Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics Sephience FDA Approval Conference Call. All participants are on a listen only mode. After the presentation there will be a Q & A session. Today's call is being recorded. I would now like to turn the call over to Ellen Cavaleri, Head of Investor Relations. Please go ahead. Thank you for joining to discuss the FDA approval of Sephience. I'm joined by our Chief Executive Officer. Dr. Matthew Klein, our Chief Business Officer Eric Pauwels, and our Chief Financial Officer Pierre Gravier. Before we begin, I refer you to. Our forward-looking statements, which are posted. On our website as well as the risk factors in our most recent 10-K. I will now pass the call over. To our CEO Dr. Matthew Klein. Thank you all for joining us today at this pivotal moment for PTC and the PKU community. I am very excited to announce the FDA approval of sepiapterin, a once-daily oral therapy for children and adults with PKU that will be commercialized under the trade name Sephience. Sephience was approved with a broad label inclusive of all disease subtypes at all ages from 1 month of age upwards. I want to begin by thanking all the patients and families who have participated in the Sephience clinical studies as well as the physicians, dietitians, and care teams at our clinical trial sites. A very big thank you to the patient organizations including the National PKU Alliance and Flock for their continued partnership. As we have discussed, we expect Sephience will be the foundational product for PTC's sustainable growth and path to profitability and I'm incredibly proud of our team's efforts to help reach this important milestone. With FDA approval, Sephience is positioned to become the new standard of care for children and adults living with PKU. The data from the Sephience clinical program demonstrated the therapy's ability to provide robust phenylalanine level reductions and the potential for PKU patients to liberalize their highly restrictive diets. Efficacy has been demonstrated across all key disease subgroups including BH4 non-responsive patients with classical PKU. In addition, Sephience has been demonstrated to be safe and well tolerated. There is a significant Sephience commercial opportunity. There are an estimated 17,000 PKU patients in the U.S. with over 300 additional individuals diagnosed annually through newborn screening. Despite there being two approved therapies, there remains a significant unmet need as the vast majority of patients are not on any therapy and would benefit from a safe, well tolerated, and highly effective treatment. We believe the Sephience revenue opportunity in the U.S. exceeds $1 billion given the strength of the clinical data and the ability for Sephience to address all key patient segments. In addition, we have experienced customer-facing teams. To maximize the revenue opportunity, our teams have demonstrated the ability to successfully commercialize rare disease therapies including starting and maintaining patients in genericized and competitive markets. Furthermore, we have guided to having intellectual property protection at least until 2039. We are all incredibly excited to have reached this approval milestone and to begin making Sephience available to all those who may benefit. I will now turn the call over to Eric who will provide details on our U.S. commercial launch. Eric? Thank you Matt. I want to begin by expressing our immense excitement at reaching this significant milestone. For the past decade our customer-facing teams have successfully launched multiple products globally. None hold greater importance for the future growth of PTC than the launch of Sephience in the U.S. today. Our goal is to swiftly deliver this highly differentiated therapy to the thousands of PKU patients living with the burden of this lifelong debilitating disease. We have a world-class commercial team ready to successfully launch Sephience. Our teams consist of experienced in-house employees with rare disease experience across all functions including marketing, sales, medical, market access, patient engagement, and patient support services. We are well positioned to leverage our core launch capabilities and more than eight years of experience in commercializing Emflaza to drive early and rapid Sephience adoption. We are ready to launch and expect first shipments to U.S. patients in August. I would like to share some details on the key aspects of our Sephience launch plan including the PKU landscape, our customer engagement strategy, our access and pricing strategy, and finally our launch metrics. It will be clear that we have the knowledge, experience, passion, and plan to realize the full potential of this Sephience commercial opportunity. I will begin with a review of the PKU landscape and our customer engagement strategy. Our team has profiled over 1,200 potential prescribers at 104 PKU Centers of Excellence. These prescribers and centers will be our immediate focus as they account for more than 80% of the PKU claims data and treat the highest concentration of U.S. patients. As Matt mentioned, our data support the ability to address all key segments and the full spectrum of the approximate 17,000 patients in the U.S. In terms of sequencing, our initial focus is on the patients who recently failed or are not well controlled on existing therapy and those who could be switched from existing oral therapies. These patients account for approximately 40% of the PKU population in the U.S. Our focus will then progress to treatment-naive patients who could benefit from a new effective treatment. To date, our customer-facing teams have focused on providing disease state education but will now pivot to educate and promote the benefits of Sephience to health care providers. To complement our face-to-face promotional efforts, we have developed digital tools, social media channels, online disease awareness campaigns, and advanced customer analytics to drive brand awareness of Sephience. In addition, we continue to engage with the PKU community to empower patients and caregivers to have informed discussions with their healthcare providers about the potential benefits of Sephience. Our key initiatives with organizations such as the National PKU Alliance and Flock include patient education programs and PTC Reimagines PKU, where patients and caregivers opt in and share personal experiences with the community. We look forward to continuing to build on these already strong relationships with these key stakeholders. Now I will detail the work our teams have done on market access to ensure immediate uptake at the time of launch. Effective market access involves the work of our regional account managers, medical science liaisons, market access experts, patient engagement specialists, and case managers. These teams are dedicated to educating healthcare professionals on the benefits and differentiated profile of Sephience and ensuring PKU patients have access to care. I want to specifically emphasize the crucial role of our PTC Cares team in the launch. This group of case managers provides white glove service to each patient, offering insurance verification, copay assistance, and coordinating specialty pharmacy shipments to help patients quickly start and stay on Sephience therapy. The PTC Cares team is ready today to process patient start forms and address Sephience inquiries from patients and healthcare providers. Our market access teams also bring years of real-world experience with Emflaza in efficiently managing prior authorizations and step edits and are ready to proactively manage insurance requirements. I also want to highlight PTC's longstanding and unwavering commitment to ensure that all eligible patients receive access to our treatments. All commercially insured PKU patients can expect a $0 copay per month upon enrolling in our PTC Cares program, and we anticipate that most individuals with Medicaid and Medicare coverage will have nominal out-of-pocket costs. I will now detail our payer discussions and pricing strategy. A key aspect to the success of the Sephience launch is its compelling value proposition for payers. Throughout the year, our team has engaged with national and regional payers in preparation for launch. Based on the robust Sephience data from our clinical trials and insights from our extensive market research, payers recognize the unmet need, the disease burden, and the clearly differentiated profile and strong value proposition of Sephience. Both commercial and government payers indicate they expect very low barriers for access to Sephience with typical prior authorization requirements linked to the indication on the label and only a small number of payers potentially requiring step edits. In setting the price for Sephience, our primary objectives were to leverage brand differentiation and minimize payer restrictions while maintaining a narrow global pricing corridor as we introduce Sephience in the U.S. and other key markets worldwide. The U.S. wholesale acquisition cost of Sephience is $41,000 per month based on an average patient weight of 45 kg. This average weight is estimated from our clinical studies and long-term claims data of sapropterin in the U.S. Health care providers will determine the prescription dosage for each individual patient and adjust dosage accordingly over time. Sephience will be available in 250 milligrams and 1000 milligrams sachets that is easily diluted in a convenient once-daily oral formulation. The final net price to payers will be determined by compliance, adherence, and our payer mix, which we expect to be approximately 65% commercial and 35% Medicaid Medicare. Finally, we would like to share the launch metrics that we intend to provide externally. We expect to share the number of patients on commercial therapy, patient start forms received, the payer mix, and healthcare provider prescribing and payer dynamics. We plan to initially share these metrics along with the progress from our international launches starting at our third quarter earnings call. In summary, we are incredibly proud to make Sephience available to the PKU community in the U.S. and worldwide. We believe the clinical profile and our expertise in launching rare disease therapies position Sephience to become the future standard of care. We stand ready to support all children and adults with PKU to access this new, highly effective treatment. I will conclude by extending my heartfelt gratitude to the PKU community for its unwavering support of PTC Therapeutics over the years helping us reach this important milestone of FDA approval. Our team is excited to continue our partnership with the PKU community long into the future. I will now turn the call over to the operator for Q&A. Thank you. Ladies and gentlemen, at this time, if you would like to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. First question coming from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open. Hi. Huge congratulations to the team on this approval and great day for the PKU community. First question I had for you is you made a comment that you're targeting about 80% of the focus from the claims data. How large is the claims data relative to the actual prevalence since in this indication we know it because of newborn screening? Kristen, thank you for the question and the congratulations. It is indeed an exciting day for the community. I just want to emphasize first that we intend to target the entire population of 17,000 patients, given the label and given the data supporting that we can reach all of those segments. I think, I don't know if Eric, you want to break down a little bit of what those data you talked about referred to, but really this is just, Kristen, these are just sort of overall guides and directional in terms of early efforts and are all estimates. I'll let Eric provide a little more detail. Yeah, Kristen, thanks for the question. You know, we're really targeting these Centers of Excellence. There's 104 of them and approximately 1,200 healthcare providers really sit in these, what we call tier one or upper decile. These are physicians that have a significant amount of PKU patients. What we're doing right now is targeting the entire population. There is really a two-pronged approach in terms of our targeting strategy. The first one really is obviously to make Sephience available to all patients in the U.S. However, we're focusing really on those centers that are engaged with treatment already as well as differentiating Sephience with those patients who have failed on existing therapies. If we look at our overall deciles and the prevalence, the 80% really accounts for approximately 104 of those Centers of Excellence. Okay, thanks. I know you said that the naive patient group is a big focus in addition to the ones that previously failed or couldn't tolerate other medicines. Do we have a sense of the breakdown of naive patients that are naive just because the subtypes of PKU they had weren't appropriate for other medications such as classical, or is it other reasons? Just that there's no impact to diet liberalization? They didn't really have any interest to get on any drugs in the first place? I'm really just trying to understand why there are so many patients with PKU that remain treatment naive despite two therapies on the market before today. I think, Kristen, it's a little. It's what you said. It's hard to pinpoint the exact breakdown, but there are a number of factors that account for that sort of therapy-naive. Part of it is an understanding from past experience that there's certain patients, that is classical patients, who tend not to have benefited from sapropterin, either generic or branded. That's one. Then there's others that were tried but didn't fail or didn't succeed or weren't able to get enough of a benefit that it made it worth taking a therapy in addition to the highly restricted diets. I don't know that we have an exact breakdown of which falls into both camp, but they're all grouped in an area. As Eric alluded to, a lot of these patients have had recent contact with specialty centers, with these Centers of Excellence. That's really going to be part of that first wave that we're hearing about that are on some of the waiting lists that we've all heard about. In addition to those who are already on Kuvan or sapropterin, the branded or generic. Our data consistently show that patients who have any benefit in Phe reduction with sapropterin have had a much greater reduction on Sephience. That's why we're seeing that first wave consisting of both of those groups of patients. Okay, and one last question for me. In the instances where there will be step edits, is a blood test to determine B levels good enough here, or what about if the patient has said that they've had prior exposure with the branded drug? Thanks again everyone. You want to cover that? Yeah, I think in our peer meetings what we know is that step edits are really easily managed. These patients here, especially that target group, which is very substantial, that have either failed or are on current therapies right now that are looking for more effective therapy, there's already prior documentation. What we've seen with most of our payer research as well as the meetings that we've had is that there will be very minimal step edits, and it will be a very simple test that we can do in a matter of days or weeks if required. The vast majority of payers would actually require prior authorization just to the label. Our face-to-face meetings have really documented that. Keep in mind that these healthcare providers and these centers are experts because they've had current therapies and they've been able to get C reductions very quickly and been able to get that information back to us so that we can get patients on Sephience. Thank you. Our next question coming from the lineup, Judah Frommer with Morgan Stanley. Your line is now open. Yeah. Hi guys. Congrats on the approval from FDA. Very exciting. Just a couple follow-ups, I guess. First, just in terms of patients that have failed prior therapy, how engaged are they with their physician or with their care team? We've been hearing that there's a risk of patients being kind of lost to follow-up the older they get and the further away they've gotten from effective therapy. Second, you mentioned kind of a $1 billion peak sales opportunity, which is probably a bit higher than consensus. Is there anything you'd highlight specifically that makes up for the delta between that $1 billion and where consensus peak sales are currently? Is it market share? Did you notice anything in pricing or anything like that? Thank you. Thanks for the questions. Judah, let me tackle the second one first and say I think consensus is where it is and there's a broad range of estimates. I think it's not just one. I think now that we have the price, everyone can now appropriately put what we think in terms of what pricing looks like. As we said, we intended to price at a premium, particularly given the highly differentiated features of Sephience and the discussions we've had with payers based on the value that the therapy brings, both in terms of efficacy as well as safety, which of course is very, very important. We've always said if you look at the population of 17,000 patients and look at the fact that the vast majority of patients are not currently on a therapy and take estimates of market penetration for a highly differentiated orphan therapy, plug in the price, what we said, what the average price is based on 45 kilos, and the math gets you pretty close to our $1 billion estimate and maybe in some cases more. We've been very clear that we believe this is at least a billion dollar opportunity in the U.S. and of course there's also the contributions ex-U.S. We're incredibly excited about the European approval. The German launch is underway. The European launch is underway and we expect there to be contributions outside the U.S. from Europe, from Japan, from Brazil, and from other countries around the world. As we said, this is a global launch. Regarding your first question, there are, as Eric mentioned in his presentation, these patients who may have failed in that first wave who are still pretty attached to the centers just because they're not on the therapy. There's still a need to interact with the centers, the dietitians, because diet modification, diet, nutrition, supplements are then the mainstay of therapy for those who are not on pharmacologic treatment. There are those who may be a little more distant from the centers just in terms of time. I think this is a misnomer. They've been called by some lost to follow up. What we hear from the patients is we're not lost. We're actually right here. We have heard that there's a great deal of interest for many to get on a therapy that could be effective in reducing phenylalanine, could be effective in allowing for diet liberalization, and be safe and well tolerated. That group may not be the first wave we're targeting in the launch, but we already have plans and already have work underway to begin to make sure that we access those patients. As Eric said, we are very much committed to making sure that any individual who may benefit from this therapy can receive it. Great. Thank you. Thank you. Our next question coming from the lineup, Tazeen Ahmad from Bank of America. Your line is now open. Hi guys. Good evening. I apologize for this background noise. I have a couple of questions. Can you clarify if you're going to be doing a free drug program at least initially as part of the launch? Secondly, I know it's a little bit of a range, but curious on how you're thinking about the time it's going to take, at least initially from the time a doctor writes the script until the patient receives drugs. I have one more follow up after that. Thanks. Thank you very much for the questions. Eric, do you want to take those? Yeah, sure. Thanks for the questions, Tazeen. Right now we have no, we're not planning on offering free drugs simply because we know that Sephience is a very convenient and oral therapy where we can measure Phe within a matter of days. Payers like that, they like to see a very rapid response. Payers right now will look more for Phe reduction than anything else and we can measure that very quickly. When we presented the profile, payers have said that there's no need for free drug here, so we won't be rolling out a program on that. With regards to time, from patient start form to actual fill, we anticipate that to be very dependent on whether or not there's a step edit or prior authorization. However, I would say that Centers of Excellence are really quite experienced at this. They've had treatments, high cost treatments for PKU and rare disease and they've been able to get products through in matters of days or weeks. This is going to depend, of course, depending on whether it's private commercial insurance or Medicaid or Medicare. We would anticipate shipping products sometime in the next few weeks to patients here in the U.S. The timeframe could be days and probably no longer than a few weeks outside of a step edit. Okay, thanks, Eric. The last question is how should we be thinking about gross to net maybe for the rest of this year? We know it will improve over time. If you can give us some guidance for modeling. Thanks. Yeah, sure. I think that's going to vary a little bit because it's going to depend on the payer mix. Right now we're estimating approximately 65% of the patients that will be on commercial plans and then about 35% will be on Medicare, Medicaid, or some kind of government plan. In the initial phase of the launch, we could have probably more private plans initially and then over time that would recalibrate. It's going to be kind of hard to give you that specific number right now, but I can tell you that that will be one of the metrics that we'll be providing in our upcoming calls. Thank you. Our next question coming from the lineup, Ellie Merle with UBS is now open. Hey guys, congratulations on the approval and thanks for taking the question. Just in terms of the patient segmentation, you mentioned that about 40% of the U.S. population has either failed or are not well controlled on therapies. I guess what's the mix in that 40% of those who have failed versus those that are not well controlled? I guess of those that have failed, how often do these patients still see their physician or are actively under care? I guess of those that have failed, what's the mix between pediatric and adults? Lastly, in terms of the initial uptake, what's your expectation in terms of the mix between pediatrics and adults? Thanks so much. Thanks for the question, Ellie. Just to clarify, I think that the 40% that Eric gave was just those who have been closely or had contact with the centers within the past year. I think in terms of thinking of the overall population, the number we've shared previously that have tried, we said about 70% of patients have tried therapies and maybe about 70% of them have tried and failed. These are all estimates. It's very hard to have exact numbers. The number Eric referred specifically to is what our research indicates of those patients who've been in close contact within, say, the past year or so in terms of trying or failing with the centers, which is why there are folks who have recently expressed an interest in being on a drug or recently tried or failed. It's sort of a prevalent at the centers and would be a logical part of a first wave of patients who might get on drug in addition to anyone who's currently on a therapy that would switch. I don't know. We have an exact breakdown of kids versus adults. Eric, do you want to talk a little bit about how we're thinking about just pediatric versus adult in that initial wave of patients that we treat in the early launch. To Matt's point, thanks for the question. Because to Matt's point, really we're targeting those who have actually seen their physicians very recently. That's a very substantial number. Over 40% of these 17,000 patients have been in their physician's office at least once or twice during the course of the year and have either failed or are poorly controlled on treatment. You know that they're actually very engaged in their treatment. There's another percentage of them, obviously, that are on existing treatments that may benefit from a new therapy. This is a cohort of patients that are very, very engaged in therapy. If you want to call it the low hanging fruit, those are the ones we'll be going after in those 104 centers because we know that they visit their physicians pretty regularly. Your question about how often do they visit? The ones who are actively engaged will visit their offices at least once or twice a year, sometimes more frequently, and of course have different ways of communicating to their physicians. In terms of split between pediatric and adults, we anticipate to have probably a little bit more of the pediatric or, I would say, adolescent population. Given that there is approximately 45 kg in the average weight, we know that there's a very high unmet need, particularly in classical patients and others with high Phe levels. Physicians have indicated that those patients who are younger, in adolescents, are going to be the areas they'll want to treat first because of the high unmet need. Of course, Phe control, diet control, and the long-term cognitive consequences are one of the priorities. We anticipate probably in the initial stages more adolescent and pediatric, but over time we're looking at everyone in that 17,000 population. Great, thanks so much. Thank you. Our next question coming from the lineup, Kelly Shi with Jefferies. Your line is now open. Thanks for taking our questions. This is Jenna on the line for Kelly. We wanted to offer our congratulations on the approval as well. We noticed on the label it seems to mention a restrictive diet. We're wondering how you plan to highlight your diet liberalization data in your marketing efforts and to what extent you expect that to help engage and convert patients. We have a second question, which is that we noticed you mentioned you're looking to switch patients from current orals. Could you comment on potential switch dynamics with Palynziq as well? Thank you. Jenna, thank you very much for the questions and for the congratulations. Your first question was about it saying that and the label saying that Sephience should be used in conjunction with a Phe restricted diet. That's just a fairly standard view from the FDA to remind that a lot of patients start on the diet, they then get a therapy, and that the diet should be monitored along with the therapy so that when diet liberalization or if diet liberalization occurs, it should be done under guidance. That's something that we've heard a lot about from patients in the studies, that the nutritionists work very closely with the patients to ensure gradual liberalization of the diet. I think one thing is for sure true from the feedback we've heard, that our presentations and publications have gotten the word out that in the long-term extension study, the interim data we've reported already to date show that patients have been able to liberalize the diet, those in the Phe tolerance portion of the protocol. We previously presented that 97% of patients in that protocol have been able to liberalize their diet and that 2/3 are reaching above the recommended daily allowance of protein, which again is very important and impressive results for patients. Those data are known. We will leave it to the physicians and the nutritionists and the healthcare teams to work with the patients to ensure that when appropriate, diet is being liberalized in a thoughtful manner. In terms of your second question, regarding switch patients in the current oral therapy and switch dynamic from Palynziq, I don't know. Eric, do you want to comment on what we heard in terms of our physician work on that? Yeah, we had a lot of work with current therapies and obviously if a patient is doing well on Palynziq, that's not going to be our initial focus. We're looking for all patients who are on therapy, who potentially are looking for a more effective oral therapy, the convenient oral therapy. We know that Palynziq has its limitations. It's for adults only. It has a lengthy titration period. There are safety and anaphylaxis issues. Of course, it's an injection that has a certain degree of burden for patients. We believe that Sephience is really going to meet the potential standard of care because it should be the first line oral therapy that provides a broad spectrum of efficacy to all patients, including those who have been on Palynziq. Anecdotally, while we have heard patients who have failed on Palynziq, of course we will provide Sephience therapy, but patients who are stable is not our initial focus. Understood. Thank you so much. Thank you. Our next question coming from the lineup, Brian Abrahams with RBC Capital Markets. The line is now open. Hey guys, my congratulations as well. Two questions from me. First off, just on the price point, I think you talked about a premium to existing therapy. It is substantially higher than what's out there. I'm curious if we. Could talk a little bit more about what shaped your pricing decision and the degree to which that particular price point was tested with payers. Secondly, I was hoping if you could expand a little bit more on the wait list out there at the Centers of Excellence, just the scope of those wait lists and maybe the timelines for center readiness to prescribe and for formulary placement that would enable prescriptions. Thanks. Brian. Thanks very much for the questions. I'll just make a quick comment on the wait list and then let Eric tackle your question about price and then a little more color on the center dynamics. As we've talked about, the feedback we've gotten is that as we did our work in mapping the Centers of Excellence, the care teams of the Centers of Excellence with our understanding that a number of them have generated lists of patients who either expressed interest to get on Sephience as soon as possible or individuals that the centers know would be very good initial candidates to get on drug, whether that means switching someone who's on once-daily oral therapy for one that has been shown to be highly effective and safe and well tolerated, or maybe someone who's tried and failed. For example, we've also had our opt-in program which Eric mentioned on the call. PTC Reimagines PKU and that's an opportunity not only for patients and families, but caregivers and others to opt into us then to provide them information and start the process of helping them get on the therapy. We think both of these approaches will be very helpful in that initial wave of the launch. Again, let Eric talk about the thinking that went into our pricing decisions and then if there's any additional color he wants to give on the wait list dynamics. Thanks, Martin. We've had a lot of engagement with payers not only through market research but also we've had our teams, our field-based teams that have been engaged with many payers. In fact, right now I think the total count is over 220 million lives that have been covered. It represents a very good mix between both commercial and government. What we learned from those payers in talking about not only science and then in market research, in presenting different pricing, is that they realize that PKU has a burden of disease, it's very high, and that there's unmet need still, and that they clearly see the product differentiation based on the clinical profile. What we also learned is that they don't spend a lot of money. There's a very low budget impact for PKU treatment and care overall, especially since there are multiple plans and there are few patients distributed through these plans. When we presented the price as well as the clinical profile, payers have said that there's a high willingness to pay for an effective therapy that works across a broad range of patients and, importantly, something that they can measure very quickly in a matter of days or weeks so that they don't waste time, months, whatever, trying to get through and understand the therapy is quick. HCPs and healthcare providers and caregivers know it's a lifelong disease, but they also want to measure the results of Phe reduction. When we presented price points in research, it's been well received, it's been very consistent with many analogs that have been launched in the last 12 months in the rare disease space. When we've again looked at the profile, they've said they expect minimal restrictions. Very, very minimal restrictions. That would be prior authorizations to the label. There might be a small number of payers that would implement a step edit, but I'd remind you that our PTC Cares team have done this for the last 8.5 years with Emflaza and doing this against prednisone, which is a very low-cost alternative. We'll be able to measure Phe reductions with existing therapies and move them quickly through to Sephience. Overall, I would say payer response has been very positive and we continue to plan further meetings with our payers here over the next few weeks. Super helpful. Thanks so much. Thank you. Our next question coming from the lineup, Sami Corwin with William Blair, your line is open. Hey there. Congrats on the approval and thanks for taking my question. I was curious that there is a stipulation in the label that patients need to be sepiapterin responsive. I was wondering how exactly that's being determined, and then is there any way that you will be able to track or share compliance data as well? Thank you. Yep, sure. Sami, on the first part, sepiapterin responsive. I think this is really something that the agency has included now in all PKU therapies, that basically patients who are on the drug should respond to the drug in the label. They talk about that patients should be started out at the, if you are over 2 years old, at the 60 milligrams per kg dose, and there'd be an expectation that there'd be some lowering of Phe over the first few weeks on therapy. That's really what they were referring to, that there should be some demonstrated lowering of Phe if someone initiates the therapy. We did not highlight compliance data in the initial information that we're going to give. That could be something that we'll look to do later on in the launch as we better understand those dynamics. Got it. Thank you. Thank you. Our next question coming from the lineup, Geoff Meacham with Citi. Your line is now open. Hey guys, congrats on approval. Thanks for taking the question. Just have a couple. It sounds like you expect initial access. To be pretty good, but I want to get your perspective on the use or whether you'll deploy patient assistance programs and how that could help initially. The second question is how would you characterize the level of physician engagement? Preapproval, I guess I'm trying to get a sense for whether you'll see a bolus dynamic at the onset or maybe the steady add as patients come in for regular scheduled visits. Thank you. Geoff. Thanks for the questions. Let me take the second one, then I'll give the first. I'll have Eric talk about the thinking about patient assistance programs and the like. We've had a high level of engagement with both the physician and the patient community. This is for us once we start work in a rare disease that we understand that working with the rare disease community includes the whole community, including physicians, the care teams, including nurse practitioners and dietitians who often make prescribing decisions at these centers, and of course with the patient groups and work very closely with them. We know that there is a great deal of enthusiasm across the board. It's been shared with us from a number of physicians, from a number of patients to get on therapy as soon as possible. As we've talked about, this is a high morbidity with PKU and the potential of having an oral, safe, well tolerated and effective therapy that can lower phenylalanine and potentially enable liberalization of diet is a very compelling profile for patients and for physicians. We're also in this unique situation where the fact that there have been other therapies on the market, there's an understanding in the community of the dynamics of prescribing a drug, what that looks like and those types of dynamics that in other rare diseases when we're the first one, there's a little bit of a learning curve everyone goes on. That's not the case here. There is newborn screening as well. There really is a prevalent population that's ready, willing and desiring to get onto therapy and an engaged physician healthcare team community ready to also engage and get patients on therapy. Eric, do you want to talk a little bit about PTC Cares as patient assistance programs and the way we think about patient support? Yeah. This is something that we've been doing for the last eight and a half years. I think to Matt's point, PKU Centers that we've been calling on, over 104 centers, are experienced in this and have been experienced for years now and decades in not only prescribing oral but injectable therapy, self-administered therapies, but high cost therapy. They understand prior authorizations, they understand steps. They also understand that we have to be exceptional at servicing PKU patients and that's what we are prepared to do. To Matt's point, we've been staffed with experienced teams right now. They will be taking patient start forms as of tomorrow and we will be beginning the process as we do, which is insurance verification. Patients, when they opt into the PTC Cares enrollment, will have a zero copay for any monthly prescription that they have through that process. If there are step edits, our field-based teams coordinate with case managers to ensure that those are done quickly and effectively and brought forward so that patients can be put on Sephience therapy. We have had a really, really good experience with the DMD community and we want that to be translated with that white glove service that our PTC Cares team will now provide for the PKU community. Great, thank you. Thank you. Our next question coming from the lineup, Joon Lee with Truist Securities is now open. Congrats on the approval and thanks for taking our questions. Is there a standard accepted definition of not well controlled on existing therapies who may be candidates for Sephience? Is it a certain plasma level of phe or inability to liberalize diet or something else? Also, do protein needs differ by age and would that guide you in targeting a specific age group? Thank you. Thanks for the questions, Jean, on your first one. Look, I don't know that there's a scientific or exact numeric definition of not well controlled. We know that in clinical trials we have looked at thresholds of a 15% reduction of phenylalanine. Our primary analysis was based on those at a 30% reduction. I think the name of the game for PKU patients, and as Eric said, it's the name of the game for payers too, they tie value to phenylalanine lowering. The idea for a patient, they like to have some lowering, ideally it might be lowering enough that you feel different, lowering enough that you can come back off your highly restricted diet. I think it may mean different things to different people and physicians may each have their different definition. One of the most impressive pieces of data from the Sephience trials was that in the run-in portion, we had 2/3 of patients having a greater than 30% reduction. That's all comers from the full spectrum of disease, including more severe classical patients. We had 75% of patients having an over 15% reduction. 84% of the patients in the trial got to beneath 360 micromolar per liter, which is important for two reasons. One, that's the target threshold phenylalanine lowering, and two, that's the point at which patients should start being able to liberalize their diet. The data, our data really support this, data show that we're getting significant reductions across a broad spectrum and a large population of PKU patients. Your second question was about protein lowering being different at different ages and will that go into our maybe targeting of patients? Not at all. Right. Protein needs. Are there certain age groups that may need to have greater protein intake for growth or development that might particularly benefit from Sephience? Yeah, I think the, you know, look, we would argue that the full spectrum, both age spectrum and severity spectrum, could benefit from Sephience. I would say that what's well understood, and it's the reason why there's newborn screening for PKU, is that neurodevelopment and neurocognition are intimately linked to phenylalanine levels. That's why there's newborn screening, so that individuals with PKU can get on low protein diets as soon as possible to minimize phenylalanine levels and optimize neurodevelopment and neurocognition. This idea that lower is important, that's important across the full age spectrum. I think that we do expect there to be adoption of the therapy at the very early ages. That's why having a label down to one month in the U.S. and no lower limit in Europe are so important. As Eric said, we expect early on that probably 2/3 of the patients will be pediatric and adolescent. Over time we expect to be able to capture the full age range. Great. Thank you so much. Thank you. Our next question coming from the lineup, Luke Herrmann with Baird, your line is now open. Thanks for taking the question and congrats on the approval. Are there any insights thus far? Into your European launch experience that have. Informed your strategy in the U.S. While not the initial focus, can you provide some insight on how strategy. For the treatment naive group, might differ functionally from the initial launch? Thanks. Yeah, thanks for the question. It's early days in Europe, and I would say that one of the advantages here is that we've got global commercial teams that have been doing rare disease commercialization for years. We have a European team that is very understanding of the particular dynamics in Europe. We have an outstanding team overseeing the launch in Germany that certainly understands the dynamics within Germany. We have highlighted that we had an early access program in Germany for two reasons prior to launch. One was to get a number of patients on therapy who could be rapidly converted to commercial therapy upon launch, which occurred on July 15th with the listing of the price and the lower tax. Also, to get experience at the top, get the physicians in the top centers in Germany experienced with the drug so that while they may not have all of their patients in early access, they certainly get familiar with the drug. So far, we're seeing that strategy has paid off. Obviously, in the U.S., we have an incredibly experienced and accomplished set of customer-facing teams, incredibly enthusiastic for this launch. As Eric highlighted, this is a team that's very experienced in understanding every step of the patient journey, all the complexities of market access. Having done this from Emflaza, where I would say there's elements that are much more complex than they'll be for PKU, they stand at the ready to really deliver on the launch. Great. Thank you so much. Thank you. Our next question coming from the lineup, Joseph Thome with TD Cowen and Ellen is now open. Hi there. Good afternoon. Congratulations on the approval. Great to see, especially in a challenging FDA environment. Thank you for taking my questions. Maybe the first one just on the. Responsiveness, the biochemical response period I noticed on the label, you do have to demonstrate that within the first two weeks. I know in part one of the study, about 2/3 of patients had a 30% or greater reduction in Phe and they were biochemical responders, I guess. Is that what we should be thinking about when we think about what payers and clinicians want to see when they think about biochemical responsiveness? Or is this more like an arbitrary, just make sure the drug is showing some level of activity and then perhaps related to that is the initial script, then I guess for a two week period. Are you sampling or kind of how should we think about that transition from demonstrating responsiveness to a commercial patient? Thank you. Thanks for the question. I'll take the first one and then pass to Eric for the second one. In terms while it says responsive. There should be response within two weeks, I think. It also says the label, if you can adjust the dose and see what happens in the next two weeks, there is no magnitude of lowering that has been sort of designated in the label. I think it leaves that open. We've talked about how in our studies we've looked at 15%. That was the qualification to get into the placebo controlled portion of the study. You had 30% of the primary analysis population. Those are well within the framework of what's understood of being responsive. Eric, do you want to talk about how we're thinking about the initial prescriptions and re- offs and the like? Yeah, and I think, you know, thanks for the question again, Joe. We anticipate that patients will receive, vast majority will receive 60 milligrams per kg and the script will actually be for a month. Payers aren't going to pay for just a few days or a few weeks. We know this is a lifelong disease. While we can see a Phe response within days and even weeks, there will be patients that will require different dose adjustments. The vast majority at 60 milligrams per kg will respond to therapy within days or weeks. The script itself is usually going to be dispensed, and once dispensed, usually reauthorization occurs likely within a six or 12 month period, depending on what the payer will require. In terms of Phe reductions, just one thing that's very important to know is that payers really look at Phe reduction as being the primary goal of treatment. Physicians look at Phe reduction, they look at diet liberalization, diet goals and patients look at diet liberalization and goals as well. Perfect. Maybe just one quick one. Will scripts be trackable by third party resources, do you believe or no? No, not at this time. Because we have two specialty pharmacies that will be distributing the product directly to patients, it will not be providing. We won't have IMS data. It will be difficult to track on that front. What I mentioned earlier is that we'll be providing metrics and data during our regular calls, including the number of patients who are on commercial therapy, those who have patient start forms that are in the queue. We'll be providing also physician as well as payer sort of dynamics along the road there, as well as gross to net and some of the other metrics that you normally would expect. Excellent. Congrats again. Thank you. Thank you. Our next question coming from the lineup. Joe Schwartz with Leerink Partners. The line is now open. Hi. Congratulations on the approval and thanks for. the insightful data you shared earlier in the call. My first question is just if you. Could you clarify how many PKU patients are actively managed at the 104 Centers of Excellence which have the 1,200 potential prescribers of Sephience? Then second, I heard you say. That payers will require some lowering of Phe. What is your understanding of how much Phe lowering they'll require? Are there certain thresholds that are commonly cited? Thanks. Joe. Thanks very much for the questions. Do you want to tackle this? Yeah, I think your second question about what payers would require from a Phe perspective, it's just really according to the label, and I think it's going to be based on their own clinical judgment. A lot of times it might be just a matter of whether a patient is getting close to or at target goals. Phe reduction can vary, and it can take a little bit of time. I think that's going to be a medical judgment. Most of the payers will probably. Look at what we've done. Clinical studies with regards to the actual number of patients. When we describe the two-pronged approach with 17,000 patients, again, I would like to make it clear that Sephience is approved for patients one month and older and we're going to be targeting all of these patients. In those 104 centers and those 1,200 healthcare providers, those are really what we would call the tier one healthcare providers. Each one of those centers can see somewhere between 60 - 100 patients. Some of these centers have hundreds of patients. It varies across the board. What we're targeting in that initial group is somewhere around 6,000 - 7,000 patients who are either poorly controlled, they have failed on therapy or on treatment right now and they're seeking new potentially better therapies or more convenient therapies. In that context, Joe, what we're really doing is that first wave is going after those patients who have been motivated to seek treatment or are on treatment. That first wave really is going to be a very large priority for us. Many of these other naive patients will be equally important for us over time. Very helpful. Thanks, guys. Thanks, Sharon. Thank you. Our next question coming from the line of Gena Wang with Barclays. Thank you for taking my questions. Also add my congrats on the drug approval. It is a challenging FDA environment, so this is a big win here. I have a few questions. First is I wanted to ask again, I know several questions already asked regarding the denominator for this 104 Center of Excellence. I think we all understand total patient population is 17,000 and then 40% is 6,000 - 8,000 patients. Out of these 40%, you got the number from what is the denominator? I think several analysts asked from different way. Just try to understand what is your sample size to derive at this 40% of the failed or not well controlled patient population. My second question is what is your expected screening rate for this 40% of patients that will be responding to sepiapterin? Lastly, my question actually two quick questions. Do you expect the bar for Phe lowering level will be higher than Kuvan or generic Kuvan given a higher price and also understanding this drug is more efficacious than Kuvan? Lastly, the fourth question, sorry, lastly is regarding your label. You do have warnings and precautions. I saw there is slightly different warnings from the other drugs, that's increased bleeding events. Maybe if you can elaborate a little bit, would that be any concern there impacting the drug uptake? Gena, thank you for the questions and congratulations. I will say indeed, given in this time of uncertainties and approval delays, we are certainly not surprised but nonetheless quite excited that this came a day early. We're basically on time, and I think it was consistent with what we had believed would be the case. As always, it was really great for this to come through. I'll make a general comment on your first three questions and then have Eric provide as much additional color as we can, and then I'll tackle the fourth question. Obviously, these numbers are based on claims analysis. They're all estimates. There's no hard, in fact, exactly 4,000 or exactly 40% or 60%. These are rough guidelines. We've heard a lot of different numbers at different times that we've referenced, and we basically use these to just have, you know, directional for us to understand. This is a first wave of patients. It's estimated about this many who have been recently engaged with the centers and would be an appropriate first wave. That being said, we've also had direct conversations with a number of physicians that speak a little bit differently about this. There was a question earlier about how attacking therapy- naive patients. We've gotten feedback from some individual physicians that say that that's actually a priority for them. The patients who may not be in that tried and failed, but who are naive, who could really, who are classical patients who could really benefit at this time for having a therapy that could lower their phenylalanine levels. Regarding your question on the bleeding warning, this is not a concern, a significant concern for us, a safety concern. This is in reference to one specific patient, which in fact the FDA has us highlighting in the label, who had a, we believe, a bleeding episode related to concomitant medication known to cause bleeding. As you can see from the adverse event table, bleeding is not listed there. We do not expect it to be a concern, a significant concern. Eric, do you want to provide any more color on Gena's other questions on these? Yeah, Gena. Good question. Gena, I think there is going to be a bar that's going to be different for Sephience or Kuvan or anything else. I think what's going to happen is we have the payers that we've actually spoken to at great length here say that prior authorizations to the label will be really what drives prescriptions, not necessarily Phe reduction. Yes, they're going to be looking at Phe reduction and a lot of them, if they decide to use that, would utilize what we've seen in our clinical studies. We don't see anything very different. All we see is a prior authorization to label and potentially a small number of payers that say they will utilize step edits. We know we can get through that very, very quickly, and again, matter of days or weeks, and then get to the point where we provide the sufficient information to a payer to get them switched. We don't really see that change. I think to Matt's point about the claims database, the 40% is a very significant number, that's 7,000-8,000 patients. These are patients that have actually been on therapy or currently on therapy. They've been highly motivated recently to try a therapy and are interested in new and potentially more effective therapies. For us, that is our first and most important target because it is the low hanging fruit and it's a very substantial number of patients that we can address very quickly and early with our therapy. Thank you. Our next question coming from the lineup. Paul Choi with Goldman Sachs. The line is now open. Hi, thank you. Good afternoon, and congratulations on the approval. Just going back to the. Patient treatment paradigm separate from their blood monitoring. How frequently is the typical patient coming in? Just to help us think about modeling the launch cadence here, is it semiannually? Annually. Just some color there on just how often the patients are coming in versus a blood test would be helpful. I had a follow up question. Sure. Paul, thank you very much for that. Questions and the congratulations. I would say that when we think about engagement with the center, there's engagement with the physician and coming into the clinic. There's now, in the age we live in, frequent not actually coming into the clinic, but frequent contact with the sites in terms of talking to nutritionists, dietitians, monitoring, and those types of things. I think what's good here is it's not only a matter of someone coming in for an annual check or twice a year check, but there's also frequent regular communications that occur that can also enable a triggering prescription. Great. My second follow up question. In terms of guideline updates, just sort of what you expect, the rough timing for that would be for PKU societies and other medical societies. Can you maybe just remind us what the timeline is for potential regulatory decisions in the other remaining major markets such as Japan and other major markets? Thank you very much. Yes, thanks Paul. I'd say just on your last question first, we expect Brazil approval in the second half of the year and Japan in December. Those are the two markets that we've called out. We expect approvals in a number of other countries in between and along the way, but we've identified those as the major additional markets beyond Europe and the United States. In terms of guidelines, the treatment guidelines have recently been updated, specifically and importantly talking about the importance of Phe lowering. The lower the Phe, the better. I think one of the most important evolutions in the guidelines is the fact that even if you are controlled, that is, have a Phe level less than 360 micromolar per liter, which is the target, that even going lower than that is better. There is a benefit to treating folks, even who may be at the less severe end of the spectrum, with a therapy. Obviously, this is not something we can go to the store and get a vitamin, a lower Phe, but it really would take a therapy that is able to be efficacious in doing that. The guidelines have certainly emphasized that lower is in fact better. There's a great awareness in the physician community about Sephience. I don't know exactly the next time guidelines will be updated, but we certainly think that the most recent updates are particularly relevant to Sephience and is also supportive of the therapy and will certainly help its uptake. Thank you. I'm showing no further questions in the queue at this time. I will now turn the call back over to Dr. Matthew Klein for any closing remarks. Thank you all again for joining the call tonight. We are obviously incredibly excited about being able to bring Sephience to the PKU community. The FDA approval is a significant milestone for the community and for the company. With our European approval and European launch underway, we've really taken a number of steps forward now towards our global launch. We look forward to keeping you updated on our progress, and as we talked about, we remain incredibly enthusiastic about this opportunity. Thank you all again for joining the call and have a good evening. This concludes today's conference. Thank you for your participation. You may now disconnect.