Hello, thank you for standing by. Welcome to ACADIA Pharmaceuticals conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask the question during this time, you will need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 1 again. I will now like to hand the conference over to Jessica Tieszen. Ma'am, you may begin.
Thank you. Good afternoon, everyone, and thank you for joining us on today's call to discuss ACADIA's expanded agreement with Neuren Pharmaceuticals. Joining me on the call today from ACADIA are Steve Davis, our Chief Executive Officer, who will provide some opening remarks before turning it over to Brendan Teehan, our Chief Operating Officer, Head of Commercial, to discuss the DAYBUE launch. Mark Schneyer, our Chief Financial Officer, will discuss the financial terms of the Neuren agreement, as well as review preliminary second quarter net sales and updated guidance. Steve will finish our prepared remarks with some closing thoughts before opening the call up for your questions. In addition, Doug Williamson, our Head of R&D, and Kathie Bishop, our Head of Rare Disease and External Innovation, will be on the call and available for the Q&A session.
I would also like to point out that we are using supplemental slides, which are available on the Events and Presentations section of our website. Before we proceed, I would first like to remind you that during our call today, we will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth, potential, timing of events, or future results, are based on current information, assumptions, and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date.
I will now turn the call over to Steve.
Thank you, Jess. Good afternoon, everyone, and thank you for joining us. Please turn to slide four. I'm pleased to announce today that ACADIA has acquired exclusive worldwide rights to trofinetide as part of an expanded agreement with Neuren Pharmaceuticals. We've also acquired worldwide rights to Neuren's clinical stage development candidate, NNZ-2591, in Rett and Fragile X syndromes. Our expanded agreement follows our April 2023 launch of trofinetide, which is marketed as DAYBUE in the United States, as the first and only drug approved for the treatment of Rett syndrome. This worldwide expansion advances our rare disease strategy and highlights our commitment to pursuing innovative new products. The unmet need in Rett syndrome outside of the United States is very similar to the dramatic unmet need that we see inside the United States.
It is a very debilitating disorder with no approved treatments outside of the U.S. Regarding potential addressable populations, the worldwide instance rate of Rett syndrome is pretty constant. Therefore, for example, the prevalent population in Europe is somewhat larger than the U.S., and in Japan, it is somewhat smaller. Please turn to slide 5. As Brendan will describe in greater detail in a moment, the DAYBUE launch is off to a great start. The Rett population is adopting faster than expected. Healthcare professionals and caregivers are reporting benefits. Approximately 20% of covered lives have a written policy in place, and our launch operational execution is going exactly according to plan. In our announcement today, we provided preliminary second quarter net sales of DAYBUE in the range of $21 million-$23 million.
We also provided third quarter guidance on DAYBUE net sales in the range of $45 million-$55 million. While it's still very early days in the launch, at this point, the demand we're seeing for trofinetide from the Rett community has exceeded our plan. While it is premature to draw long-term conclusions on compliance and persistency, we're very encouraged that the hard work we put into educating the medical and caregiver communities appears to be making a difference. However, once again, I want to stress that it's still very early days. In addition, we've made very good progress in establishing access to trofinetide. Most patients on therapy today have been given access under a letter of medical necessity, as most payers have not yet adopted a formal written policy. With that, I'd like to pass the call over to Brendan to discuss the launch in more detail.
Thank you, Steve. As Steve noted, we're excited to have the opportunity to serve the Rett community worldwide as a function of this agreement. Today, I'd like to give you a little more insight into the early days of our launch of DAYBUE for the treatment of Rett syndrome here in the United States. As a reminder, DAYBUE received FDA approval in March 2023, and then we made the product commercially available in mid-April. I'll be sharing insights from commercialization over the first 12 weeks of the launch. Let's start with the market demand dynamics. As we previously described, we expected demand to be high, and it has been in the early days of the launch.
We also expected demand to be somewhat moderated by patients and caregivers gaining access to their Rett physicians, who generally have small staffs and are seeing patients largely through scheduled Rett clinic days, generally once or twice monthly, depending on resourcing. Patients, caregivers, and healthcare professionals are also working through the early prior authorization process with their payers to gain appropriate access to DAYBUE. Let me double-click on a couple topics and provide a bit more insight. As we noted, our first focus was on assisting our clinical trial patients in converting over to commercial therapy once they completed their participation in the open-label extension portion of our phase 3 studies. This conversion has continued to progress as expected.
From here, we turned our attention to the broader Rett patient population, first focusing on the Rett Syndrome Centers of Excellence and high-volume institutions where a disproportionate number of Rett patients are treated. As anticipated, we are seeing significant demand in all treatment settings. There were a few centers of excellence, in particular, that contributed to our early strong uptake. That said, we are also encouraged by the breadth of prescribers we are seeing from not only centers of excellence, but also high-volume institutions and smaller community-based practices. We will work diligently with these existing centers and new prescribers as they continue to see additional Rett patients, many for the first time since the product's approval. Our sales team is gaining access to these Rett centers, and we are pleased by the reception we're receiving and the relationships we're establishing with these treatment teams.
Next, as you know, we established a comprehensive support system for patients, caregivers, and providers, comprised of our dedicated distribution and specialty pharmacy services, our patient hub, staffed by clinical nurse care coordinators, our clinical pharmacists and benefit services team, as well as our field-based Family Access Managers, who are all specifically paired with each new DAYBUE patient and family as they initiate their treatment journey. The goal here is to set the appropriate clinical benefit and treatment management expectations with physicians and families to ensure the optimal initiation and treatment journey for the patient. We are pleased by all the feedback we have been receiving regarding the high quality of the personalized service our teams are providing.
Most importantly, we are excited about the clear clinical benefits caregivers are sharing with us about the day-to-day meaningful improvements they are seeing in their loved ones who have started treatment with DAYBUE. Caregivers are readily reaching out to their Family Access Managers to share these early success stories, often noting abilities their daughters or sons are demonstrating either for the first time in a long time or for the first time ever. Let me now turn to compliance and persistency. What we know from market research and discussions with our prescribing physicians, is that the majority of healthcare professionals are titrating up on dose for DAYBUE with their patients to find the dose that works best for the individual patient.
With that background, it will take some time for us to see what titration will mean to both the average dose per patient over time as well as the refill rate. As stated above, we have a highly valued, proactive program to educate healthcare professionals and caregivers on the benefits of DAYBUE, as well as GI management, which we believe is leading to thoughtful titration to find the best dose to provide long-term benefit for these patients. Physicians and families have been very receptive to other elements of our GI management plan, including management of anti-constipation medications, as described in our package insert. While it's very early, we are very encouraged that this titration regimen, as well as elements of the GI management plan that we've invested in heavily, appear to be showing benefits. Let me turn to payer policy and access.
It's still early innings regarding access. However, patients covering approximately 20% of Rett patients have issued a written policy for DAYBUE. These formal plans generally have been consistent with our expectations. Where formal plans don't exist, which is the case for the vast majority of patients on therapy, access has been granted by medical exception. Of course, we work diligently with payers as they establish formal policies at the remaining plans. We continue to work very closely with plans to ensure broad access for DAYBUE to all appropriate patients. As a reminder, we are very pleased with the DAYBUE label, which has no restrictions on gender, no age restrictions over from 2 years or older, and no requirement for MECP2 testing. Let me turn to our operational execution.
Our sales teams have established very good access to Centers of Excellence, high-volume institutions, and key community practices, and we're seeing prescriptions coming from each of these treatment locations. Our hub services and Family Access Management teams are supporting successful patient onboarding and continued HCP patient and family engagement along the treatment journey. Finally, our treated patient population is very much in line with our age, weight, and gender expectations for the patients being treated in the early post-launch phase. We look forward to sharing more insights as we progress through the into the launch of DAYBUE. I'd like to turn the call over to Mark, starting on slide 7.
Thank you, Brendan. Let me briefly describe the financial terms of the expanded agreement on slide 7. As you can see on the left side, the financial terms for our existing rights to trofinetide in North America remain unchanged. Moving to the right side, the consideration for our expanded rights to trofinetide outside North America and for global rights to NNZ-2591 in Rett syndrome and Fragile X include: a $100 million upfront payment,... region-specific milestones for trofinetide in Europe, Japan, and rest of world, as listed in the table. These milestones are awarded upon first commercial sale and the achievement of annual net sales thresholds. Region-specific tiered royalties for trofinetide, ranging from the mid-teens to low 20s as a % of trofinetide net sales. For NNZ-2591, global payments for this asset are identical to the global payments for trofinetide.
The upfront consideration will be funded from cash on hand. Our cash balance continues to be strong as we are already close to cash flow breakeven, and our results from DAYBUE will accelerate our pathway to becoming cash flow positive. We ended Q2 with a cash balance of approximately $375 million, and we will have pro forma cash of approximately $275 million after completing the transaction. We do not require any additional financing to support our current business plan, which now includes execution of the ex-North American trofinetide opportunity and the continued advancement of our pipeline, including our phase 3 program with pimavanserin in negative symptoms of schizophrenia, our phase 3 program with Prader-Willi syndrome with ACP-101, our Alzheimer's disease psychosis program with ACP-204, and our early-stage portfolio. Please turn to Slide 8.
Today, we are also announcing preliminary Q2 net sales ranges as well as forward guidance for DAYBUE and NUPLAZID. Starting with DAYBUE, we expect to record Q2 net sales within the range of $21 million-$23 million, and are providing a Q3 net sales guidance range of $45 million-$55 million. As discussed by Steve and Brendan, the launch is off to a great start, and we are highly encouraged by the level of demand we are seeing for DAYBUE. Our Q2 preliminary net sales benefited from the prevalent population adopting faster than expected, both from patients converting from our open-label extension trial, as well as from naive patients starting therapy. As a reminder, our longer-term net sales trajectory will be influenced by patient compliance rates and levels of persistency.
As most of our patients are titrating their initial doses and have only had 1 or 2 scripts filled, we are not yet at the stage where we have meaningful data on the go-forward rates of compliance and persistency. Finally, we continue to engage with payers as many of them are still working to formalize their reimbursement policies. Let me now turn to Nuplazid. We expect to record Nuplazid Q2 net sales within the range of $140 million-$144 million. This represents approximately 3% year-over-year demand and selling growth. Our Q2 growth in Nuplazid was driven by an increase in new patient starts across both office-based and long-term care channels, with particularly strong performance in long-term care.
Based on our year-to-date performance, and now that we're halfway through the year, we are narrowing our full year net sales guidance range for NUPLAZID. We are increasing the bottom end of the range by $10 million to $530 million, and adjusting the top end by $5 million to $545 million. I'll now turn it over to Steve for closing remarks.
Thanks much, Mark. I'd like to end today's prepared remarks by highlighting our execution across our four strategic priorities on Slide nine. First, as we highlighted today, our execution of the DAYBUE launch is going extremely well, and we're seeing early uptake faster than planned. Today, we acquired worldwide rights to trofinetide. Second, NUPLAZID in PDP is delivering steady volume and increasing market share while increasing profitability. Third, we plan to complete enrollment in our phase 3 ADVANCE-2 study for the negative symptoms of schizophrenia mid-year, with top line results expected in the first quarter of 2024. Fourth, we plan to initiate a global phase 3 study of ACP-101 for Prader-Willi syndrome in the fourth quarter of 2023. Finally, we plan to commence phase 2 clinical studies of ACP-204 in the second half of this year.
We look forward to providing additional updates on our second quarter earnings call. As always, I would like to thank our employees for their accomplishments and their ongoing commitment and passion as we continue our mission to elevate life. I'll now turn things back over to the operator.
Thank you. Ladies and gentlemen, as a reminder to ask a question, please press star 1 1 on your telephone and then wait for your name to be announced. To withdraw your question, please press star 1 1 again. Please stand by while we compile the Q&A roster.
Our first question comes from the line of Neena Bitritto-Garg with Citi. Your line is open.
Hey, guys. Thanks so much for taking my question. Congrats on the update. I'm just curious if you can give us some more details on the trofinetide launch, in particular, if there was any stocking or any inventory impact in the likely range that you provided. Also, if you could give us some details on the number of patients that you actually had on drug at the end of June, just so that we can get a sense of how, you know, how the guidance quarter-over-quarter, what that implies about patient numbers in Q2 and Q3. Thank you.
Yeah, Brendan, I'm gonna let you take the first question. Mark, I'll ask you to take the second.
Sure. Thanks for the question. As it relates to inventory, no, inventory was not a component of our performance. The second question around patients, I think that we're more focused on, at this very early stage, trying to give you the right types of metrics that will avoid misinterpretation of the early kind of post-launch dynamics. That's why we're giving guidance for the third quarter, to give you a sense of progression from where we are today, to where we think we'll be, roughly 90 days from now.
I thank you. I think you answered both questions.
My fault.
That's great. Mark, did you wanna add something?
Yeah, just to add, I think the revenue recognition model for DAYBUE will be different for NUPLAZID. There's no kind of difference between selling and demand. You know, we have a single specialty pharma distribution. We sell on a consignment model, then it's only really right before a script is filled that the distributor takes possession and ownership, then we recognize revenue. You can think of this as a really a sell-through model for revenue purposes, our revenue will very closely match demand for DAYBUE.
Okay, got it. No, that makes sense. I guess maybe if I can just ask them, the question on patient starts a little bit differently. I guess then, what are the assumptions that are going into the 3Q guidance range that you've provided, and how should we think about, you know, the growth to net and I guess, the net adds and how all those things should play into that number?
Sure, Mark, you want to take that?
Yeah, I mean, as we think about, right, it's all of that, right? It's assumptions on, you know, rates of continuations for existing patients, new patients adds, patients that are still working through the access program that have already submitted enrollment forms, and just overall levels of compliance and persistency. Those are the assumptions that we're going forward. I think it's just as Brendan mentioned, at this very early stage, we think, you know, providing kind of our guidance is more informative, as, you know, any one of these variables, you know, is really very preliminary kind of the data that we have now, and they're certainly open to, while, you know, wide bands of interpretation, in and of themselves.
Got it. No, that's super helpful. Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Ritu Baral with TD Cowen. Your line is open.
Hi, guys. Thanks for taking the question, and thank you for not limiting me to one. You can't do this to guidance and make me ask just one question. The profile of the patients, you said that they're sort of along with your expectations, and I believe previously you had said that you would expect younger patients, smaller patients, given this is weight-based dosing, to start earlier. Is that, is that still what you're seeing? Because in many other orphan launches, we've seen sort of the larger, older, bigger patients bait earlier. I've got a follow-up on Europe.
Yeah, we'll take the first question. Brendan, you wanna take that?
Sure. Ritu, thanks so much for the question. Yes, I would say in the very early days post-launch, we are seeing age, weight, and gender very much in line with what we expected. At age range, towards the younger end, although we have been heartened by the number of prescriptions for patients over the age of 20, in line with our with a broad label. We've also been excited to see male enrollment forms at about the proportion that we would have expected for the patient population. If that gives you some sense, I think we're largely on track with what we described.
Got it.
You see yet another...
As far as Europe goes, you, well, first of all, where are you with discussions with your primary regulators, like the EMA? Has Neuren gone through scientific advice, or is that something that you'll be embarking? I mean, I think the bottom line is, do you have an idea of path to approval in Europe right now?
We do. Kathie, you wanna take that?
Hi, Ritu, it's Kathie, and thanks for the question. Neuren previously held this, and now we're very excited to take it over. We've had a lot of interest from patients around the world since we had positive data, we're excited to take that forward. To answer your question, our first step will be to have those regulatory interactions. There has been some country-level scientific advice, we wanna sorta accelerate that and move into a full path to get to regulatory approval in Europe. We'll be starting with those appropriate regulatory interactions.
Got it. I'm gonna squeak in one more that came in from a client. Can you give the rough breakout of patients between open label patients that are converted to commercial and just fundamentally new patients to DAYBUE for us? Thanks. I'll stop now.
Yeah, sure, Ritu. Thanks for the question. Just going back to previous statements, we had an expected number of patients that had been in the open-label extension. They are, as you would expect, making an increasingly small proportion of our overall patient population. De novo patients, in the middle of the quarter, certainly began to outpace the clinical trial conversion patients. I would expect that, as we move into future calls, they'll be an increasingly small minority of patients on DAYBUE.
Very helpful. Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Charles Duncan with Cantor. Your line is open.
Hi, this is Elaine on for Charles at Cantor. Just wanted to ask a quick question on NNZ-2591. Do you have an option to expand development into other rare disease indications?
We do not. We acquired rights to NNZ-2591 for Rett and Fragile X. Neuren is already developing the compound. It's in the clinic. They've already completed phase 1. They're working on studies in four different neurodevelopmental indications. We acquired rights for Rett and Fragile X.
Okay, got it. Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Gregory Renza with RBC Capital Markets. Your line is open.
Hey, good afternoon, Steve and team. Congratulations on the updates all around, and thanks for taking my question. Steve, just to follow up on your commentary and Kathie's on the regulatory proceedings outside of the U.S., I'm just curious if you could comment on maybe the calculus involved with respect to the infrastructure and the resources required for you and the team to go ex-U.S. I would imagine that there are some considerations on broadening that infrastructure, given the sort of new grounds for ACADIA. Any commentary you have on how that would look would be great. Secondly, just with respect to the priority review voucher, what are the latest plans there, seeing one transaction more recently in the space?
Just curious how you're handling of a sale versus a hold on and what the latest is on the PRV. Thanks so much, and congratulations again.
Yeah, thanks. I'll take the second part first, the PRV, and then I'll ask Brendan to respond to the infrastructure question. In terms of the PRV, we've not made a determination about whether we will use it ourselves or sell it. There obviously is an established market for selling these. Just as a reminder, if we sell it, Neuren is entitled to a third of the proceeds, and we're entitled to two-thirds. If we use it, Neuren is entitled to a payment that would be equivalent to the market value, excuse me, one-third of the market value at that point in time. Brendan, do you want to address the infrastructure question?
Yeah, sure. Thanks for the question. A couple of things. Obviously, with the U.S. launch, we've leveraged a lot of our internal infrastructure and have added as appropriately for our target audience. In addition to that, at ACADIA, there are a number of people who have both worked in rare disease in the U.S. and outside the United States. There are a number of us who have launched products internationally as well. We've done early diligence in the major markets to have an understanding of our options, and I'm sure we'll provide, you know, updates as we get closer to the commercialization process. We will leverage those learnings to make the appropriate infrastructure decisions.
Great, guys. Thank you very much, and congrats again.
Thank you.
Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Yatin Suneja with Guggenheim. Your line is open.
Hey, guys, thank you for taking my questions and very nice transaction. Congratulations. Just with regard to the estimates that you have provided, especially for DAYBUE, can you just comment on, you know, how should we think about the net price now? I mean, obviously there's a difference between a gross and a net, when you talk about the guidance, what sort of a price you are assuming? That's one. Anything, if you can comment on the compliance, I know might be the discontinuation rate or compliance that you might be seeing in the field.
Yeah, I'll speak to the compliance issue, and then I'll ask Mark to answer the other question. On compliance, of course, we see what the doctors write on the script. But based, as Brendan mentioned, based upon our market research and just our very, very, close interactions with the medical community, we know that a significant majority of doctors are having their patients titrate up, which we again, that's part of our GI management regimen that we recommend, and we think that is a good thing.
We don't know precisely what schedule they're on because they typically, almost always write whatever the dose is for the drug on the script, but tell the patient: "But I want you in the 1st week or 2 or month or 2 to titrate up." We just don't have visibility as to precisely how that titration is going on, kind of a brand-wide basis. As we move forward, we'll get better information, we'll get a better lens on that as we go forward. I think the right way to think about it is, a significant majority of patients are titrating up for the, you know, relatively brief period of time.
Then again, at this point, we have, you know, some patients that have had one refill, some patients, a few patients that have had two refills. I think by the time we get to the next quarterly call, not the call coming up in a couple of weeks, but after that, we should have better information at that point.
Okay, Mark, you wanna
I think just to follow up on that,
you know, as we gave our guidance, we did think about a range of what just Steve mentioned there, compliance, because that really does impact the kind of net price for a patient. Then obviously, as we've talked about on previous calls, we do have, you know, mandatory government discounts that impact net pricing, and that we are accounting for both in our results and in our forecast going forward. You know, at this time, that, you know, those numbers are, you know, are variable, so we're not, you know, giving information on gross to net at this time.
Got it. One more, if I can. Can you maybe also articulate for us the market opportunity outside U.S., both in patient terms and maybe the dollar terms? Again, it does not have to be accurate, but, you know, just as a % of U.S., how should we think? Thanks.
Yeah, thanks, Manish, for the question. At this juncture, we're just gonna really speak at very high levels. You know, as I mentioned in my remarks, the incident rate worldwide is very consistent. That would tell you that the prevalent population in Europe is somewhat larger than U.S., somewhat smaller in Japan. In terms of pricing, what we typically see with rare drugs is lower prices outside of the U.S. For rare diseases, of course, they're significantly closer to U.S. pricing for non-rare disease, most non-rare diseases, I guess I would say. In terms of the overall population size, in terms of patients and revenues, we'll get back with, you know, more details as we get closer to a launch.
We'd simply say at this point that it's a very sizable opportunity and a very attractive opportunity outside of the current market we're approved in the United States.
Very good. Congratulations again. Thanks.
Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open.
Hi, this is Jeremiah LoRe for Tazeen Ahmad. Congratulations on the exciting news, and thanks for taking our questions. We just have two quick ones. The first being, how long you expect it to take to reach peak sales in both U.S. and ex-U.S. for DAYBUE, given the strong early launch? The second question being, if you think this space can support annual price raises in the future. Thanks, and congratulations again.
Well, I'll take the second question because it's really straightforward. We just don't comment on pricing adjustments in the future. You know, I think the right way to think about the dynamics of the launch is, you know, as is the case with most of our diseases, of course, we have a sizable prevalent population for Rett syndrome. This is a fairly sizable market in rare disease. We've indicated that the prevalent population is 6,000-9,000. Addressable population today is about 4,500. However, what we often see in rare disease is, you often see that gap between diagnosed patients versus the prevalent population, particularly when there's no drug approved to treat the disorder.
When you have a drug approved, many times you see that gap narrow. We would expect that we will see the diagnosed population increase. The rate at which that increases, the rate at which the incident population feeds in beyond the prevalent population are, of course, going to be important determinants of when we peak. We haven't guided, and we're not guiding at this time in terms of when we would peak, but I would say the dynamics are very similar and across rare diseases, typically, and when you have no drug previously approved, and that is you have a very sizable prevalent population that you get access to as quickly as you can. We're obviously very, very focused on that. And just very, very happy with the results we have today.
Understood. Thanks for taking our questions, and congrats again.
Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Tessa Romero, J.P. Morgan. Your line is open.
Hi, Steve and team. Congrats on the progress here. First question from us is, if you can provide any further granularity on what the right way to think about it for your persistence that you're assuming for the $45 million-$55 million in net sales for 3Q? Curious, are there any changes with respect to what you are hearing on how long physicians will try the drug before assessing for treatment benefit? Then the second question is a little bit more big picture. It's really around what the key focus areas for physician education are for you going forward. Now that you have some time under your belt, where are there gaps in knowledge that you're hoping to fill? Thanks so much.
Okay, Mark, I'm gonna ask you to take the first question, Brendan, then the second and third.
Yeah, I, you know, I think for us, clearly, we've done a range. You know, keep in mind, at this early stage of the launch, right? It is much kind of, you know.
... the impact from new patients as it is from continuing patients. The, as we mentioned in our prepared remarks, you know, most of our patients, you know, only had, have had, like, one, maybe two scripts. They're very, you know, early in their life of treatment. We're very encouraged by, you know, what we're hearing, you know, through, you know, our, you know, Family Access Managers, and our sales reps of how, you know, ADPs as well as caregivers really want to give, you know, their loved ones and patients, you know, a really fair shot at seeing the benefits that come from DAYBUE. With all of that, you know, that's considered in kind of what we look at for forecasts very, in the very near term.
The long term, we, of course, we're gonna be monitoring, compliance levels and persistency. As I said earlier, you know, that information at this, you know, couple months into launch, you know, we really don't have great actual data for yet.
Yeah. Thanks, Mark, and Tess, thanks so much for each of the questions. When it comes to clinical benefits, I think one of the more heartening things that we've seen since the introduction of DAYBUE has been the interaction between caregivers and our Family Access Manager team. The degree to which there are conversations taking place about the day-to-day benefits, even early on, that these families are seeing, and as I said in my prepared remarks, sometimes, you know, they can be improvements that a family's seeing for the first time in a very long time, or they can be improvements that are, or they can be changes that are noted for the very first time ever.
Those are paramount to the conversations that are going to take place between the caregiver and Rett treaters about the progress of patients on DAYBUE over time. We are certainly working to facilitate those discussions and create that dialogue so that clinicians have a very clear understanding of the day-to-day benefits that are seen. Even before we launched DAYBUE, clinicians would remind us that the caregivers spend 99.9% of their time with these patients, and so they look to them to find what those clinical benefits are that they're seeing, that they wish to continue to pursue.
Of course, they, during Rett clinic days, will be able to see for themselves, the changes that are noted in the young women, girls, boys, and men that are treated with DAYBUE. Over time, this question of education, it does come back to a little bit of what I just said, making sure that there's clarity on what treating the core symptoms of Rett syndrome really look like and how those translate into day-to-day benefits that we're already hearing these families want to, not only are noticing early, but are hoping to see, and improve over time. That's definitely, one of our key areas of focus.
A second, which is, I think, equally important and why we created this surround sound around patient support, is around understanding the label and making the very best decisions on GI. You know, we have very explicit language in the label to make sure that you discontinue anti-constipation medicines, which I think has been very helpful, also to make sure that they're progressing through a logical process to make sure they're managing diarrhea if and when that occurs.
Great. Thanks so much for taking our questions.
Thank you.
Thank you, Jess.
Thank you. Please stand by. Thank you. Please stand by for our next question.
Our next question comes from the line of Ami Fadia with Needham. Your line is open.
Hi, good evening. Congratulations on the great initial performance and the deal today. I had a couple of quick questions. Firstly, has there been a change in kind of how you are thinking about the compliance rate, as you know, prior to the initial launch versus today? Can you give us some color on how long do you think patients need to be treated before the caregivers and the physician can start to see some of the benefits from treatment, or at least what are the expectations that are being set with the caregivers when the patient starts treatment? I have a third very quick question on payers. You mentioned 20% of the target population, coverage decisions have been made. When do you anticipate decision for the remainder?
Thank you.
Yeah. Thanks much, Ami, for the questions. I'll address the first one. Kathie, I'm gonna ask you to address the time to-
Okay.
benefits, and then Brendan, I'll ask you to address the payer question. In terms of compliance, and maybe I should just confirm that we're all speaking the same terms. By compliance, we mean compliance to dose. How much of 100% of the dose is a patient actually taking? By persistence, we mean how long do they continue taking the drug. In compliance, we expected that a lot of physicians would titrate and find the optimal dose or the best dose for each patient on a patient by patient basis. From that perspective, it's gone exactly according as to plan and as we expected. The...
We just don't have sufficient data yet to have a good picture on that compliance regimen, nor at what dose will patients ultimately land. Again, we'll get better information on that as we go forward. Today, we have refill rates, but a refill rate doesn't really tell you much at this juncture, and particularly given that, you know, we just have a month, or in some cases, two months of refills, so we don't really have a lot of that data. We will get as we go forward. I wish I could give you more clarity today, but we don't. I would say, just in terms of our expectations on compliance, it's very consistent so far with what we expected. Kathie, you wanna take the second question?
Yeah. On the time to benefit and setting expectations to benefit, maybe I'll speak first about the clinical trial data and how clinicians are initially using that to set expectations. Then I'll ask Brendan to chime in about what we're hearing, so far, from the launch. To remind you, the Phase III trial was a 12-week trial, where we saw statistical significance from placebo, but we did have 1-month and 2-month time points and did see an improvement at those early time points as well. As we've previously talked about, we also followed patients in open-label extension studies, and beyond that first 3 months, we continued to see benefit on both of our clinical outcome measures, the RSBQ and the CGI-I. Over the long term, that benefit increases, and becomes greater in magnitude.
Based on that data, I think a lot of the clinicians have sort of set the expectation that parents should try and stick with it and be on drug for about three months or 90 days. That it takes that long to see benefit. I think I'll pass it over to Brendan to describe the reports we're hearing at this early stage is certainly we're very heartened to hear of improvements and benefits much earlier than that from caregivers and clinicians.
Yeah. Thanks very much, Kathie. I would go to the first point that it was a study with a 12-week endpoint. I think practically speaking, physicians are saying a couple of things: with no approved therapy prior to DAYBUE, with a study that demonstrated benefits, and increasing benefits through the 12-week time period, they really are encouraging families to give the product time to demonstrate that benefit. They are setting them up for a treatment journey that would be at least three months. Sometimes they even set it up to say: Please give it even longer than that. I think the mindset is, this is a product that you could be on for the duration, for the long haul.
Just building on Steve's earlier comments, you know, the point around titration is essentially to get to the best dose that patient will benefit from. If you start at a low dose, then you would expect that the magnitude of benefit that you would see might also take some time as you get to that optimal dose. I think the community is working to make certain that this is a therapy that you're establishing for this patient and family for the long haul, and setting appropriate expectations for that initial trial period. Then your last question was around payers. We have about 20%, give or take, of covered lives that have written plans that cover DAYBUE.
I'll just remind you that because it's such a rare disease, there are certain payer plans that may never make a coverage decision and may manage the product through the medical exception and letter of medical necessity process. We're obviously already dealing with that and very prepared to handle it. As for some of the Medicaid state decisions and some larger plans, I would expect we will continue to see and report back on increased payer coverage decisions in the next, I would say, 90 to 180 days.
Got it. Thank you.
Thank you. Please stand by for our next question.
Our next question comes from the line of Jason Butler with JMP Securities. Your line is open.
Hi. Thanks for taking the questions, and let me add my congrats on all the positive news as well. Couple from me. First one on NNZ-2591. Any early thoughts on how we should think about the development path here? Is it essentially following the same roadmap as trofinetide? From a mechanism perspective, is there any potential to combine the drug with trofinetide? On Nuplazid guidance, just looking at the guidance for 2Q and then full year, it looks like you're essentially even at the top end of the range, pointing to relatively, you know, flat sales in 3Q and 4Q over 2Q. Just any thoughts on the guidance there or the trends we might see in the second half of the year? Thanks.
Yeah. Thanks, Jason. Mark, you want to take the last question, and Kathie, we'll go back to you on the first question.
Mark, I think you're on mute.
Mark, can you hear me?
Sorry, I was on mute.
Yeah, no worries.
On Nuplazid, you know, we're continuing to see, you know, steady to, you know, above steady volumes on Nuplazid, and we're pleased with the performance, thus far this year. We expect to continue that through the remainder of the year, and that's reflected in, you know, our, you know, kind of narrowed guidance at this stage.
Okay. On NNZ-2591, on the mechanism question, both NNZ-2591 and trofinetide are modified, more stable derivatives of parts of IGF-1. We think they may have a similar mechanism of action, but there's no reason to believe that they might not be synergistic or additive. We don't have any data, but I wouldn't rule that out at this early stage. That's something we'll think about and explore, now that we have access to the compound and can start to work on it. Similarly, I think it's a little bit too early to comment on what a development plan might look like for Rett, but we'll mention that NNZ-2591 has already completed phase 1 study. If we were to move forward, we could start right away with phase 2. It's already clinical stage.
Okay, great. Thanks for taking the questions.
Thank you. Please stand by for our next question.
Our next question comes from the line of Paul Matteis with Stifel. Your line is open.
Hi, this is James on for Paul. Thanks for taking our question. Just a quick payer one. I believe based on, you know, some prior commentary, you mentioned that a lot of decisions could happen pretty quickly, within 90 days or so. Just wondering if that 20% number is kind of, you know, tracking with your expectations and how you quickly you expect that number to ramp. Just second, you mentioned, you know, these policy decisions are coming in line with your expectations, and curious if you could expand on that a little bit and kind of what exactly was baked into those expectations. Thank you.
Sure. Brendan?
Yeah, sure. Thank you very much for the question. I would say that the dynamics around access for patients are largely what we expected. As I said, in the early days, it's an interim period. I still consider us in that 90-day period, and most of what we've been reporting on would be any decisions made for coverage of patients, obviously, before that, you know, 30, 60 days into the launch. In those cases, the vast majority of patients received access through a medical exception, letter of medical necessity, prior authorization process, because there is no, there was no written policy.
As the written policies have come in, I think what we are noting is that payers have heard the message that this is a highly debilitating disease, that they understand the affected patient population and the size of that audience. For that, we're seeing a number of the early plans that suggest an understanding of our label and the addressable population, male and female, and much in line with what the label would suggest. The earlier plans that have written policies have not been surprising in terms of those that tend to lead the way. I expect that as we get into this really first full quarter of launch or second quarter, sequentially that we're getting into, that we'll start to see a ramp in payer policies.
As I said, over the next 90 to 180 days, I think most of those plan decisions will likely come to fruition.
Makes sense. Thank you.
Sure.
Thank you. Please stand by for our next question.
Our next question comes from the line of Kyle Qian with Canaccord. Your line is open.
Hello, guys, this is Kyle Qian speaking for Sumant Kulkarni. Congrats on the progress. One question from us. You mentioned titration up in the majority of the patients. Could you disclose where the dose in those titration is relative to the recommended dose on the label? Would it be 50%, 25%? Just any number would be great, thanks.
Sure. We just don't have hard data on that, because as I mentioned, while we know a significant majority of physicians are titrating up, they almost all of the time do not write the titration schedule on the prescription, so we just don't see it. We know through our Phams network that are interfacing with families on through the access process and thereafter, we know that, through information collected from them, that again, very much a benefit to titrate up and that the titration schedule is relatively quick. So it's within a week or two. Sometimes it's up to a month or so, but for the most part, they titrate up pretty quickly.
Again, as we get further into the launch, we'll have better information on that, but today, that's as much as we know.
Okay, thanks.
Thank you. Please stand by for our next question.
Our next question comes from the line of Jeffrey Hung with Morgan Stanley. Your line is open.
Hi, this is Michael Riad on for Jeffrey Hung. Thanks for taking our questions, and congratulations on the launch progress. First, you said the majority of patients are up titrating in the first few weeks in the month. Does this, like, at a high level, open up the potential if needed for a down titrating instead of discontinuations? Thanks, and I have a follow-up.
... we'll answer that first. Just to be clear, the data we have on trofinetide in terms of the effective dose is comes from our clinical studies. In rare times, you just don't have the luxury of doing a lot of dose ranging, the data we have in our LAVENDER Phase 3 study is all at one dose. We do have data from an earlier Phase 2 study that Neuren conducted, a successful Phase 2 study, where they saw a statistically significant benefit that was approximately two-thirds of the dose that we are approved at. We knew that, we knew through the experience we had in our LAVENDER study and beyond that titrating up or down can be very beneficial.
We were pleased to make that part of our titrate or our GI management recommendations and get reference to that in the label. In terms of what physicians are actually doing, they're doing what we believe they should be doing, and there's a real benefit to it, and that is titrating to get to the best dose on a patient-by-patient basis.
Okay, thank you. That's very helpful. Maybe just a second question on NNZ-2591. Could you talk about the rationale for pursuing Fragile X? Was there anything you learned with DAYBUE and Rett that gave you greater confidence in prioritizing Fragile X in your discussions with Neuren? Thanks so much. Congrats.
Yeah.
Yeah.
Kathy's gonna take that.
For NNZ-2591, of course, before we licensed it and we did diligence, and Neuren has conducted preclinical studies in a mouse model of Fragile X, which look, I think, quite positive. That combined with that, it is a clinical stage compound, I think, gives us good confidence in moving ahead in that indication.
Thank you. Ladies and gentlemen, we have time for one more question. Our final question comes from the line of Uy Ear with Mizuho. Your line is open. Uy Ear, your line is open.
Hi. Sorry, I didn't hear my name. Congrats, guys, on the good start to DAYBUE. I guess my first question is, would you be able to provide the split between the in terms of %, you know, the % of patients who've rolled over from the long-term extension study and the de novo patients for the first quarter? I guess the second question I have is, you mentioned, you know, patient, you know, the docs are titrating these patients. Just curious, Yeah, I don't know how long this, you know, just wondering, are you seeing scripts lasting longer than a month, you know, long on the first scripts because of the need for titration?
just curious about how long it would, you know, would take for patients to refill their scripts. Thanks.
Yeah, thanks much for the question. I'll take the first one, and Brendan can answer the second one. Just in terms of the proportional split between rollover patients and total patients on therapy, we're not providing that information at this juncture. Patient data or patient numbers, script numbers, et cetera, are the type of thing that we think it's still moving a lot. There's still a lot of moving parts in general, and we felt like at this juncture, the best information that we can provide you is to give you a range for what we expect revenues to be in the next quarter.
The range that we provide is based on very solid data. We have a very good view of what we expect the range to be going forward. It's reflective of the very strong start that we have at this juncture. We've decided to go that route in lieu of trying to give a lot of individual data points that in isolation would be more difficult to synthesize and get to the right number. We felt like it's better just to give you the range, give you the guidance range.
Yeah, thanks for the question on titration and maybe supply of product as well. I think we said it in our, in some of the early, earlier remarks, but oftentimes, the clinician will be telling the caregiver verbally what they want, what they think titration should be. The written or prescribed dose that shows up at our specialty pharmacy is more often perhaps for the appropriate dose for the weight band for the patient, with a verbal titration schedule that is agreed upon between clinician and family. That can vary based on an individual clinician's experience or conversations they've had with people that have more experience with DAYBUE, so there's a reasonable degree of variability there.
It's difficult to tell you over time what might happen as they kind of settle into the most appropriate dose. The initial doses don't, the initial approved or prescribed dose may not give us, you know, full insight into that.
Okay. Thanks. Can I sneak in a last question? Sorry. You know, you provided guidance, I guess, for the revenues. Just wondering if there's anything in expenses that we should sort of watch out for?
Mark, you want to take that?
Nothing on expenses to watch out for. We'll give a complete report when we get into our, you know, our full second quarter earnings in another few weeks.
Okay. Thank you.
Thank you. At this time, I would now like to turn the call back to Steve Davis for closing remarks.
Great. Thank you, operator. Thanks again everyone for joining us today. We look forward to updating you on our progress.
Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.