially affect its antipsychotic efficacy, relatively speaking, as well as its safety profile.
Sanjeev, would you like to address that one?
Yes. Great question. So as we have understood our molecules better and the receptor profile better, what we have concluded that with pimavanserin, there is some 5-HT2C activity, but it is orders of magnitude lower than 5-HT2A, roughly 40 x or more. So at the therapeutic or marketed dose of pimavanserin, there is essentially no 5-HT2C activity. In conclusion, 5-HT2C is not, in our view, contributing to antipsychotic efficacy. Similarly, that would be the case for ACP-204. We believe that the activity and the efficacy result from 5-HT2A, where ACP-204 is highly selective and very potent, and in our functional assays, works as well as pimavanserin, if not better.
All right. I think maybe time for one. Oh, actually, I guess.
Time.
We're at time. All right. Hold thoughts. We will have a couple more question periods throughout the day. Okay. All right. Thank you both. Appreciate it. I said earlier that we would be walking you through how we expand our areas of focus in a measured and strategic way. In this section, we're going to talk about the next subset of neurological diseases that we focus on. In specific, that's our neuromotor programs. With the first and only approved product for patients living with Parkinson's disease psychosis, neuromotor is a natural adjacency for us, and it's one with many areas of significant unmet need. You'll be hearing about ACP-711 in this section, as well as the first part of the story about ACP-271, with the ACP-271 sequel as we move into the rare disease section of our day.
Starting with ACP-711, this is our GABA alpha-3 specific positive allosteric modulator that we're developing for the treatment of essential tremor. I am delighted to introduce Dr. Vic Abler, a Vice President within our Medical Affairs organization. Vic is a neurologist who was previously the Professor of Neurology at the University of Cincinnati College of Medicine, as well as the attending neurologist at the VA Hospital Medical Center in Cincinnati, Ohio. He has more than 20 years of pharmaceutical experience within medical affairs and has published more than 40 scientific articles in peer-reviewed journals. Today, he's going to share both his professional and also his personal experience with essential tremor. Vic, come up and join.
Thank you, Liz. Appreciate it. I am really excited to talk to you today about ACP-711. ACP-711, as Liz mentioned, is a positive allosteric modulator for the potential treatment of essential tremor, or ET. We are partnering actually with a company called Saniona based in Denmark. Let's start by asking, what is essential tremor, and why is it so important to bring another medication to market to treat ET? As a neurologist who's practiced for years, I've seen many patients who've had essential tremor. It's actually a very unique tremor. It's very different, for example, than a Parkinsonian tremor.
It's described as postural and/or kinetic tremor. What do I mean by that? Postural tremor is, let's say you're holding a full glass of water straight out in front of you. You would actually see a tremor there. Kinetic tremor is if you brought that full glass of water closer and closer to your lips, the water would splash around because the tremor would worsen as you got closer to the lips. That's what I mean by postural and/or kinetic tremor. There is a large unmet need in this space. Current treatments are not always effective and can have really unwanted side effects. We are striving for better treatment options for the patients. ACP-711 is meant to fill that unmet need. It's a selective GABA A alpha-3 modulator that targets GABA dysfunction within the cerebellum.
We do have phase I data that supports the potential absence of negative cognition, sedative, and sleep effects. It's very common. In fact, it's 10 x more common than Parkinson's disease. In the United States., it's estimated that 2.2% of the population suffer from ET, which equates to about 7 million patients. There are 1 million patients who are seeking treatment. You may ask yourself, if there are 7 million people that have ET, why will only 1 million be seeking treatment? In part, the answer is that especially early on, ET is mild enough not to necessarily warrant treatment. Now, I'm going to share a personal story. My dad actually has severe essential tremor.
This created a roller coaster ride for us as a family where we started him initially on some oral medications that did not either seem to work or he just could not really tolerate them. Let me give you an idea of what was happening. For example, he could not bring a spoon full of soup to his mouth because the tremor would worsen. He could hardly button a shirt any longer, and he could not write a check. He stopped playing piano because he could not do it because of the tremor, which he loved to do and found this was a way to relax. Also, ET is an autosomal dominant disorder. What this means is that the child of an affected parent will have a 50% chance of developing ET. True to the genetic form, I have actually inherited this disorder as well.
I'm one of those who do not yet quite need treatment because it is pretty mild. The reason I bring this personal story, it does speak to the larger population where half the patients who are treated with essential tremor see no benefit, and half of those who actually see that benefit will reach this plateau where there is just no satisfactory improvement. Not surprisingly, one-third of the patients will stop their medication. Propranolol, the only approved drug currently in the United States, was FDA approved way back in 1967. There are other treatments off-label being used, such as benzodiazepines and anticonvulsants like primidone. Most of these off-label treatments were investigated in these small studies with like 20-30 patients per treatment arm. They were done many decades ago. There is so much room for improvement here.
Now I really want to talk to you about why do we think what causes ET? I'm going to start with a structure called the cerebellum that's depicted on the left-hand side here on the left-hand side of the slide in blue. The cerebellum is a neuroanatomic structure that's slightly smaller than the size of the fist. It's tucked in the back of the brain underneath the occipital cortex adjacent to the brain stem. Now, the cerebellum is a key important structure for balance and motor control. Now, within the cerebellum, there are important neurons called Purkinje cells. These Purkinje cells, for unknown reasons, start to degenerate. Now, I'm going to show you the Purkinje cells in this slide. If you look to the black and white panels, you're going to see Purkinje cells.
The two side by side in the green panel or in the green box are actually postmortem cells from humans who did not have ET. Now, I want you to look closely at that panel, and you're going to see these Purkinje cells that look like healthy trees full of thick branches and many leaves. Now, look to the right side in the red box. That's a Purkinje cell, human Purkinje cell postmortem in a patient who had ET. And look at the difference. It looks like the tree has kind of thinner branches, and many of the leaves have been lost. Now, this signifies loss of dendritic spines, as pointed out by the dark arrows. This is all due to Purkinje cell degeneration. Now, most Purkinje cells release a neurotransmitter called GABA, gamma-aminobutyric acid. GABA is an inhibitory neurotransmitter.
This degeneration of Purkinje cells creates this dysfunction within the GABA system, as you see here on the right-hand side of the slide. This results in the loss of inhibition that creates this increased pacemaker activity of the neurons that are trying to work overtime in the cerebellum. In turn, there is an increase in thalamocortical activity. The thalamus is the main relay station of the brain. It receives input from the arms and the legs and the lower extremities, and it sends this information up to the cerebral cortex. This increase in activity is thought to cause tremor. The brain loves homeostasis. It relies on this nice balance between inhibition and excitation. When inhibition is lost, excitation takes over. On the next slide, I am going to dig deeper into the cerebellum itself.
Now, GABA, that inhibitory neurotransmitter, needs to land on a receptor in order for it to work. These are called GABA receptors. Actually, there are multiple GABA receptors in the brain. GABA receptors are made up of different subunits. These subunits are called alpha-1, alpha-2, alpha-3, alpha-5, for example. Different receptors made up of different subunits can be located in different places in the brain, making this a very complex system and historically difficult to target with precision. As I mentioned before, evidence currently suggests that the cerebellum is the location of the problem. Now, let's look at the right-hand side of the slide. What you're looking at is a confocal microscopy of a rat cerebellum. The arrows that you see are pointing to various layers of the cerebellum, such as the Purkinje layer, white matter layer, granular layer.
Now, take a closer look within the green, and you're going to see these bright spots. These bright spots are showing you alpha-3 GABA receptors. This means that within the cerebellum, there are abundant alpha-3 receptors in all layers of the cerebellum. Now, what I want to do is talk to you about the connection between ACP-711 and these GABA receptors. As a recap, Purkinje cells degenerate, so they cannot release that inhibitory neurotransmitter. This, in turn, is thought to cause tremor. The GABA receptor alpha-3 is an abundant and key receptor in the cerebellum, as you saw. What's that connection between ACP-711 and the receptors? As I mentioned earlier, ACP-711 is a positive modulator of GABA alpha-3. What you are looking at here in this slide is a study, in vitro study, of cells expressing human recombinant GABA alpha-3, but also alpha-2, alpha-5, and alpha-1.
The line graph is showing you the activity that ACP-711 has on the various receptors. Now, you see that there's high activity with the GABA alpha-3 receptors, as shown by the top dark blue line, and little to no activity with the other receptors mentioned, alpha-1, alpha-2, and alpha-5, as shown by the other line graphs lower down. Now, this is an important distinction because we know from research that alpha-1, alpha-2, and alpha-5 subunits are implicated in things like anxiety, cognition, memory problems, and reward-enhancing issues. On the other hand, alpha-3 receptors are associated with motoric control. Now, what I want to do is let's move on to some evidence of some efficacy with ACP-711. So what I'm going to do in this slide is show you something called a Harmalane model.
Harmalane is a chemical that actually originates from a seed from a plant that's indigenous to South America. It's in the alkaloid family. Once Harmalane is injected into an animal, it produces a tremor similar to the frequencies seen in essential tremor in humans. The Harmalane model is considered the standard model for preclinical exploration for efficacy in ET. Now, let's look at the graph on the slide. Let's look at the left side of the slide looking at that graph. The Y-axis stands for the percent motion power. In other words, how much tremor the animal is or how much tremor the animal is experiencing. The X-axis is showing you what was administered to that animal. Let's start to the left. On the far left, you see a white bar. This is saline in a normal animal without tremor.
The gray bar is vehicle or placebo that's given to the animal that now has tremor induced by the Harmalane. The dark red bar is propranolol. The three colored blue bars are different doses of ACP-711. Note that propranolol does reduce the tremor significantly compared to the vehicle or placebo, as well as a reduction using the higher doses of ACP-711. Now, looking at this, propranolol appears to be more effective in the tremor model. In this case, the animals were actually all rendered recumbent due to the muscle weakness after given propranolol. This was not seen with ACP-711. Now, look to the right bar graph. This is a similar approach, but the difference here was that the animals were given primidone, again, another commonly used drug in ET. This graph shows efficacy of ACP-711 in different doses that significantly reduce tremor versus vehicle, as well as primidone.
However, drugs used to treat ET, like primidone, have limiting side effects that cause sedation in humans, for example. Now, what I want to do is let's talk about some human studies on this next slide. I'm going to start with some pharmacokinetics that were done in healthy subjects, the left-hand side of this slide. ACP-711 was given orally to these healthy subjects, and we noted that there was rapid absorption, about two hours or less. After ACP-711, the mean half-life was about 10 hours across different doses that supports the possible twice-a-day dosing. Now, the most common side effects seen here were headache and some dizziness. Now, let's switch over to brain imaging study. On the right-hand side of this slide, it's called PET scan, PET, positron emission tomography. PET scans can actually show us what kind of occupancy a drug may have on the various receptors.
In this case, healthy subjects were given radio-labeled injections. In the first column, they were given radio-labeled flumazenil. Flumazenil is a potent GABA receptor-binding agent. What you're seeing here is an intense uptake of flumazenil on those GABA receptors. The middle column are subjects that were given radio-labeled ACP-711. What's happening here is within 30 minutes of infusion, you see that ACP-711 is actually displacing the flumazenil and occupying those very same receptors. Third, the last column is 24 hours post-dose ACP-711. What you're seeing here is that flumazenil receptor occupancy is starting to come back. It's returning. In summary on this study, the PET scan showed us that there's an 86% occupancy of GABA receptors with ACP-711. We're currently exploring even higher doses, as well as the impact of dosing on the elderly.
Now, this suggests that we'll be able to achieve good target modulation with ACP-711 at the planned clinical doses. Next, what I want to do is talk to you about the effects that ACP-711 has on brain activity versus other drugs in ACP-711. On this slide, what I'm going to show you is the impact that commonly used drugs like benzodiazepines have on essential tremor when it comes to brainwave activity, EEGs, electroencephalograms. There are various brainwave patterns that are seen that are going to be described to you that you're going to see at the right lower side of the slide. I'm going to start with something called delta activity, delta waves. Delta waves are those long undulating waves that are seen during times of sleep and heavy sedation. Next is something called alpha wave activity.
Alpha wave is when you're in a deep meditative, very focused state, relaxed. Last, beta wave activity. These are seen when you're in an intense concentration maybe with somebody, or maybe you're doing a very complex mathematical equation, beta waves, fast activity. Healthy volunteers in this case were admitted to an observation unit for nine days. They were given ACP-711 orally for those days and monitored with EEGs. Now, what was seen in this study was that there was, with ACP-711, a decrease in delta activity. This suggests that possibly ACP-711 has no sedation properties. Now, with benzodiazepines, you're going to see the opposite. You're going to see an increase in delta wave activity, suggesting drowsiness. Next, the subjects given ACP-711 experienced an increase in alpha activity. Remember, that alpha activity is that experiencing when you're in a deep meditative focus state.
Now, with benzodiazepines, again, you're going to see the opposite. Alpha wave activity decreases. Last, ACP-711 caused no changes with beta wave activity in the brain, those waves that are seen with doing a complex mathematical equation, for example. Interestingly, benzodiazepines will actually increase beta activity, that fast activity. We think it's due to a compensatory mechanism to overcome sedation in order to maintain normal behavior. Now that we know what happens with brainwaves, let's go to sleep. What happens in sleep now? We know that drugs used in ET have a negative impact on sleep by interrupting sleep architecture and sleep patterns while you're sleeping. Let me set the stage here on this slide. There are various stages of sleep. There's non-REM sleep, stage one, stage two, stage three, for example.
Now, in stage one sleep, that's when you go to bed and you're probably like 10 minutes in, very brief. There's no deep sleep here, and you can be easily aroused out of the sleep, but sometimes when you pop out of stage two, you don't even realize you were sleeping at all. Stage two sleep is a little deeper. It's a little longer, 25 minutes in, and you start to get this deeper stage of sleep. Even though you can still be aroused fairly easily, some people will actually feel very refreshed after that period. Now, stage three sleep is that deep sleep. That's where I was talking about that delta wave activity on the previous slide, where you get these delta wave activity in a very deep stage of sleep, stage three. It's hard to arouse some people from this stage.
The last one I want to talk about is something called spindle rate activity. We call this a microarchitecture because spindle rate activity occurs within stage two sleep. This is very important. Spindle activity is very important in sleep because what it does, it consolidates memory during times of sleep. Obviously, it's important to have this sleep. I want to draw your attention to the graphs on this slide. The blue bars you're seeing on this slide represent various doses of ACP-711 given orally to the healthy volunteers. The red bars are placebo. What we see here with ACP-711 given over the nine-day period to healthy subjects was that there was no significant change in sleep architecture. You will see sleep variability in anyone during these stages of sleep.
What these bar graphs represent is no significant change in that variability over that nine-day course. This suggests that there's no impact on sleep after taking ACP-711. This is not the case in research that was done with other drugs in ET, such as benzodiazepine, primidone, and even propranolol. Finally, I want to go to what's going on next with us. We have an elderly multiple ascending dose phase I study that's currently underway. We plan a four-week randomized double-blind placebo-controlled phase II study looking at lower doses of ACP-711, higher doses versus placebo over four weeks. We're going to be using an endpoint called TETRIS. It's a validated scale used in essential tremor. It stands for essential tremor rating scale. This scale measures the overall severity. Very importantly, it also measures ADLs or activities of daily living.
I'm going to bring this back to my dad who has ET. If we have a drug that helps the overall severity, but it doesn't do much for your ADLs, like being able to dress or write a check, then the quality of life probably just won't be there. What I want to do is just go over some of the key takeaways. Essential tremor is the most common movement disorder worldwide. Existing treatment options remain suboptimal. Fewer than 50% of the patients experience meaningful benefit, and there's no new therapies that have been approved for over 50 years. ACP-711 selectively affects GABA on the GABA alpha-3 containing receptors expressed in key brain regions that I described in essential tremor. ACP-711 improved tremor without sedation in preclinical studies. In phase I, ACP-711 demonstrated high receptor occupancy with minimal impact on sleep and no evidence of sedation or cognitive impairment.
We have a current study evaluating dosing in the elderly cohort and a phase II trial that is designed to explore dose response, efficacy, and safety impact on daily functioning that is being planned for 2026. I really appreciate your attention. Thank you. Back to you, Liz.
Thanks, Vic. We're now going to turn to some of the most novel biology in our pipeline. ACP-271 is a GPR88 agonist, and we think it has first-in-class potential. We see this as a mechanism with substantial potential, particularly in the neuromotor space. We are excited to be taking this oral treatment into first-in-human studies by year-end. Dr. Rachel Hotton is Acadia's Vice President of Translational Sciences. She has nearly three decades of translational science leadership experience, including broad therapeutic area exposure across oncology, autoimmunity, and rare diseases, including rare neurologic indications. She is experienced with multiple therapeutic modalities, including small and large molecules, antisense oligonucleotides, and gene therapy. She joins us most recently from Ultragenyx, and she is going to introduce you to this exciting program. Please welcome Rachel.
Thanks, Liz. Hello, everybody. As Liz referenced, GPR88 agonists have considerable potential in several neurologic indications. We're initially focusing on lead molecule, ACP-271, and tardive dyskinesia and Huntington's disease, or TD and HD. Before showcasing our preclinical data in these two indications, we're going to share with you a brief movie that introduces this novel target.
Every movement you make, from walking up and down stairs to carefully removing a splinter from your finger, is dependent upon exquisite communication between neurons in the motor cortex and striatal and thalamic regions of the brain. Modulating these movements are circuits made up of neurons from the cortex that connect with neurons in the striatum, which in turn manage and pass the message on to neurons in the thalamus, where messages are modulated and relayed before delivery back to the cortex. These circuits are called corticostriatal-thalamic cortical loops, or CSTC loops, and similar CSTC loops exist to regulate cognitive and emotional functions. Within the striatum, medium spiny neurons, MSNs, play a crucial role in processing signals. Distinct subtypes of MSNs, in particular D1 and D2 containing MSNs, work together to facilitate smooth and controlled motor activity as part of the CSTC loop.
D1 MSNs express D1 dopamine receptors and promote movement like a go signal, and D2 MSNs express D2 dopamine receptors and inhibit movement like a stop signal. GPR88 receptors are orphan G-protein-coupled receptors located on both D1 and D2 containing MSNs and are thought to help modulate the balance between go and stop signals. They act much like a dial that can be turned up or down to regulate the balance of signaling through the CSTC loop. Imagine the striatum as a traffic control center. GPR88 receptors help balance the flow of signals between the go and stop pathways, ensuring smooth and coordinated movement. In conditions such as tardive dyskinesia and Huntington's disease, where the normal stop-go signaling balance from the striatal MSNs is disturbed, GPR88 agonists can help address that imbalance.
Tardive dyskinesia is a neurological movement disorder that can arise from long-term antipsychotic use and leads to involuntary and repetitive movements, primarily of the face and trunk regions. Through GPR88 receptor modulation, ACP-271 can play a potential role in the treatment of tardive dyskinesia symptoms by addressing the imbalance in D1 and D2 pathways that results from chronic use of D2 blocking antipsychotic treatment. In Huntington's disease, the initial loss of D2-containing MSNs leads to predominant signaling from D1 MSNs, resulting in excess go signaling. This excitable state is associated with cognitive impairment and a decline in motor coordination with involuntary sudden jerky movements known as chorea. As the disease progresses, loss of D1-containing MSNs results in further cognitive and motoric decline. The GPR88 agonist ACP-271 may address the D1 and D2 MSN signaling imbalance and potentially ameliorate both psychiatric and motoric disease manifestations.
GPR88 receptor agonists may offer a promising approach to potentially treat neurologic diseases such as tardive dyskinesia and Huntington's disease by rebalancing abnormal MSN activity in striatal motor output pathways.
We've just shared a little bit about GPR88 as a target and why GPR88 agonists may be beneficial to patients with TD and HD. Being a novel target, we just bombarded you with quite a bit of new information, and we'll be revisiting these themes throughout the next two sessions. ACP-271 is an orally dosed GPR88 agonist entering first-in-human studies later this year. We also have follow-on assets with differentiated characteristics such as increased potency and brain penetration. These are currently earlier in preclinical studies. Now I'm going to walk us through an introduction to tardive dyskinesia and share some of the data that support the potential for GPR88 agonists in this indication. Tardive dyskinesia is a disorder that arises in patients being treated for extended periods with dopamine-2 receptor antagonists.
It manifests as hyperkinetic, repetitive, involuntary movements affecting the face, for example, lip smacking, the trunk, the limbs. It can be disabling and disfiguring. This is on top of the patient having to deal with their underlying mood disorder or psychosis. Treatment options for these patients are limited. One option is to reduce the dose of the dopamine-2 receptor antagonist. However, this exposes the patient to increased risk of psychotic episodes and will be ineffective in those cases of irreversible TD. Currently approved treatments for TD reduce dopamine availability at the synapse. These carry side effects of sedation that affect everyday life and also boxed warnings for depression and suicidal behaviors, characteristics that compound the challenge already experienced by the patient dealing with their underlying psychosis or mood disorder. I'll come to this in a little bit more detail in a few slides.
Our rationale for applying GPR88 agonists in TD is based upon the novel dopamine-sparing mechanism that was introduced to you in the movie and which brings the associated potential to avoid sedative side effects. Our molecules also show durable activity in preclinical models, which distinguishes them from the currently available treatments. I will show you that also in a couple of slides. The disease burden of TD is high, being experienced in the United States by up to approximately 30% of patients being treated for extended periods with D2 receptor antagonists. This represents upwards of about 500,000 people. The rationale for GPR88 agonists in TD is elaborated on in this slide. A patient presenting with TD due to extended use of dopamine-2 receptor antagonists may be treated with a VMAT2 inhibitor or vesicular monoamine transporter 2 inhibitor.
Inhibiting VMAT2 reduces the availability of dopamine at the synapse. This provides relief from the involuntary hyperkinetic movements. However, a challenge is that reducing dopamine levels can cause sedation. Importantly, as I mentioned, these agents carry boxed warnings for depression and suicidal behaviors. In contrast, GPR88 agonists do not reduce dopamine levels, but aim to balance D1 and D2 medium spiny neuron signaling from the striatum, as described in the video. By leaving dopamine availability untouched at the synapse, there's the potential to relieve the involuntary movements without causing sedation or carrying the risk of depression and suicidal behaviors. To explore this potential, we asked ourselves the following three questions in preclinical studies. First, do GPR88 agonists relieve involuntary movements in animal models? If so, for how long?
Second, does GPR88 agonism interfere with the dopamine-2 receptor antagonists, bearing in mind, of course, that these patients are already being treated for psychosis or mood disorders, and we need to maintain that therapeutic activity? Thirdly, is there an advantage to the mechanism of action of GPR88 agonists over the currently available VMAT2 inhibitors? I'm going to walk through these data in the next four slides. To explore whether GPR88 agonism does reduce involuntary movements, we used a rat model of oral dyskinesia. In this model, the animal's jaw moves involuntarily for absolutely no reason at all. These are called vacuous chewing movements, or VCM. This is a standard model for the analysis of involuntary movements in TD. We explored whether vacuous chewing could be relieved by GPR88 agonism, and we compared with tetrabenazine, which is a VMAT2 inhibitor.
We'll be comparing GPR88 agonists with tetrabenazine in the following data slides in this section. If we focus initially on the left-hand side, these data show the activity of tetrabenazine in this model. The open bar represents animals treated with nothing at baseline. As you can see, the green bar's treatment with tetrabenazine significantly reduced the VCM. Similarly, we see on the right-hand side that treatment with a GPR88 agonist reduced the VCM in this model. Therefore, these data support the potential for GPR88 agonism to reduce involuntary movements. Part B to this question was, how long does this effect last, given that the currently available VMAT2 inhibitors need to be administered daily? The answer to that question is shown here. Here we're capturing the duration of VCM over time, so time on the X-axis in hours and VCM count on the Y-axis.
As you can see, we're comparing ACP-271 with tetrabenazine. Both molecules caused an initially rapid reduction in VCM counts. However, in the case of tetrabenazine, these returned to baseline within about six hours. In contrast, the effect of ACP-271 extended to about three weeks. Now we've established that we do see a reduction in involuntary movements in this model, and we have a protracted pharmacodynamic effect compared to the VMAT2 inhibitor tetrabenazine. Our next question is, does GPR88 agonism interfere with the dopamine-2 receptor antagonists that the patient requires for alleviation of their underlying psychiatric disorder? To explore this, we used a mouse model of induced psychosis in which the effects of the antipsychotic risperidone were evaluated in the presence or absence of tetrabenazine or a GPR88 agonist. The results of that experiment are shown here. Here, locomotion is used as a surrogate for psychosis.
The open bar shows control animals treated with vehicle and saline, and it's walking around in its little cage. The black bar represents the animals in which psychosis was induced. You can see there's a significant induction of psychotic locomotion. In the adjacent gray bar, we're looking at the effects of risperidone, where we see a significant reduction in psychotic locomotion. The adjacent blue bar evaluates the activity of risperidone in the presence of a GPR88 agonist. You can see the effect is entirely comparable. There was no effect of the GPR88 agonist on the activity of the antipsychotic. When we look at the green bar for tetrabenazine, we see there's a further reduction in locomotion. What we're looking at here is likely the additive effect of reduction in dopamine availability and the sedation associated with these molecules.
Comparable results were also captured using other endpoints, such as the animal rearing up on its hind legs in the cage. We have now shown that GPR88 agonism can reduce involuntary movements, has a durable PD effect, and does not interfere with the activity of a dopamine-2 receptor antagonist. Our next question is, is there any advantage to GPR88 agonists over the VMAT2 inhibitors? To address this question, we explored the effects of the two mechanisms on wild-type rodents. Here we are showing the effects of GPR88 agonism and tetrabenazine on locomotion and motivation to receive a reward. If we focus initially on the left-hand side, here we are looking at locomotor activity in wild-type mice treated with negative control vehicle, GPR88 agonist, or tetrabenazine. In the blue line, what you can see is that it closely resembles the vehicle control line.
Basically, GPR88 agonist did not affect locomotion in these wild-type animals. However, in the green line, the animals treated with tetrabenazine, we see a significant reduction in locomotion, representing the sedative effects of these inhibitors. Now, on the right-hand side, what we're looking at are wild-type animals in a cage where they have to press a lever to get their pellets, which are tastier than the regular chow that's readily available. The graph to the left of this box here is quantifying lever presses, and the graph on the right is quantifying pellet intake. The open bar represents animals treated with vehicle control, and the blue bars represent animals treated with increasing doses of GPR88 agonist. What you can see is that the GPR88 agonist had no effect on lever pressing or consumption of the pellets.
In contrast, tetrabenazine was associated with a significant reduction in lever pressing and pellet consumption, suggesting in these wild-type animals that they have a reduced motivation to obtain their reward and reduced ability to press the lever to obtain it. Combined, these data support the potential advantages of a GPR88 agonist over the currently available VMAT2 inhibitors, which are associated with sedation and depression. The contrasting mechanisms of the VMAT2 inhibitors and GPR88 agonists, as measured by the effects on dopamine metabolism, are shown here. What the graph is quantifying is dopamine metabolism in isolated wild-type rats' striatum following dosing with either tetrabenazine or a GPR88 agonist. As you can see, increased doses of tetrabenazine are associated with increased metabolism of dopamine, whereas the GPR88 agonist has absolutely no detectable effect.
Now, we've reviewed the application of this mechanism in TD and its potential benefits, but the attributes listed here also apply across neurologic indications, that being the potential to avoid sedation and depression and with a durable pharmacodynamic effect. After the break, we'll come back to this concept in the context of Huntington's disease. To conclude this section on GPR88 agonists in TD, we've shown that these molecules may ameliorate the involuntary movements of TD with a mechanism that has significant potential advantages over the currently available VMAT2 inhibitors. By restoring the balance of D1 and D2 receptor signaling without removing dopamine availability at the synapse, GPR88 agonists may avoid the sedative effect and boxed warnings of depression and suicide that are associated with the VMAT2 inhibitors. The positive pharmacodynamic effect is also durable, suggesting the possibility that less frequent dosing may be required.
After the break, we'll return to these concepts with the application of these agonists in the context of Huntington's disease. Thank you very much for your attention.
All right. Thank you, Rachel. We have a few more minutes for questions now, and then we're going to go into a short break. Again, top two or three maybe questions based on what you've heard about ACP-711 and 271 in TD.
Hi, Tazeen Ahmad from Bank of America. Can I just ask one on each, if I may, really quickly for essential tremor? Can you talk about the heterogeneity of the patient population? As you design studies, this current study and future ones, how are you going to think about the best type of patient to enroll? From your own experience and what you know about the advancement of the disease, what is the right type of patient profile to enroll to be able to show the biggest effect? Secondly, for tardive dyskinesia, how are you thinking about positioning of this product, given that there are already approved drugs on the market, which by the time I'm assuming your products could launch, could be integrated into a highly generic market?
Do you feel like this would be initially used for refractory, or could you see it being used for frontline right away? Thanks.
Okay. I'll make a couple of comments and then maybe invite Vic and Rachel to expand. Certainly, I think one of the key things that we heard about in Vic's section is the heterogeneity in terms of degree of severity and what might or might not require treatment. That's obviously going to be a place that we're going to be focusing in substantially. I don't know if there's anything else you want to expand on there, Vic.
Yeah. As I mentioned, as you get older, it gets worse. We are kind of looking at some multiple ascending dose studies in the elderly, which is going to be our focus for treatment. As I mentioned, a lot of times early on, you do not really need treatment. The focus on more elderly patients would be key to this study.
Yeah. That is why a big focus on the elderly cohort right now. As far as TD is concerned, I think we talked through some of the things we see as potential differentiators from what is currently available in the space. Obviously, some of this is going to play out over time in terms of what the profile of 271 actually winds up looking like and what benefits we really can deliver. We do think from a patient experience perspective, being able to get away from something that is heavily sedating, being able to get away from a situation where patients might be having to cut back on the dosing of the therapies that they require in order to treat psychiatric diseases, we think these are potentially some pretty compelling aspects to the story.
You answered it beautifully.
All right. Fantastic. Nothing else to add on that one. I think we've got time for at least one more.
Hey, Matt Herschenhorn from Oppenheimer. Really appreciate the question. We were wondering, I guess, for ET, there was SAGE-324 that failed its phase II-B study, but that was a GABA, I believe, alpha 1/3, nonspecific to alpha 3, unlike 711. Just curious, I guess, how that confers the higher specificity, potentially better efficacy and safety as an overall benefit-risk, and if there's anything from learnings from SAGE's studies that you could apply to your own clinical study. Appreciate it.
Yeah. I think, and Vic touched on this in his presentation, I think what we do know is that the GABA system is immensely complex and is involved in a tremendous number of different activities. We do think that data to date suggests that alpha 3 is what we should be focusing in on, and that's going to give us our best benefit-risk profile. That gives you the opportunity potentially to push a dose compared with what you might be able to do with something that has a more affected alpha 1 or other alpha-containing subunits. We really do think compared with SAGE and other molecules that have been explored historically, this gives our best opportunity to thread through that needle of targeting what we think is going to drive the disease the most while sparing those aspects that might bring additional risk on board.
Maybe one more?
One more? Okay.
Sumanth Kulkarni from Canaccord Genuity. Thanks for taking my question. Given the protracted effect you saw in preclinical models of 271, what's the potential for developing a long-acting version, and what do you think of eventual dosing frequency?
It's a really good question that I don't think we are ready yet to propose what that's going to look like. We want to take this into humans and see how this PK/PD relationship plays out there. We'll be starting that phase I first in human study towards the latter part of the year. We are encouraged by the fact that there looks like the possibility for a PD effect that could be less frequent dosing, but obviously, we're going to have to see how that plays out. All right. With that, I think we have time for a 10, 15, 15-minute break, and we'll see everybody back here in, I'm not going to try to do the math, 15 minutes from now. All right. Thanks.
Bonus gift to everyone who's back in the room already is you're going to hear all the content, and anyone who's late back from break is going to miss things. Thank you for being back. So far this morning, we've been focused on more common diseases, and you see that these are and will continue to be an important part of our future. Our next adjacency step has been into rare diseases, and we're now going to share some of the rationale behind the second half of our ambitions for ACP-271. I'm going to welcome Rachel back to tell you about the data underscoring our interest in exploring 271 in Huntington's disease. Rachel?
Hello again, everybody. Now we're going to switch gears and discuss the application of GPR88 agonists in Huntington's disease.
Huntington's disease is a rare, inherited, neurodegenerative, autosomal dominant disease, meaning that a person inheriting one copy of a mutant gene will develop the disease. It's caused by the expansion of a CAG trinucleotide repeat within the Huntington gene, which results in the production of toxic mutant RNA and protein. The disease presents with both motor and psychiatric symptoms. The initial symptoms typically occur around age 45, but they may present quite a bit earlier or later in life. Motor disturbances are typically the first clinically apparent signs of the disease, possibly with some detectable impairment of executive function. These motor disturbances involve involuntary movements, which are known as Huntington's chorea and loss of coordination. Once those symptoms appear, the disease progresses relentlessly, with a devastating effect including severe psychiatric changes such as aggression, mood swings, depression, and dementia on top of significant motor decline.
These manifestations are the result of significant neuronal atrophy, particularly in the medium spiny neurons of the striatum, and death occurs within about 15-20 years of symptom onset. There are currently no approved treatments to arrest or prevent Huntington's disease. Approved treatments for the chorea, the involuntary movement seen early in the disease, include the VMAT2 inhibitors, which we discussed in the previous section. As we discussed in the previous section, these are associated with box warnings for depression and suicidal behaviors. Now, HD patients are already at risk for depression and suicide as part of the disease course and as part of living with this disease. These drugs need to be used with caution in the treatment of Huntington's chorea. In addition, about 50% of patients do not respond to treatment. The unmet need in this devastating disease is therefore significant.
Our rationale for applying GPR88 agonists in HD is based again on that novel dopamine-sparing mechanism that was introduced in the movie and that we highlighted in the TD discussion. In the context of HD, this has the potential to relieve psychiatric symptoms of the disease as well as the motor symptoms. I'll review the rationale in more detail in a couple of slides. Prevalence of HD is around 4.9 per 100,000 people worldwide. In the United States, there are an estimated 21,000 patients currently diagnosed, and almost that number estimated undiagnosed in the USA The rationale for GPR88 agonists in HD includes multiple lines of evidence, several of which are captured in broad strokes on this slide. Huntington's disease patients experience significant loss of the striatum, which is composed of about 95% of medium spiny neurons, and it's where GPR88 resides.
As shown in the diagram on the upper right, comparing the healthy brain with the Huntington's disease brain, and we're calling attention to the caudate nucleus and the putamen, both areas of the striatum, and both of which are atrophied in Huntington's disease. On the lower right, the diagram captures the fact that early in the disease, the D2-containing MSNs are preferentially sensitive, resulting in loss of D2-MSNs and the choreatic movements that are seen early in the disease due to the predominance of D1-expressing MSNs. As the disease progresses, there is loss of D1-expressing MSNs, and the patient experiences bradykinesia, or slowness of moving. In addition to these characteristics, individuals who do not have Huntington's disease but who do have a deleterious mutation in GPR88 show characteristics of Huntington's disease, including choreatic-like movements and learning disabilities.
Here, there's a direct association between the loss of GPR88 function and manifestations of Huntington's disease-like symptoms. Animal models of Huntington's disease show reduced expression of GPR88, and preclinical models have shown involvement of the target in multiple phenotypic domains, including both motor and psychiatric domains, including impulsivity, motivation, and cognition. A GPR88 agonist therefore has the potential to ameliorate both the motor and the psychiatric components of Huntington's disease by balancing out that signaling between the D1 and D2 medium spiny neurons. In the next two slides, I'll be showing you the effects of GPR88 agonists in two animal models of Huntington's disease. The first of this is a zebrafish model of the disease. The zebrafish is very small, and it is a fish. However, it does retain that corticostriatal-thalamic-cortical loop, the CSTC loop, that we were introduced to in the mechanistic video at the very beginning.
Therefore, we can explore the effects of perturbation in this loop via GPR88 agonism or VMAT2 inhibition. In order to efficiently swim forward, zebrafish need to effectively coordinate their bodies. We therefore measured the motor control of a mutant Huntington's zebrafish in the presence or absence of a GPR88 agonist or tetrabenazine and compared this with wild-type fish. Focusing initially on the left-hand side, we're looking at locomotor activity. What you can see is that the wild-type fish is happily swimming along. The mutant Huntington's fish shows significant reduction in locomotor activity. In the presence of a GPR88 agonist, we see an increase towards the wild-type fish in locomotion. However, animals treated with tetrabenazine show a further reduction in locomotion, probably representative of the sedative effect of these molecules. If we look on the right-hand side at motor coordination, we see a similar effect.
Wild-type animals showing a certain level of coordination, significant increase in the mutant Huntington's fish towards the wild-type level, tetrabenazine has no or mild effect. These data support the potential for a GPR88 agonist to ameliorate the loss of coordination in Huntington's disease. Now, as you'll recall, Huntington's disease progresses slowly. It's observed initially through the more readily detectable motor presentation, but psychiatric effects of the disease appear and then become increasingly detectable. Based upon this disease progression, it's important to measure the effects of potential therapeutics in a representative system that itself develops slowly and enables the capture of multiple aspects of the overall disease phenotype. To this end, a mutant Huntington's disease mouse known as the Q175 mutant Huntington heterozygous mouse is considered a relatively representative genetic model of the disease. It contains one mutant copy of the Huntington gene.
The disease progresses slowly with detectable motor and psychiatric components. Now, in order to capture the multiple aspects of the disease in these animals, a phenocube can be used to measure the phenotype based on multiple components of the disease in the presence and absence of potential therapeutics. Because of the dimensional nature of the information obtained using this approach, the data are represented as clouds comprising hundreds of data points collected over time. We can't simply plot them as a line graph or a bar plot. With that description, I'm now going to show you data that we obtained in this model where we explored the effects of a GPR88 agonist. There is a lot of visually unusual information here, and we're going to walk through it slowly to clarify what we're sharing with you.
We're looking at data obtained from three treatment groups of mice: mice treated with mutant mice, I'm sorry, treated with a GPR88 agonist, mutant mice treated with vehicle control, or wild-type non-mutant vehicle-treated control mice. Mice in these treatment groups were dosed for either one day or eight days with twice-a-day dosing followed by observation and data capture in the phenocube for 48 hours. Now, as I just mentioned, multiple aspects of their behavior are captured in these data clouds, including both motor and psychiatric indices. Here we're looking at day one, and you can see the three data clouds representing the three groups. This pinky one is representing the mutant mouse treated with vehicle control. The green cloud is representing the mutant mouse treated with a GPR88 agonist, and the blue cloud is representing the wild-type mouse.
What you can see here is that there is direct superimposition of the two mutant groups of mice. They're not distinguished by whether or not they receive GPR88 agonist. However, when we examine the mice after eight days of dosing, we see that the green cloud is moving away from the pink mutant mouse data cloud and towards the wild-type healthy animal cloud. This reflects a trend towards the healthy phenotype and away from the mutant phenotype in animals that have been treated with a GPR88 agonist. To capture this numerically, we saw approximately 47% normalization of the HD phenotype in this experiment. These data support the potential for a GPR88 agonist to ameliorate multiple characteristics of Huntington's disease and the cumulative disease presentation.
To summarize what I've shared with you in this section, multiple lines of evidence support the potential for GPR88 agonists in the treatment of HD. There are no approved treatments to prevent or arrest HD or to broadly address the motor and psychiatric symptoms. VMAT2 inhibitors are approved for treatment of Huntington's chorea and are only effective in about 50% of patients and need to be used carefully in this population. GPR88 deletion in non-Huntington patients is associated with features of Huntington's disease, and Huntington's disease patients experience loss of their striatum, which is comprised of over 95% of medium spiny neurons where GPR88 resides. Animal models support a role for GPR88 in HD symptomology. Now today, we've shared with you some data in animal models that support the potential for GPR88 agonists to relieve the symptoms of both motor and psychiatric effects of Huntington's disease.
In summation, by balancing dopamine-1 and dopamine-2 receptor signaling from the striatum, there's the potential to ameliorate both the motor and psychiatric symptoms of Huntington's disease, sparing the sedative effects and avoiding the box warnings of the VMAT2 inhibitors, which are currently used to treat the chorea. Next steps for our GPR88 program include filing an IND for ACP-271 and the initiation of our first in-human study later this year. This will be the first time a GPR88 agonist has entered the clinic. The study will be exploring the safety, tolerability, and pharmacokinetics of ACP-271 in healthy volunteers. In parallel, we're going to continue to advance our follow-on molecules through preclinical studies to maximize the potential that this mechanism has to offer for patients living with neurologic diseases. Thanks again for your attention.
Neural rare diseases offer an opportunity to apply our expertise in neurological disease while also building a foundation in how to develop and commercialize rare diseases. Drug development in rare disease is a passion of mine and has been an important part of my career, and it encourages different and creative thinking at every step along the way. First, in this section, we're going to turn to ACP-101, our investigational product aimed at the hyperphagia associated with Prader-Willi syndrome. For this section, I'm pleased to invite some friends to join me. First of these is Dr. Shawn McCandless from the University of Colorado. Dr. McCandless is a clinical geneticist with special expertise and interest in inborn errors of metabolism, Prader-Willi syndrome, and generally rare genetic diseases. Thank you for joining us, Dr. McCandless.
You're welcome.
Excellent. We have audio. Okay. Joining us live from the United in Hope Conference is Susan Hedstrom, Executive Director of the Foundation for Prader-Willi Research. The United in Hope Conference is the main conference of the year for the Prader-Willi community, and it brings together patients and families, physicians and scientists, all in pursuit of a better future for these families. Susan's son Jayden is living with PWS. She is a fierce and formidable champion for her community, and I know she'll bring home to all of you the patient perspective that drives us every day. Susan, it is a pleasure as always.
Thanks so much for having me.
Yes, two of two. Okay. Finally, I'm pleased to introduce Dr. Jim Youakim, Vice President of Clinical Development, who's in charge of the ACP-101 program here at Acadia. Dr. Youakim is a psychiatrist by training, and he's worked in the pharmaceutical industry for nearly 20 years. In addition to rare disease indications such as PWS and Rett syndrome, he's worked in clinical development of treatments for schizophrenia, major depressive disorder, Alzheimer's disease, and other psychiatric and neurologic indications. He'll be sharing some insight into the historical data set as well as an overview of our ongoing program. Welcome, Jim.
Thank you very much, Liz.
Excellent. All right, going into interviewer mode over here. To level set us all for the discussion that we're going to have today, Dr. McCandless, can you start off by giving us an overview of PWS?
Surely. I may have the first slide, please. Prader-Willi syndrome is a rare genetic disorder, but is actually one of the more commonly diagnosed genetic disorders. It's caused by the absence of products of several genes on chromosome 15. How those specific genes cause all of the symptoms is not entirely clear.
The genes are typically only active when they're inherited from their father. So if you're missing those copies of the genes from your father, you'll have the disorder. Or if you have got both of your chromosome 15s from your mother, which happens occasionally, you will also have the condition. It typically has several stages that we see clinically. The first stage is in the newborn period where the babies are very sleepy. They're very poor feeders. They have difficulty gaining weight, typically require tube feedings, and just are very slow to develop, and also very placid babies. Then things sort of normalize in terms of their feeding behaviors. And then over the next few years, we begin to see that they start to gain weight, and it really seems as though their metabolism is slowing down greatly. And then they become more and more hungry.
The children that have this are acting like they're starving. Their body's telling them they're starving, even though we can see from their weight that they're not starving. In fact, they're excessively heavy. That's a continued theme throughout their lifetime. The low muscle tone that we see in the babies persists through life, although it becomes less of an issue. Some other symptoms become readily apparent over time. There's a relative deficiency of growth hormone, so short stature and low muscle mass is very common. There are a number of respiratory complications, and there are a lot of behavioral regulation issues with difficulty with emotional regulation, rapidly becoming angry or upset for little or no reason. What really kind of overshadows all of this is this intense hunger that the patients clearly feel.
It seems like their body is telling them that they're starving, and they are driven to get food the way any person who's literally starving to death would be. They steal food. They think about food constantly. Anytime there's an opportunity to get food, they will do it without a second thought. That combination of they also have mild intellectual disability, so that in most cases, although 20% or 30% of people with Prader-Willi syndrome have functional IQ testing in the normal range. Overall, that complex of behavioral dysregulation, anxiousness, and hyperphagia leads to really, really huge challenges for the family. I'm going to circle back to that in a minute.
I do want to go back to the last slide for just a minute to point out that over the past 25 or 30 years, the life expectancy has been shown to be around 30 years of age on average. Although we have many patients who are much older than that, the rate of mortality for a wide variety of reasons is really quite high, 3x-6x higher than we see in other children with developmental disabilities. There is a, in spite of that, there is a fairly large population of people living in the U.S. Some estimates say 8,000- 10,000. It could even be a bit higher than that. The mortality is caused by a variety of things. Early in life, it is typically respiratory symptoms. Later in life, it may be accidental deaths. It may be pulmonary embolism.
In a disturbingly large number of patients, it's actually related to intestinal catastrophes from gorging food and rupture of intestine or stomach. That's just awful. If we could go back to the next slide then, I just want to point out a couple of things. The hyperphagia, that unrelenting pathological hunger, and the complete inability to regulate food consumption for the person's self drives their care. They have to have 24-hour attention to make sure that they're only getting access to the food that they need to gain weight. Because their muscle bulk is low, that's usually about 60% of what another person their size would need to maintain their weight.
Because of the obesity, the hypotonia, and everything else that goes along with it, there are significant comorbidities with metabolic conditions like diabetes and right-sided heart failure secondary to obstructive sleep apnea are extremely common, as you can see here. Renal and liver disease and just a wide variety of other problems. Orthopedic problems are very common, both in childhood and in adult life because of the obesity, scoliosis, hip dysplasia. Altogether, this is a really difficult condition for the patient, but for their family. It just is, as I said, a 24-hour-a-day job to keep the person with Prader-Willi syndrome safe. I think I'll stop there, and you'll hear more about that from Susan.
Thank you so much, Dr. McCandless. I think that gave us a really good grounding. Susan, tell us a little bit about what your journey has been like with your son, Jayden, what diagnosis was like, what it was like to learn about PWS.
Sure, absolutely. Jayden was born 16 years ago. We were fortunate enough to be in San Diego, where we have excellent healthcare. He was able to be diagnosed pretty quickly. Within a day or two, we are whispering Prader-Willi syndrome. He was diagnosed clinically at only six days old, which is pretty early on. Like many people with children with Prader-Willi syndrome, we had no indication that he was going to have any genetic disorder. We were expecting a perfectly neurotypical baby. When he was born, it was quite a surprise to us when they rushed him to the NICU. Frankly, when they start giving you this diagnosis, for most families, it is quite traumatic.
You're given a laundry list of things that your child will never be able to do. They will never be able to go to school. They will never be able to live independently. What's hurtful for a lot of people, they will never be able to have children. As a family, you begin to grieve for the life that you thought your child was going to lead. We all have dreams of what our children will do, or assumptions even. We assume our children will be able to drive a car, go to college, live independently. Those things are all taken away from you in a single diagnosis. For many of us, that initial journey is quite bleak.
Thank you for sharing that. It sounds incredibly difficult. Dr. McCandless told us a bit about hyperphagia, and as we'll be touching on shortly, that is the primary focus of our ongoing study. Now, I think Dr. McCandless did help to address this, but I'd really love it, Susan, if people can hear this, I think, and say, "Oh, no big deal. They're a little bit hungry." Can you tell us a little bit about what hyperphagia has meant for you and for your family?
Sure. So oftentimes when I begin to tell people about my son and hyperphagia, I'll start with, "He feels hungry all the time." And people very quickly will say, "Oh, well, I'm hungry all the time. Maybe I have Prader-Willi syndrome." I have to explain this is very different from just being hungry or thinking about your next meal. This is all-consuming.
He is always thinking about food, how much food he's going to get, where he's going to get it. Every minute of his life, he is hungry and thinking about food. We have two other children, as you can see in this photo, a 14-year-old and an 11-year-old. Prader-Willi syndrome absolutely impacts their lives as well as that of our family. The first thing you'll notice when you come into our home is there is never food accessible or in view. If you look at countertops, there is nothing on the counter ever. It's not that we're clean freaks. It is to keep our child safe. Our refrigerator is locked. Our pantry has thumb locks on it so that the kids can access the food, but Jayden cannot. As he's gotten older, we've had to get more and more crafty. We cannot leave food in the garbage can.
There cannot be food in the sink. He will pick up food from the floor that is not edible to eat it. We really have to be very cautious. Eyes have to be on at all times. We have cameras in our house so that he knows we're watching. He wants to be good. He doesn't want to do things that are not socially acceptable, but he has a drive to do it. It is innate and cannot be taught out of him. Impactful to our family is our ability to go out into the community. I think that is actually the biggest inhibitor of Prader-Willi syndrome. Because he's always thinking about food, it leads to anxiety. If we're going out to a restaurant, he wants to know where we're going, what he's going to eat, what time it's going to be.
If anything changes in those factors, you are facing the potential of a massive public meltdown, which is the biggest fear of our family when we're going out in public. You can imagine a three-year-old having a temper tantrum in a restaurant or in a grocery store. It's socially acceptable. Now, imagine that same toddler meltdown with a full-sized grown man. Now it's not acceptable anymore. In fact, it can be dangerous. We try to avoid that at all costs. Sometimes we simply have to say, "It's just not going out is not going to work today. Going to the community barbecue is not going to work today. Thanksgiving meals with the family is not going to work today because hyperphagia is just all too present and the anxiety that goes with that."
Thank you. I think that hopefully helps people get a sense of the importance of this aspect of the disease and why we are so devoted to trying to find something that can help with that. With this, I'd like to turn and spend a little bit of time talking about the ACP-101 program. To start out, Jim, can you tell us a little bit about what ACP-101 is and what the scientific rationale is behind the program?
Yes. We've just heard about hyperphagia and what a terrible burden it is for patients and their families. We have a lot of hope for the treatment of hyperphagia with ACP-101, which is intranasal carbetocin. Oxytocin is a natural hormone that regulates several functions in the body, including, importantly, hunger, but also anxiety, bonding, and other social behaviors. There's good evidence that in people with Prader-Willi syndrome, there are fewer neurons that produce oxytocin. This deficiency is associated with hyperphagia and with behavioral issues in PWS. Carbetocin is a long-acting synthetic analog of oxytocin and is actually thought to bind to oxytocin receptors with greater selectivity than oxytocin itself, which we think means potentially fewer side effects. Carbetocin was designed to overcome the functional deficit in oxytocin receptor agonism in PWS. ACP-101 is a drug-device combination product of carbetocin for intranasal administration.
ACP-101 has some history. I'd love it if you can give us an overview of what we know, particularly on the side of potential efficacy about 101 based on the prior phase III clinical trial.
Yes. Another reason we're excited about ACP-101 is that there's already been a phase III trial that showed some evidence of efficacy for ACP-101 for the treatment of hyperphagia. This was a study of 130 patients who were randomized to two doses, 9.6 mg and 3.2 mg versus placebo for eight weeks of treatment. The primary endpoints were the change from baseline for the 9.6 mg dose on the HQCT, which is the Hyperphagia Questionnaire for Clinical Trials, and also on the CY-BOCS, the Children's Yale Brown Obsessive Compulsive Scale. As you see on the right, the results showed that while the 9.6 mg dose did not show a statistically significant difference from placebo on the HQCT, the lower dose, the 3.2 mg dose, did show a difference with a nominal p-value of 0.016, suggesting that the lower dose is effective in treating hyperphagia.
If you go to the next slide, another reason to believe in the potential of ACP-101 is that there were important signs of consistency in the 3.2 mg dose data in that study. First of all, on the left, you can see that at the first assessment, which was after two weeks, there was already a difference between the treatment arms with the 3.2 mg dose and with a p-value of 0.0145, with that difference also being observed at week eight, as I already mentioned. On the right-hand side, you can see that not only for the HQCT, but for various endpoints, there were outcomes favoring the 3.2 mg dose, including the PADQ, which assesses anxiousness and distress in patients with PWS.
The efficacy is obviously an important part of the story, but an equally important part of deciding whether we continue to progress through development is understanding the safety profile of a molecule. What.
Events in the higher dose arm? In addition, there were no serious adverse events reported in the placebo-controlled period. There were no adverse events of edema during any parts of the study. So far, the profile of the drug suggests that there will be no need for additional laboratory monitoring. For example, only one patient had an event of hyperglycemia, and that was transient and in the long-term portion of the study.
I know everyone wants to get to the ongoing phase III trial. Before that, a question I get very frequently, and in fact, I got in the hallway on the way in a little bit earlier, was about the dose response that we saw in the prior trial. Love you to share some thoughts there.
Yes. There are some possible explanations for the fact that there were better results for the lower dose than there were for the higher dose in the previous phase III study. So carbetocin has greater affinity for oxytocin receptors than for vasopressin receptors and greater selectivity at oxytocin receptors than oxytocin itself. While carbetocin's enhanced selectivity may reduce off-target effects, it still has some activity on vasopressin receptors at higher doses. That effect may diminish the benefit that we see based on activity at oxytocin receptors. There is evidence in the literature suggesting that high doses of exogenous oxytocin given to patients with PWS may lead to increased emotional outbursts due to off-target vasopressin receptor agonism. It is possible that activity at vasopressin receptors can lead to feelings and behaviors that would work in opposition to the benefit derived from targeting the oxytocin receptors.
Thank you. We do have a phase III trial that is currently running. It is 12 weeks long. It is placebo-controlled in a parallel group study. What this means is if it were to be positive, this is a study that could help us describe for physicians and for patients what you can expect upon initiation of therapy. We recently announced that we were closing screening, and I'm delighted that we can now confirm that our trial is completely enrolled, and we continue to expect data out of this trial in early Q4 of this year. Jim, anything you'd like to highlight about the design of this trial, places that we've learned from the prior study, for example, or things that we've done to maximize the likelihood of success?
Yes, we believe we've designed the study to maximize the chance of success. It's a parallel group study. It's a larger study with 170 patients studying only the 3.2 mg dose versus placebo. This is for a 12-week time period. The only primary endpoint is the HQCT again, with a focus on training on the primary endpoint. As you say, we're expecting top-line results early in the fourth quarter of this year and potentially approval in the third quarter of 2026.
All right. Thank you. We're all keeping our fingers crossed for that. Going back to Susan, there has recently been a drug approved for Prader-Willi, and this is a first for a community that has waited for a really, really long time. We'd appreciate your perspective on whether there is remaining unmet need in the community and whether you see a place for more than one medicine. Susan, do we have you?
Audience going in and out a bit. There's absolutely more opportunity for additional treatments. We've seen, first of all, the approval of VYKAT is a huge milestone for our community, but it's not a cure. There's a lot of opportunity here for additional treatments. We fully appreciate that not every treatment will work for every individual. Until we have found treatments that address every challenge that our loved ones face, we have to keep moving forward and bringing more treatments to market for our loved ones with PWS.
Thanks, Susan. Dr. McCandless, I'd love your perspective on what you see as continued unmet need in the space.
Thanks. I agree with what Susan said. I would also say that there are very few problems as complex in medicine. There are very few problems as complex as the hyperphagia and Prader-Willi syndrome. I can't think of too many conditions in medicine where one drug is ever enough to meet all the need. I think even just for hyperphagia, we're likely to need other options, whether it's because of incomplete effectiveness, variability in effectiveness among individuals, side effects that are intolerable in some people, lots of reasons that additional treatments for hyperphagia will be necessary. There's just such a huge unmet need that's already been addressed. We've mentioned at least the behavioral meltdowns, the behavioral-emotional regulation, the anxiety and anxiousness that goes with Prader-Willi syndrome.
Once we have a treatment for hyperphagia, we're going to realize how disruptive those findings are to the lives of our patients and their families. There's additional need there as well.
Thank you. I'm going to give you a hypothetical, practically impossible-to-answer question. Brace yourself for this. It's obviously going to depend on the specifics of the medicines in question. Dr. McCandless, how might you think about treating patients if you had more than one medicine that was available to you? How might you make those decisions?
Great question. I think the first thing is a growing sense now that we do not think of medicines as much as having a desired effect and then side effects anymore. We just think about the effects of chemicals and treatments. What we will be looking for is what drug is going to give us the most benefit in treating our patient. If you have three choices to treat hyperphagia and they all have the same profile of effects, you'll probably just go with the least expensive.
If you have one drug that alters hyperphagia and has benefits for behavioral or anxiety issues, that's probably going to be a better first choice for that individual because it's going to address more of their needs. Likewise, what are the tolerables? What are the side effects? A drug that has—well, I already said we do not talk about side effects anymore, so forget I said that. What are the effects of the drug that are undesirable for this patient, and which should we be trying hard to avoid? I think the profile of effects will be important. The more beneficial effects and the fewer undesired effects will be what determines what will be the drug of choice to start with. Cost will play into it. For rare diseases, these drugs are all going to be expensive.
Thank you. Appreciate that perspective. It would be helpful if you could—I have talked before with much of this audience about how I would see a good outcome and a desirable outcome of our current study to see a magnitude of effect of the 3.2 mg dose that is similar to the magnitude of effect on hyperphagia that was shown in the prior study. Dr. McCandless, can you give us a sense of the clinical relevance of that magnitude of effect if it were to be shown in this study?
I think that is a really important question. Thank you. The scale itself, the numbers seem like not that big of a difference. A four-point difference, maybe that is not that big a deal until you translate that into what does it mean for the life of the person and the family. If your child is going through the neighborhood alleys, going through dumpsters a couple of times a week, and they stop doing that, that's a significant improvement in your quality of life. That's a one or two-point change in the HQCT scale. Likewise, going from not being able to go out to a restaurant for fear of a meltdown to being predictably able to go out, that might be a one or two-point change, but that's a huge change in the life of a family.
We wish we had a direct measure of hyperphagia because that's what's really challenging. We're only looking at behaviors related to hyperphagia. If I could just add an aside, that really makes it challenging and can likely lead to some lag in seeing the full benefit of the medication. I think it's going to be very difficult to assess, but even a four or five-point change in the HQCT can represent a huge change in the life of the patient and the family. Susan could probably address that better than I could.
That's a really nice segue into Susan telling us a little bit about what that order of what that magnitude of change would mean for her family.
Thank you so much. Dr. McCandless, I think you really did lead that in well. A couple of points on the HQCT, while that sounds insignificant, means so much to families with loved ones with Prader-Willi syndrome. Not to be melodramatic, but we're desperate. We are desperate for treatments. Our loved ones are often essentially institutionalized at home, and their parents, our caregivers, become prisoners as well because they simply cannot go out. It is all-consuming.
When you have someone who is spending 24 hours a day thinking about food and how they're going to access it, you as the caregiver have to be ahead of that, meaning that you are thinking about it 24 hours a day as well. Having lived through many a tantrum in our house, I can tell you it takes days for the caregiver to recover. When you start having food-related challenges or temper tantrums on a regular basis, there's no time for recovery. Even a few-point change on this hyperphagia scale could mean that we could go out as a family more often. It could mean that our home is more peaceful. It brings us to a greater sense of normalcy, which we simply don't have right now.
Yeah. Thank you. Susan, I'd really love you to bring us home for this part of the discussion. Since you are coming to us from United in Hope, tell me about what you hope for for the future for yourself, for your family, for your community.
Absolutely. I want an independent future for my son, which currently he can't have. Even individuals who have incredibly high IQs and are high-functioning struggle and cannot live independently because of hyperphagia. If we had treatments for even just hyperphagia, it comes down to two things, which are more opportunity and more life. Our loved ones currently can't go out into the community. They can't participate in adult day programs for people with special needs because of hyperphagia. If we can get carbetocin approved and additional treatments approved, we are opening up the world to these people with PWS and their families. I appreciate all that you are doing to help bring this independence to our loved ones with PWS. Thank you so much.
Thank you, Susan. Thank you all of you for your generosity of time and insight. Thank you. Now, Jim, can you give us a summary of the 101 discussion that we've had today?
Yeah. Here are some of the main points that we've discussed today. First of all, PWS is a rare and complex neurobehavioral disorder, and hyperphagia is a highly impactful symptom of PWS. The PWS patient population has many complex needs and requiring a number of treatment options. ACP-101, which is intranasal carbetocin, is a long-acting analog of human oxytocin with greater selectivity for oxytocin receptors and targets the functional deficit in oxytocin receptor agonism in PWS. The data from the previous phase III study suggests that the potential benefit of the 3.2 mg dose of ACP-101, with a safety profile that supports continued development, and the ongoing phase III trial was designed for the potential to show results similar to the 3.0 mg dose arm from the prior phase III study. We're expecting results in the fourth quarter of this year.
All right. Thank you so much. We appreciate your perspective, and we're going to move on to the DAYBUE portion of our day. DAYBUE is the first and only approved therapy for patients living with Rett syndrome. It provides us with the opportunity to expand globally as well as bring forward next-generation therapies. Dr. Ponni Subbiah is a neurologist. She has been in industry for more than 20 years with experience launching products globally, and she has been here with us at Acadia for more than five years. She leads our Medical Affairs organization and is our Chief Medical Officer. Today, she is going to update you on our experience with DAYBUE.
Good morning. I have the pleasure of updating you on DAYBUE or trofinetide for the treatment of Rett syndrome. First, let's step back. Oops. Let's go back one here. There. First, let's step back to review the underlying pathology in Rett syndrome, which occurs due to a mutation in the MECP2 gene. If you look at the bottom part of the slide, you will see a picture of a healthy neuron, which includes the spiky projections called dendrites, which arise from the soma or the body of the neuron.
Now, these dendrites serve as the main receiving area for signals from other nerve cells. Now, as shown on the right, the neurons in Rett, however, are smaller, with fewer and shorter dendrites and with a smaller body. Now, this leads the brain affected by Rett to be smaller when compared to a healthy brain because of these changes in the nerve cells and because they're packed more densely, leading to the smaller weight. Now, this is shown in the MRI scans on this slide. On the left-hand side is the scan of a normal brain, whereas the scan on the right, which is from a patient with Rett syndrome, the brain is smaller, reflecting the immaturity of the brain.
Now, because the impact of the MECP2 mutation can vary between individuals with Rett syndrome, patients can present with various signs and symptoms reflecting the heterogeneous nature of the disease. Now, trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1, or IGF-1. Now, IGF-1 is important because it plays an important regulatory role in central nervous system development as well as its maturation. Now, animal studies suggest that trofinetide acts by increasing the branching of the dendrites that form the synapses or the communication between nerve cells, as well as on the synaptic plasticity signals, thereby improving communication between neurons. Now, based on clinical data from both the pivotal as well as the long-term registration studies, trofinetide was approved in the U.S. in 2023 and has now been on the market for over two years.
I'd like to now show you the U.S. experience since launch. So DAYBUE is the first and only approved therapy for Rett syndrome. Approximately one out of three patients with Rett syndrome have been prescribed trofinetide, which translates to about 1,800 patients who have initiated treatment since launch. Now, DAYBUE has been prescribed by over 870 unique prescribers, including specialists such as pediatric neurologists, as well as pediatricians, general neurologists, internists, and nurse practitioners. Now, the age range for those who have received prescriptions is across the spectrum, as you can see here, from children as young as two years of age to older adults, the oldest being 60 years. Now, while females are predominantly affected with Rett, male patients can also be affected, as reflected in this graph, with 4% of prescriptions in males. Overall, for those ever on therapy since launch, persistency is above 50% at 12 months.
Of those currently on treatment, 65% of patients have been on therapy for 12 months or longer. Now, in the next few slides, I'm going to remind you of the data that led to DAYBUE's approval in the U.S. and Canada, as well as some relatively new data to provide additional context. The LAVENDER study on your left is the pivotal phase III study, which had two core primary endpoints. They were both statistically significant compared to placebo at week 12. Now, the graph on the left shows the change in the total score on the Rett Syndrome Behavioral Questionnaire, or the RSBQ, from baseline to week 12. Now, the RSBQ is assessed by the caregiver. It has been validated for use in clinical trials, and it's composed of 45 items that assess a range of symptoms in Rett syndrome that really reflect the heterogeneous nature of the disease.
Now, a lower score reflects improvement in symptoms, with 4.9 improvement in the trofinetide group versus a 1.7-point change in the placebo group. Now, the graph on the right shows the results of the clinical global impression of improvement, which is assessed by the clinician. Now, this also showed statistically significant differences at week 12 favoring the trofinetide group versus the placebo group. Now, common adverse reactions reported in the LAVENDER study are at the bottom, with the two most common being diarrhea and vomiting. Next, I would like to show you data from a large natural history study with RSBQ scores that are followed over time in an untreated population. The Australian natural history study is one of the largest cohorts of patients with Rett syndrome who have been followed for almost 20 years.
Now, the graph on top shows a subset of 205 patients who were followed from an age range of 5- 20 years. Now, this is similar in age range to the cohort that was studied in the trofinetide registration studies. Now, the X-axis depicts the time of follow-up in years from the first observation, while the Y-axis depicts the RSBQ scores. Remember again, a lower score reflects improvement in symptoms. The various blue lines depict individual patient scores as reported by the caregiver. Now, you can see there's a lot of variability in the scores, and this again reflects the heterogeneous nature of the disease. Now, the fitted line in the middle shows the average value, which remains close to the baseline and doesn't really change much during the first several years.
Now, the table at the bottom shows the average change in RSBQ score over two years from the baseline of the natural history study. Now, the reason I'm showing you this timeframe is because this reflects the same time period in the trofinetide LAVENDER and LILAC studies. You can see the mean score at the beginning of the interval in the Australian study in this cohort was 44, and this was similar to the baseline score in the LAVENDER study, reflecting comparable populations. Follow-up at two years showed the change on the RSBQ total score to be minimal. I showed you this data to provide context for what happens with the total score in the RSBQ over time in an untreated population. Now, let's turn to the trofinetide registration studies and look at the long-term data.
Now, on the far left is the LAVENDER study that I already shared with you. Now, this study was followed by the LILAC- 1 study, which is in the middle. Now, this was an open-label 40-week study and included patients who completed LAVENDER and opted to continue to receive trofinetide. Now, at the end of 40 weeks, there is a 7-point reduction or improvement in the RSBQ total score compared to the LAVENDER baseline. Now, those patients who completed LILAC- 1 and who opted to continue to receive trofinetide were followed in the open-label study LILAC- 2, where the positive changes in the RSBQ total score from the LAVENDER baseline were maintained. Now, I already described RSBQ in the context of its use in the clinical trials, but this slide goes a little deeper into the specific symptoms that are assessed by the RSBQ.
This ranged from breathing to hand movements to eye gaze as well as mood. Now, this is important considering the heterogeneous nature of Rett syndrome and the fact that every patient with Rett syndrome presents with a unique set of signs and symptoms. When you see one Rett patient, you see one Rett patient. I will now be showing a video to illustrate how these results can be understood from an individual patient perspective. Introduction to Maddie. Maddie was diagnosed with Rett syndrome at the age of three, just a few years after the discovery of the MECP2 gene. Now, some of her signs and symptoms included loss of purposeful hand use, breath holding, and loss of communication abilities, as well as waking up in the middle of the night with laughing spells or night terrors.
Now, Maddie started DAYBUE in 2020 as a participant in the phase III clinical trial and then transitioned to commercial drug after launch. Now, you can find out more about Maddie as well as other caregiver stories at daybue.com. Here now is the video with Maddie and her family.
Maddie has been on DAYBUE for over three years. Now, DAYBUE is FDA approved, and all these girls who participated in the clinical trial made it happen, and that's so cool. Since she's been on DAYBUE, Maddie's had a decrease in the severity of several of her symptoms. Before DAYBUE, she would hold her breath quite often during the day. We called them blue spells because she turned blue, and it was terrifying. Now, her breath holding has improved, and she has far fewer blue spells.
Maddie would often wake up in the middle of the night with laughing spells or night terrors. One of us would have to stay up with her. She does not do that as much anymore. Before DAYBUE, I wish you could have seen what she was like with her eye gaze device. You would bring it out, she would close her eyes, she would turn her head to the side, or pretend to be asleep. Now, when you bring it out, she tells me that I am boring. Maddie realized that her communication device is her voice, and her participation has skyrocketed. She even asked for people's numbers and if we have seen any cute boys. She is now using her eyes more to make choices. Before DAYBUE, if you held up two T-shirts, she would not give you a choice, or it would take her a very long response time.
Now, she can make her choice much quicker and with her eyes. Maddie used to be super aggressive with her hand movements, and it left sores. She had to wear gloves all the time. Now, with DAYBUE, she does still wring her hands, but it's not as bad. The gloves are off, and her hands can be pulled apart much easier. Sometimes, her hands will be still in her lap when she's relaxed and listening to music. Maddie's even grabbed a few things on her own. She grabbed a French fry off my husband's plate at a restaurant, a strawberry, and she even grabbed a cookie once and put it in her mouth. Usually, it's food. Another change for Maddie is she doesn't stick her tongue out as much anymore, and she's grinding her teeth less. Overall, she looks calmer and more relaxed.
I'd encourage you to please visit daybue.com to learn more about Maddie as well as other caregiver stories. Now, I would like to show you the results of a post-hoc analysis we conducted to assess the estimated time to response after starting trofinetide based on the data in the LAVENDER and LILAC studies. Now, the results on the graph are from the Clinical Global Impression of Improvement, or the CGII, which was again one of the core primary endpoints in the registration studies that I already reviewed with you. Now, this scale is based on assessment by the clinician, and the clinician will determine has the patient improved, not changed, or had no change, or worsened. Of those patients who received trofinetide for 12 months in the LAVENDER and LILAC studies, 72.5% at the end of one year were rated by the clinician as improved.
Now, we looked at this cohort of patients who showed improvement at one year to assess when did these improvements occur. At three months of treatment, you can see 56.9% showed improvement. However, from month three to month six, an additional 20% showed improvement, and from month six to month twelve, another 20% showed improvement. This is really consistent with what Rett experts are recommending based on their clinical experience over the last two years, specifically patients who received trofinetide for at least six months after titrating to their weight-banded dose or their highest tolerable dose to properly assess the efficacy of treatment, so at least six months. I would like to share with you data from an ongoing real-world observational study called LOTUS.
Now, this study was initiated soon after launch in the U.S. and included any patient who was prescribed trofinetide and whose caregiver elected to participate in the study. Now, the results shown here were the improvements that were observed by the caregiver called the Behavioral Improvement Questionnaire. Now, this tool was developed in consultation with Rett experts as well as caregivers to really capture observations in a real-world setting, but in the least burdensome manner. Now, this is an ongoing study, and I'm going to be showing you the results of the interim analysis, which includes data up to nine months. Now, the different colors on the graph represent different months from month one to month nine. The two graphs on the top show the percentage of caregivers who reported at least one area of improvement.
Now, this ranged from 76%- 85% from months one through nine in the pediatric cohort, and it ranged from 59%- 77% in the adult cohort. Now, the top three areas that were reported by the caregivers were in the bottom, and the top three areas were in nonverbal communication, alertness, and social interaction and connectedness. Now, this was also consistent between the pediatric group as well as the adult groups. Now, it is important to keep in mind that this is a real-world study with no active comparator, and caregiver observations could be chance findings. Now, let's switch to tolerability in this study. Now, diarrhea is the most common side effect of trofinetide.
Now, to really better understand the nature of the bowel movements after starting trofinetide in a real-world setting, we requested the caregivers to assess the stool over the previous three days on a weekly basis for the first 12 weeks and then monthly. Now, the graph on the left is an average of the type of stool that was reported over the first 12 weeks. Now, the blue color represents constipation, which was 10%. The maroon color represents normal or formed stools, which was observed 45% on average, and the green color represents diarrhea. Now, if you look at the green colors, the lighter green shade of green represents stool that was either loose or watery, but it was contained within the diaper, which was 33%. The darker green represents stool that was watery and outside the diaper and outside the clothes or on the clothes, and this was 10%.
Now, the graph on the right shows the average over the first 12 weeks of specific caregiver-reported diarrhea management and prevention strategies that the caregivers used after initiation of trofinetide. Now, the three most common strategies that were reported were stopping constipation medications, increasing fluid intake, and administering supplementary fiber. Now, clearly, there is underutilization of many of the strategies that could be really utilized to improve the patient journey. We see this as an important opportunity to continue to educate clinicians and caregivers on this important topic. Now, from the U.S. experience, I would like to now transition to our plans to expand beyond North America. We filed our marketing application in Europe earlier this year, where an estimated 9,000-12,000 patients are impacted by Rett. Now, we are building our EU launch team to support a potential approval in the first quarter of next year.
In addition, we have a strong focus on Japan, where an estimated 1,000-2,000 patients are impacted by Rett. Of note, we have been assigned an orphan drug designation status, and the submission file will be based on the global data, but also supplementary data from patients with Rett in Japan. We anticipate starting this local study in the third quarter of this year. Now, in addition to DAYBUE, we are committed as Acadians to bringing new solutions to the market based on the extensive learnings we have had with DAYBUE in Rett syndrome. This includes ACP-2591, which is licensed from Neuren. Now, this compound is an IGF-1 fragment analog. Now, we're excited about this because early research suggests that it may have better brain penetrance with potential impact on the benefit-risk profile.
Now, in addition, we do have other undisclosed programs that are in the exploratory research stage and which we hope to continue to develop based on our disease learnings in this area with the aim of bringing different types of solutions to the Rett community. I would like to now finish with some key takeaways. First, Rett is a complex disease with a range of symptoms that require lifelong care, and trofinetide or DAYBUE is a synthetic analog of the N-terminal tripeptide of IGF-1, which plays an important role in brain development and maturation as well as plasticity. Now, DAYBUE is the first and only approved treatment of Rett syndrome in adults and pediatric patients two years of age and older in the U.S. and Canada.
Now, in addition to data and registration studies, we are continuing to gather data from the LOTUS study, which continues to provide information on caregiver-reported improvements and GI management strategies in the real-world study. Lastly, we want to reach more patients affected by Rett outside of North America, including in Europe and Japan. Thank you for your attention, and I'll now turn it back to Liz.
We'll wait so I don't tower over everybody. Thank you. DAYBUE and ACP-101 give us firm footing in areas of rare neurological diseases, neurodevelopmental, neuroendocrine, and seizure disorders, and they offer an opportunity to further utilize our development and commercialization capabilities. One place we're capitalizing on this is through a focus in rare epilepsy. I'd like to spend a few moments talking about our currently disclosed program in this space, which is through our collaboration with Stoke Therapeutics in SYNGAP1.
Beyond this program, we do have additional undisclosed programs in rare epilepsy that I look forward to discussing with you all in due course. SYNGAP1-related disorders are neurodevelopmental disorders. They can be associated with childhood-onset epilepsy, developmental delays, movement disorders, and features of autism spectrum disorder. SYNGAP1-related disorders are what's called a haploinsufficiency, and this occurs when one copy of a gene is inactivated or deleted, and the remaining functional copy of the gene doesn't produce enough product to preserve normal function. Roughly speaking, this means that a patient with a haploinsufficiency has about half the amount of a particular identifiable protein that a healthy person does. In theory, all that would be needed to ameliorate the disease impact would be to increase the amount of protein to normal levels.
Stoke's technology is especially suited to increasing the amount of protein that's produced out of the wild-type copy of a gene to achieve healthy levels. We are really pleased with the data that we are seeing from this collaboration so far. The data to date support dose-dependent target engagement. We have evidence that we drive protein expression towards normal levels, and we are seeing clear signs of activity in patient-derived neurons suggesting that with meaningful increase in protein levels, there is actually a phenotypic consequence that getting the right amount of protein may be able to drive benefit. I have mentioned before that we approach drug development with rigorous criteria established at every step along the way, and here we are looking forward to our next tranche of decision-enabling data in the early part of next year.
By now, I'm hoping we've convinced you that we know how to take smart steps from one area of success and expertise to the next. We are, and we always will be, committed to development of high-conviction molecules in neurological diseases, both common and rare. There are numerous areas of unmet medical need within clearly defined therapeutic areas outside of the neurospace that are still Acadia-sized and where we think we can capitalize on key capabilities: our expanding abilities to navigate the regulatory, clinical, and logistical complexities of rare disease development, for example. We see these opportunities in diseases within the endocrine and metabolic space, nephrology, immunology, and cardiovascular. Each of these represents an area of some overlap with physicians currently within our universe or where we believe we can build a right-sized commercial and field force to support any medicine we develop.
We prioritize assets where we have reason to believe in the potential for differentiation. In line with our expanding focus on data innovation, we're actively focused on biomarkers as an avenue to de-risk clinical development. Looking to diversify the types of risk in our pipeline, we also prioritize assets with objective endpoints. Recognizing that these opportunities can be hard to find, we are diligently applying ourselves to every avenue of potential business development. Throughout the day, you've heard about what we're currently doing and a sense of how we plan to continue that momentum into the future. We do this because we're motivated by the everyday moments that unaffected families take for granted. We're here to deliver a robust and sustainable pipeline, and we do that by utilizing to the fullest potential what we think makes us special.
We aim to prudently make the most of molecules in our care, those that are currently on the market and those that are heading toward it. We do this through our sharp commercial insight, and that is honed from a deep understanding of the needs of the full healthcare community, from patients and their families to healthcare practitioners to payers. We feed our pipeline largely through external innovation, but we're maintaining the ability to both evaluate earlier stage innovation as well as drive forward projects in areas of unique internal insight. In particular, a focus on some earlier stage projects helps us smooth our pipeline growth and supplement later stage projects from partnerships, licenses, and acquisitions.
We move forward our pipeline with urgency and rigor, always being mindful that the best way to ultimately serve patients is to ensure that molecules have to earn their way into our pipeline and then earn their right to stay there. We know that our job is to give the molecule a chance to give its job. We're supplementing this with an eye to risk diversification, but we'll always be skewing towards scientific risk rather than financial. To enable all of this, we have a strong focus on our people. You can't make the right bets or move forward without the right talent brought together in the right places. Throughout today, I hope we've convinced you that our pipeline is robust and active, but biotech is very much a business of what's next, and our ambitions don't end with today's pipeline. We're looking to build a sustainable future.
We do this with a significant skew towards external innovation while ensuring that we maintain the capabilities to drive forward in areas where we have distinct insight and expertise. At the most internally driven end of the spectrum, we have the ability to build molecules through a network of external vendors in areas where we have deep insight into what we need. I would give ACP-204 as the prime example of this approach, where we were able to drive the production of a molecule within a mechanism of interest that met our rigorous TPP. In the middle, we have a relationship with Axcelead that gives us access to high-class chemistry as well as innovative insights, letting us explore mechanisms that we find interesting. Finally, recognizing that the ideal therapeutic is always the marriage of mechanism and modality, we partner for unique capabilities and technologies.
Here, this is typified by our partnership with Stoke on the SYNGAP1 program that I discussed earlier. Like R&D, BD deals come with no guarantees. Our industry is one of risk, and even the best ideas do not always work out. We are proud of our track record, though, where we have shown willingness to take smart scientific risk in financially disciplined ways. Today, our cumulative net sales for DAYBUE are already about 5x greater than the total at-risk R&D investment that we made leading up to the positive phase III top-line results. Note this is only sales to date, and it is limited to the U.S., and it is only going to grow from here. ACP-101 is another product that we thought of similarly: the opportunity to focus our at-risk spend on registration-enabling late-stage clinical work.
The return here will be substantial in the event of a positive study outcome, given the potential future sales. Looking to the future, we expect this type of profile to continue to be an important part of our pipeline expansion efforts, supplemented by carefully chosen places where we'll aggressively pursue assets with lowered scientific risk. The foundation of any organization is its people, and we're all shaped by the companies where we learned and refined our trades, as well as the projects that we've had the opportunity to be part of. I am proud to have an R&D leadership team, of which you saw some today, that honed its drug development and commercialization skills at leading companies within our industry. This team has been part of bringing more than 100 medicines to patients in need, and among those, about 30 blockbusters.
Equally, while our expertise in neurological disease has long been a core part of our identity, we have key leaders in our R&D organization, including regulatory, translational, and biometrics, who've spent significant time in their careers focused on bringing therapies to patients living with rare diseases. These leaders have had a hand in 30 drugs serving patient populations of 200,000 in the U.S., and some of those patient populations are much, much less. I'm proud of the talent we've built to date in the U.S. and beyond, and we look to continue to recruit top-tier talent. We've recently committed to building a hub in the San Francisco Bay Area. This is a hotbed of biotech and pharma talent and will help us build the teams of tomorrow to help serve the pipeline of our future.
You've invested almost four hours with us today, which I hope you consider to be as wise of an investment as Acadia itself. I hope you'll join me in seeing how Acadia is advancing care for neurological and rare diseases, harnessing our strong development and commercial capabilities. Our pipeline is active, and it is gathering momentum over the next few years. This includes nine disclosed programs, of which eight are expected to be in the clinic by year-end, and multiple undisclosed programs. We have seven phase II or phase III studies that are anticipated to start between now and the end of 2026. On top of that, we have five study readouts from phase II or phase III studies between now and the end of 2027. We are here at Acadia are motivated by the everyday moments that unaffected families take for granted.
We are driven to bring more of those moments to patients and their families, and we're going to deliver on that commitment with this team, this portfolio, and this pipeline. Thank you for your time and attention. We have a few minutes for questions. I'm going to invite Catherine up to the stage and the other presenters to be at the ready. At this point, please feel free to ask questions spanning the morning as a whole.
Hi, Tessa Romero, JP Morgan. Thanks so much for today. Toggling back to one of the first slides that you shared here, I think it was slide six.
Oh, wow.
Wow.
Can you help us understand how you think through relative risk across your portfolio? Which of the key opportunities do you view as lowest risk and/or which carry the largest reward here? What I'm interested in is what are the key inputs to that blue bar graph that you showed today? Thanks.
I think you're talking about the $2.5 billion-$12 billion. I thought I might get a question on that.
Thank you.
The $2.5 billion represents the five molecules risk-adjusted for their stage of development. As you know, risk adjustment is standardized across the industry, but also we take internal views of our position on risk. Those are risk-adjusted. The $12 billion is the five molecules in their peak. Of those, 204, we believe, has the potential to be well over $2 billion at peak. It is a large population that we will be addressing with relatively high medical need. I would say all of them have the potential to be blockbusters over $1 billion. After 204, we believe that 711 and 211 have very significant potential above $2 billion, and the others are somewhat in between. We wanted to give you a view to how we thought about these drugs. There is a lot of assumptions in there, Tessa, which I hope you will appreciate.
There's a lot of market share assumptions, uptake assumptions, which we can maybe elaborate on a little bit more, but I feel very comfortable talking about those numbers in the context of a fairly sort of conservative view on those assumptions, having lived through some of those situations prior. I feel very comfortable sharing those with the risk adjustment caveat. We are excited because we think Acadia's pipeline, as I said at the time, has been undervalued, and we just wanted to give you a perception of where we think those drugs can go.
Thank you.
Hi. Hi, Booba lan from Roth Capital. A couple of questions. Firstly, with respect to your PWS program, I wanted to know how you are factoring the compliance because your drug is thrice a day and you're competing with the first in space that's delivered once a day. In that context, if you could talk about the side effect profile with all the extra glucose and fluid retention, and how does it compare with your drug? That's the first question. The second, maybe at a broader level with respect to Huntington disease. I know we have gene therapy that's also currently in clinical development, and gene therapy is very good for monogenic diseases such as Huntington.
I wanted to know how do you feel more confident about your program if you keep, as I said, the usual suspects like high pricing for gene therapy and then the delivery, the way it's delivered. For instance, you have to break the brain and deliver the drug for a unique molecule. If you keep all of that aside, what gives you more confidence in your Huntington program? Thank you.
Okay. I'll try to make sure I hit on everything there. As we think about ACP-101, I'm not going to comment on the ongoing trial in particular, but what I'll say is that we have generally seen good compliance with dosing. We do firmly think that different patients will do well with different routes of administration. I think you heard a little bit of that with Dr. McCandless, that you're going to fit the treatment to the patient in front of you. That said, in our program to date, we've seen good acceptance of the dosing modality, and we feel like this is going to be an acceptable modality for patients, and we've heard good feedback from KOLs as well.
In terms of the adverse events and safety profile, again, I think physicians are going to want to match the person they have in front of them with the agent that they think is going to have the best, how did Dr. McCandless put it, best fit of different kinds of effects, both positive and negative effects. To date, and again, I'm commenting on prior data. I'm not commenting on the ongoing study at this point, but to date, we really haven't seen evidence of edema. We haven't seen suggestions that this dose or that ACP-101 is going to require ongoing monitoring. We think if that safety profile continues to bear out, those are things that will make this a helpful agent for some patients. In terms of Huntington's disease, we are delighted to see that there are potential gene therapies continuing forward.
That's always an area where there's high hope. Monogenic diseases are at least theoretically more directly applicable. That said, I think what we've seen is that in these complex disorders in terms of their presentation, thus far, I don't know that gene therapies have really played out to be a cure. I think that we do anticipate that there is likely going to be continued room for impact on the different symptoms. We do think part of the promise of 271 is its potential impact, not just hopefully on motor symptoms, but also psychiatric. We think there likely is still going to be a role to play for that. Obviously, there's a lot to play out, both in clinical development of the gene therapies and 271 as well, but conceptually, that's how we see the potential future.
Thank you. I'm Ami Fadia from Needham. A couple of questions on ACP-204. What was the rationale for picking a 30 mg dose as opposed to selecting two doses that have higher exposure than the NUPLAZID commercialized dose? What's your expectation for the difference in efficacy or response that you might see within the two cohorts in the Lewy body study? What's your rationale for capping the PDD to 50% within the study? Do you have the option of moving straight into a phase III if you see encouraging data just in the interest of moving forward that program efficiently?
I'll try to make sure I get all the bits. If there's anything I miss, Sanjeev, you should definitely jump in here. As we were thinking about the 204 program in ADP originally, part of what we wanted to do was base our understanding in what we've seen with pimavanserin and then expand beyond. The lower dose is looking at roughly equivalent exposures to the currently marketed dose of NUPLAZID. That gives us, we think, the best opportunity to replicate the overall profile there while also dose ranging to explore whether that exposure response graph that we see really does play out to support greater efficacy with the higher doses. That was the rationale behind keeping one at a roughly NUPLAZID marketed dose equivalent and one higher than that.
As we think about the Lewy body program, we were looking to make sure that we were really understanding the behavior in both of these patient populations. When you look in the data we have with pimavanserin in that HARMONY study that we showed you, that is the combination of the dementia with Lewy bodies population and the PDD population. That is getting into very small numbers of patients in each individual population. We designed our phase II to help us understand whether those two groups behave similarly. To support that, we did look to cap the population to ensure that we're getting roughly equivalent patient sizes in both cases.
Whether we'd be in a position to go directly into a phase III is, of course, going to be dependent on the data we get out of it, but we have designed this with the intent to be a phase III enabling program. We're looking to understand the dose response in each of these subpopulations. We're looking to understand the consistency of response across those two populations and get some initial insight into both the efficacy and safety profiles. The goal would be that we'd be able to go into a phase III thereafter. Were there any questions there that I missed? I think that was all of them.
We're good.
Okay. One or two more, yeah?
A couple more.
Yeah.
Okay. Sure.
Thanks so much for the presentation. David Hong with Deutsche Bank. Maybe first one on ACP-101, could you just talk a little bit about the commercialization strategy and approach? How accessible are the 8,000-10,000, I think, prevalent patients that were highlighted? And then one on DAYBUE, given the learnings now to date, is there any opportunity maybe to go back to earlier patients that may have discontinued, let's say, prematurely due to shorter time on treatment or maybe not having an optimal GI management strategy? Thanks so much.
Yeah, no, I'll take those. In terms of PWS, you heard from Susan that most patients with PWS are diagnosed fairly early on. She was very early at a week, but what we know from our research is that most patients are diagnosed certainly within the first couple of months. Compared to Rett, which isn't actually diagnosed until far later in terms of the child's development, these patients are pretty well diagnosed. Because, David, there is actually an ICD-10 code associated with that, we believe that the prevalent population, the diagnosed population, are sort of pretty similar. Whilst we saw the Rett population grow over time in terms of diagnosis because some of them were misdiagnosed, we believe we've got there or thereabouts the size of the PWS population.
I guess you can compare that with Saniona's view of the world, and they kind of come out in the same place, so we feel pretty confident about that. In terms of patients on DAYBUE restarting, it's a really good question. What Ponni shared from the ongoing LOTUS study and what our physicians are learning is that some families, when they go back to them, and we stay in contact with all families that have tried DAYBUE, and we periodically do go back to them to see if they're interested in trying, some families are willing, now that we've got more learning and more understanding of those diarrhea management strategies, to try again. We have seen a little bit of a pickup in restarts.
I know in our Q2 call, we'll probably give you a little bit more color around that, but we are definitely seeing some families wanting to try again. Not all, but certainly it's picking up a little bit right now. Did that cover your questions, David?
All right.
Yeah. Okay.
One more?
One more?
Okay.
Sumanth from Canaccord, thanks for the follow-up. Two quick ones. On ACP-211, how do you define minimal in clinical monitoring, in clinic monitoring, and do you expect eventual use to be limited to an in-clinic setting? Second, a bigger picture question. You have so many molecules in development, so do you think the current commercial products, the cash flow from those, can defray the costs of developing these drugs, or how do you think about funding given the strange environment we seem to be in on small mid-cap biotech?
I'll make a couple of comments, and then if you want to expand any further. Again, 211, it is going to continue to be informed by the emerging data. That said, we do think that if you are able to get to a profile that is oral, that has no sedation, and has only minimal and mild dissociation, there's not really a good reason to think that there's going to need to be any substantial amount of time at the clinic. We are considering that this is, again, what we're looking for here is truly minimal time that's spent going into the clinic. As far as our overall portfolio and making sure that we're able to fund our R&D efforts, I'll say a couple of things, and then Catherine should definitely expand. I think that what we have here is an excellent and interesting portfolio.
We try to be very disciplined in our decision-making to make sure that we are pulling back on any spending that we do not think is going to bring forward a molecule that is truly going to be impactful for patients and meet what we see as our high bar around unmet need and what a molecule needs to deliver. We are in the beneficial and relatively rare, frankly, situation of having a profitable overall business. We believe that we are going to be able to continue to fund promising innovation with our marketed products. As we start getting readouts from studies, which again, five phase II or phase III readouts over the next few years, we should be getting new things that are coming into our marketed part of the portfolio as our currently marketed medicines move their way along. Anything you would add?
No, I think you've answered it beautifully. Just to reiterate the fact that we make diligent decisions on trimming our pipeline as well as adding to it. Unlike maybe some larger pharma companies where maybe some of us have grown up, we do not allow things to mushroom and develop into science projects. We are making very specific decisions so that we can stay very focused on ensuring that we are able to fund because we pride ourselves on being able to do that, and we want to maintain that diligence moving forward.
All right. Thank you so much. Additional questions can go to Al, and then the rest of us will be bopping around for a little bit. Thank you so much for your time. We really appreciate it.
Thank you.