Thank you for standing by, and welcome to the PTC Therapeutics PKU Deep Dive. 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 a question during the session, you'll need to press * 11 on your telephone. As a reminder, today's program is being recorded. Now I'd like to introduce your host for today's program, Kylie O'Keefe, Chief Commercial Officer. Please go ahead.
Hello, everyone, thank you for joining today's call. We are excited to share with you this presentation on PKU and our product, Sepiapterin. Before I begin, I refer you to our forward-looking statements on this slide, which are also posted on our website, as well as our risk factors section in our most recent 10-K. Let me now begin by introducing our presenters. First, I am joined by Dr. Matthewhew Klein, our Chief Executive Officer. Second, I'm joined by Professor Anja Muntau, a German pediatrician. Anja was awarded her MD degree from Ludwig Maximilian University of Munich, Germany, in 1992, where she also received her postgraduate training in pediatrics. Since 2014, she has headed the Clinic for Pediatric and Adolescent Medicine at the University Medical Center Hamburg-Eppendorf.
Her main area of work is research into genetic diseases in children, particularly inborn errors of metabolism. Professor Muntau is a recognized global expert on PKU and has an active clinical practice treating PKU patients. Lastly, myself, Kylie O'Keefe, the Chief Commercial Officer. We will cover three key topics today. Matthew will begin by providing an overview of PTC and our product for PKU, sepiaterin. Anja will discuss the current clinical practice in PKU, including the significant unmet needs that remain despite current therapies and the opportunity of sepiaterin to address many of those needs. I will discuss the commercial landscape for sepiaterin in PKU. With that, let me hand the call over to our CEO, Dr. Matthewhew Klein. Matthew?
Thanks, Kylie. Let me start with a brief introduction to PTC. PTC is a science-driven global biopharmaceutical company focused on the discovery, development, and commercialization of innovative therapies for patients with rare disorders. We have built a robust commercial portfolio with 6 marketed products, 5 of which we commercialize globally, and the 6th, Evrysdi, from which we collect collaboration and royalty revenue. We are very proud of our commercial team's performance in generating substantial year-over-year revenue growth, and in the first quarter of 2023, each product achieved double-digit year-over-year revenue growth. This strong first quarter performance puts us in position to achieve our 2023 total revenue guidance of $940 million-$1 billion. This revenue guidance includes $545 million-$565 million in DMD revenue.
To sustain our product portfolio, we have also built a robust pipeline of compounds in research and development in three therapeutic areas: neurology, metabolic disorders, and oncology. With the readouts from several clinical trials completed in the first half of the year, we look forward to an active second half of 2023, including continued progress on our PIVOT-HD trial of PTC518 in Huntington's disease patients, our SUNRISE-LMS study of unesbulin leiomyosarcoma patients and the CardinALS trial of Utreloxastat in ALS patients. In addition, we have a number of planned regulatory activities in the second half of the year. In the third quarter, we are planning to submit the BLA for Upstaza, and we expect to receive an opinion from the CHMP on the Type 2 variation to convert the Translarna conditional marketing authorization to full authorization in Europe.
We also expect to have a pre-NDA meeting with the FDA for the sepiaterin PKU program in the third quarter and expect to submit the NDA for sepiaterin in the fourth quarter of this year. In addition, we are also preparing to request Type C meetings with the FDA to discuss the potential NDA resubmission for Translarna in the U.S., as well as to discuss the potential for an NDA submission for vatiquinone, based on the recently released MOVE-FA results. The focus of today's presentation is our sepiaterin program for PKU. Let me begin the main part of our program with a brief recap of the results from our phase 3 Aphenity trial. We are thrilled that we met the primary endpoint of blood phenylalanine reduction in the Aphenity study, with highly statistically significant and clinically meaningful results.
Sepiapterin demonstrated substantial phenylalanine reduction from baseline of 63% in the overall primary analysis population and 69% in the subset of classical PKU patients. The vast majority of patients were able to reach target phenylalanine levels in line with U.S. guidelines of less than 360 micromoles per liter. Importantly, sepiaterin was also well tolerated, with no serious adverse events. As I mentioned, for the overall primary analysis population, the mean blood phenylalanine reduction in the sepiaterin-treated group was 63%, with little change in the placebo group, as expected. This result was highly statistically significant, with a P value of less than 0.0001. In the subset of classical PKU patients, the sepiaterin-treated group demonstrated a 69% mean blood phenylalanine reduction, again, with minimal change in the placebo group.
These are outstanding results that clearly differentiate sepiapterin for the treatment of PKU patients of all ages and disease severity. As part of the secondary endpoints of the trial, we looked at the important question of how many patients achieved the recommended target phenylalanine level. For the U.S., guidelines for all ages and European guidelines for children under 12 years of age, 84% of the patients achieved a Phe level of below 360 micromoles per liter. For the European guidelines for adolescents and adults, 93% of subjects achieved a target level of below 600 micromoles per liter. Of note, the proportion of patients achieving target blood phenylalanine levels in the Kuvan placebo-controlled trial was 32%, achieving below 360 micromoles per liter, and 54% achieving below 600 micromoles per liter.
One of the questions that we have gotten often in recent months is the treatment effect of sepiapterin in patients previously treated with Kuvan. In the Aphenity study, 27 patients entered reportedly on active or generic Kuvan. These subjects had an average phenylalanine level on study entry of 581 micromoles per liter. These subjects underwent a 7-day washout, after which their average level was at 691 micromoles per liter. We were able to determine the relative effect of sepiapterin treatment on these patients in the run-in phase of Aphenity. After 2 weeks of sepiapterin treatment, the mean phenylalanine level in this group was 304 micromoles per liter, which is below the U.S. guidelines target Phe level of 360, and represents 48% lower phenylalanine levels following sepiapterin treatment in patients receiving Kuvan at study entry.
Following the placebo-controlled study, patients were eligible to enroll in a long-term open label study, which is ongoing. This study had several objectives: to assess long-term safety and durability of sepiapterin treatment effects, as well as to assess phenylalanine tolerance. The phenylalanine tolerance assessment looks at the ability of sepiapterin to control phenylalanine levels following the regimented increase of phenylalanine intake. In the open label extension study, patients who had a phenylalanine level of below 360 were eligible to enroll in the phenylalanine tolerance protocol. Essentially, a dietitian prescribes a biweekly % increase in phenylalanine intake based on measured phenylalanine levels. We are able to measure changes in phenylalanine levels with increased dietary phenylalanine intake. The graph on the left side of the slide demonstrates the average biweekly prescribed phenylalanine intake for the first group of 12 subjects who are participating in the phenylalanine tolerance protocol.
Of note, the recommended phenylalanine intake for adult women is about 55-60 milligrams per kilogram per day, and for men it is 60-65 milligrams per kilogram per day. You can see patients in this protocol are taking greater than the recommended daily allowance of phenylalanine. On the right side, we see the corresponding phenylalanine levels at each time point. As you can see, in the face of increased phenylalanine intake, phenylalanine levels have remained relatively stable and below the 360 micromoles per liter threshold target level. Of course, these are preliminary data, but they are very encouraging given the importance of Phe tolerance in patient quality of life, physician uptake and payer engagement. We look forward to sharing more of these data once available. Now I'd like to invite Professor Anja Muntau to give her perspective as a clinician treating PKU patients.
Anja?
Thank you, Matthew. It's a pleasure to be here and to share my views about the treatment challenges in PKU and the potential benefit that sepiapterin may offer. Before I begin, I'd like to say that the Aphenity data that Matthew just highlighted is exciting news for the PKU community, and I am amazed. The data is much more than we all expected and is really surprising in a positive way. I'm excited about the opportunity to offer sepiapterin to my patients. I'd like to begin by giving an overview of phenylketonuria or PKU, which is sometimes called PAH deficiency. PKU is an inherited autosomal recessive condition caused by variants in the PAH gene that encodes the PAH protein, leading to impaired PAH function and PKU. Today, we know of more than 1,000 variants in the human PAH gene.
Both the environment, which is the dietary intake of Phe, and the genotype, are causal components of PKU. Unfortunately, PAH genotypes may not predict the clinical phenotype or be used to evaluate or treat the disease. There are some very severe mutations, the most frequent being R408W in the homozygous state, where we know there will be severe PKU without residual function. In many compound heterozygous genotypes, we cannot predict the phenotype. This slide shows the role of the PAH protein in the phenylalanine metabolic pathway, specifically the phenylalanine hydroxylating system. The enzyme PAH catalyzes the first and rate-limiting step in the metabolic pathway of Phe, and converts Phe to tyrosine. Interestingly, the natural cofactor of the PAH enzyme, BH4, has been shown to correct misfolding and early degradation of PAH, and in this way improves in vivo PAH enzyme activity if taken in pharmacological doses.
Impaired PAH enzyme function leads to systemic accumulation of Phe, and this has a number of neurological consequences. Elevated blood Phe concentrations interfere with the normal production of neurotransmitters and leads to PKU. Blood Phe accumulation, and in particular accumulation in the brain, is toxic to the central nervous system and impairs several neurological functions. To give you some examples, we know very well that patients who have been off treatment for some time show white matter lesions and reduced myelin production. We see, in particular, deficiency of large neutral amino acids due to the Phe-mediated competition for the transporter LAT1. We also see neurotransmitter deficiency that can be well translated to symptoms. In addition, the excessive Phe in the brain causes oxidative stress, and there are other examples shown here. PKU severity is associated with higher blood Phe levels and decreasing Phe tolerance.
Historically, we have observed different clinical phenotypes of PAH deficiency. The severity of PKU is related to PAH variants and is categorized by blood Phe levels and Phe tolerance. You see increasing blood Phe concentrations with more severe phenotypes, and decreasing Phe tolerance with the increasing severity of the disease. Here you see the historical classification of PKU into three classes: mild to moderate, and severe. Although I want to make the point that PAH deficiency covers a continuum of severities. There are American and European treatment guidelines for PKU, and here I want to focus on the main differences. In the U.S., the treatment of PKU should be initiated as early as possible.
Treatment is lifelong, with the goal of maintaining blood Phe levels in the range of 120-360 micromoles per liter in patients of all ages. The European guidelines recommend treating all patients with levels above 360 micromoles per liter. The target level for patients less than 12 years and for maternal PKU is 120-360 micromoles per liter. The target level for patients older than 12 years is 120-600 micromoles per liter. It is worth noting that the Phe levels that are recommended in these guidelines are 10 times normal physiological levels. These guidelines represent a compromise and are not the ideal treatment goal, which would be normalization to Phe levels below 120 micromoles per liter.
Lifelong diet restrictions remain a key requirement for PKU patients. A PKU diet is a very low-protein diet accompanied by Phe-free medicinal foods, because the allowed intake of natural protein is too low for normal functioning of the patient. The patients must eat modified low-protein products, such as pasta or bread. Some patients take glycomacropeptide as a low-Phe protein substitute. In some countries, patients are treated with large neutral amino acids. There are several barriers to long-term continuation of this diet. It is very burdensome due to poor palatability and the lack of variety in the PKU diet. Many patients have low-protein pasta with tomato and salad day after day. Adding to this challenge, the cost of the medicinal food is very high. In many countries, the cost must be covered by the families due to a lack of insurance coverage.
This very strict diet, even if very well done, is still associated with considerable risk of malnutrition. Patients have increased GI issues from changes in their microbiome. There are significant social barriers, as having meals with others in public is really difficult. We have made considerable progress with the implementation of diets suited to PKU patients. Nonetheless, we still experience suboptimal outcomes. Even with early and continuous management of diet alone, many PKU patients experience cognitive symptoms as well as emotional and behavioral problems. In children and adolescents, we see poor academic performance due to PKU-related suboptimal learning capability. In particular, we observe abnormalities in executive function. We see reduced processing speeds and impaired bone formation. Many adults, particularly those who are off treatment, come to the clinic because they are not doing well.
They present with depressed mood, a very high incidence of generalized anxiety, phobias, decreased positive emotions, and social maturity deficits. They are very often socially isolated and show even lower bone density. We have 2 main goals with therapy for PKU patients. First, to decrease blood Phe concentrations, to bring them as much as possible to physiological concentrations, and at the same time, to increase the dietary protein tolerance. This is the amount of phenylalanine protein that a patient can consume without experiencing an increase in blood Phe concentration. It has increased Phe tolerance. This second aspect, of course, is the main determinant of the quality of life for PKU patients. We currently have 2 approved treatments for PKU patients, Kuvan and Palynziq. Kuvan is sapropterin dihydrochloride, which is the synthetic form of the natural cofactor of the PAH enzyme tetrahydrobiopterin or BH4.
It is indicated for adults and pediatric patients older than 1 month. There are several clinician-reported challenges with this drug. It has a limited response rate. A maximum of 30% of patients respond to it, both initially and over time. Most of the patient population does not receive adequate control from Kuvan. Importantly, the classical PKU patient population receives little to no Phe reduction from Kuvan. In patients that do respond to Kuvan, the decrease in Phe concentration is usually around 30%, but not more than 50%. This is not a drug that allows for reaching physiological Phe concentrations. The other approved drug is Palynziq, which is pegvaliase. This is an injectable drug of a phenylalanine-degrading enzyme derived from plants and genetically produced. It converts phenylalanine not to tyrosine, but to trans-cinnamic acid and ammonia.
This drug is indicated for patients who are older than 16 years and have uncontrolled blood Phe of greater than 600 micromole on existing management. Palynziq has several challenges. Of particular importance are the known safety issues seen in clinical trials and clinical experience. In the first 3 months, it is associated with a high number of adverse events, including anaphylaxis, that requires patients to carry an EpiPen. It also has inconvenient injectable administration and lengthy titration. All of these factors mean clinicians often relegate Palynziq to being a treatment of last resort. It can take up to 2 years for a patient to see a response. Those patients who do respond do reach physiological Phe concentrations. With Kuvan and Palynziq, we have 2 drugs that have incrementally helped PKU patients, but present several challenges. As a result, there is a need for a new approach.
Sepiapterin has several mechanistic advantages over sapropterin. First, sepiapterin is a precursor of tetrahydrobiopterin. After being taken by mouth, sapropterin is rapidly oxidized and converted to BH2, much of which is then quickly excreted from the body. The BH2 that does get absorbed and arrives at the cell, doesn't enter the cell very easily. Essentially, very little of the BH4 actually gets to where it needs to get to the cell, and when it gets there, it doesn't get inside the cell very well to exert any beneficial effect. Sepiapterin, on the other hand, is rapidly absorbed intact from the intestines, transported to the cell, and actively transported into the cell, where it's rapidly converted to BH4, the cofactor for the defective enzyme, so it can exert its effect with high bioavailability.
This partly explains the substantial and clinically meaningful Phe reduction that we saw in the Aphenity study. Second, we believe that sepiapterin provides additive effects as a molecular chaperone, as shown here. As we covered on the previous slide, sepiapterin is actively transported to misfolded variant PAH tetramers inside the cell and converted to BH4 in pharmacological concentrations. Sepiapterin and BH4 act as independent pharmacological chaperones by binding to different variants of PAH. Sepiapterin corrects the conformational structure of the tetramer and promotes metabolism of Phe to tyrosine. This has been shown in preclinical experiments where sepiapterin has increased the activity of various PAH variants.
The community of metabolic physicians is hopeful that sepiapterin will treat the majority of PKU patients, including untreated patients, therapy-naive patients, including classical PKU subjects, patients who have failed on other therapies and are desperately looking for a new alternative, and patients who are currently not well controlled on one of the two existing therapies. The Aphenity study has shown that one of the big differentiators between sepiapterin and Kuvan is that sepiapterin can treat classical PKU patients, which means patients with the severe phenotype of PKU may have a new treatment option. There is a huge unmet need for PKU patients that can potentially be addressed by sepiapterin. We know that PKU leads to a toxic accumulation in the brain and must be treated from birth. Current PKU therapies are not suitable for all patient subgroups.
Sepiapterin has advantages over both Kuvan and Palynziq, and can potentially treat a much broader patient population. Sepiapterin is easy to take, is well-tolerated, and the Aphenity results show that it has very convincing efficacy for a broader range of PKU patients. This can help close the gap in care, with the goal of having some patients not be required to have the restrictive PKU diet for life. It is clear to me that sepiapterin could lead to a better quality of life for many PKU patients. As for my own clinical practice, I am excited to offer this new therapy to classical patients.
I would also retry all of my patients who have been unsuccessful on Kuvan on sepiapterin, and also a significant group of patients who are partially responsive to Kuvan, but not completely satisfied, with the goal of achieving lower blood Phe concentrations and higher protein intake. The results of the Aphenity study are really convincing. Now I'd like to hand things over to Kylie. Kylie?
Thank you, Anja. Thank you very much for joining us today. I'm excited to share some additional details on the unmet need for PKU patients and how sepiapterin will fit into the PKU landscape. As discussed by Professor Muntau, despite the availability of some treatment options, there clearly remains a significant unmet need in PKU. Of the diagnosed PKU population, less than 10% of PKU patients are well controlled on Kuvan or Kuvan generics, and the majority of patients are looking for a better therapy to achieve Phe control. Around 70% of diagnosed patients have been trialed on Kuvan. Of these, approximately 70% of them do not respond and are considered to fail.
Of the remaining patients trialed on Kuvan, approximately 30% will respond, but around 40% of those 30% are well controlled, and around 60% see a reduction in blood Phe, but are still not well controlled, with blood Phe levels outside the target thresholds. This leaves an additional 30% of patients who have never been trialed on Kuvan, which also includes many classical PKU patients who are therapy naive. In totality, this demonstrates a large unmet need in the PKU marketplace and market opportunity. The patient journey for PKU is well understood, and it all begins with a heel prick and a blood spot test soon after birth.
Newborn screening is widely available in most developed countries, these babies and their families are immediately connected with their healthcare team, that may either be a geneticist or a pediatric metabolic specialist, depending on the country you live in, and also a dietitian being their primary medical carers and support network. These relationships are generally maintained right through childhood and well into a PKU patient's adult life. The urgency to reduce blood Phe levels means that these babies immediately need to reduce their protein intake and be started on medical formulas to supplement the essential amino acids that will be lacking in their protein-restricted diet. These medical formulas, and later in life, medical foods, will likely be a lifelong companion to the PKU community and patients. The impact of diet for life, as it is commonly known, is quite dramatic for PKU patients.
The need to restrict protein has multiple implications, ranging from social isolation, anxiety, depression, to fatigue. The need to try and stick to the PKU diet has an enormous impact on the patient's quality of life. There are three key issues in PKU management. First, most patients on diet alone do not achieve effective Phe control. As mentioned previously, the diet is extremely difficult to consistently adhere to, and the unpalatable and expensive medical foods and formulas only make this even more challenging. Second, the currently available pharmacological treatments are not addressing the needs of the majority of the PKU patients, and this is due to both efficacy limitations, side effects, and convenience challenges. Third, as a result of this poor Phe control, many patients are faced with neurocognitive challenges impacting executive function and quality of life.
In the case of prolonged high Phe levels, this can lead to hyperpigmentation, motor deficits, ataxia, seizures, and irreversible intellectual disability. As Professor Muntau mentioned, the two main goals of therapy when treating PKU patients are decreasing blood Phe levels and increasing dietary protein intake, well known as improved Phe tolerance. I want to first focus on the importance of reducing blood Phe levels. Uncontrolled blood Phe levels lead to reduced executive function, headaches, anxiety, depression, impairing daily function for these patients. Specifically, there is a significant correlation between blood Phe levels and IQ. Across a review of 40 different studies, it was shown that each 100 micromolar per liter increase in blood Phe predicted a 1.9 to 4.1 point reduction in IQ, and this is meaningful.
This just reinforces how important it is to provide PKU patients with a treatment that can control their blood Phe levels to within the target Phe range. The second goal of PKU therapy is to allow patients to liberalize their diet, allowing them to increase their protein intake through improved Phe tolerance while maintaining target Phe levels. It cannot be overstated how important this is to both PKU patients and physicians alike. Staying on the diet for life is an enormous burden on PKU patients and leads to them feeling frustrated, stressed, anxious, and ultimately limited in their daily life. The implications are significant. Not being able to eat the same foods as their friends, being excluded from many social interactions, for example, birthday parties, barbecues, restaurants, school cafeterias, and many more.
As a result, the ability to ease their diet restrictions is the primary driver for patients to seek new therapeutic options. To put this in context, many PKU patients are restricted to, on average, 5-10 grams of protein per day. Compare this to what could be considered a normal meal day for many people. As an example, a breakfast of eggs and bacon with some potatoes, maybe a wrap for lunch with some chips and cookies as accompanying snacks for the afternoon, then a dinner of grilled chicken with some broccoli, salad, and bread. This would give a total daily protein intake of about 115 grams. That's more than 10 times what many PKU patients could, should consume in a day. Compare this meal on the left of the slide to the images on the right of the slide.
PKU patients must vigilantly select low-protein foods and weigh them carefully to ensure they strictly limit their Phe intake. The PKU foods required to replace things like bread, pasta, biscuits, and other daily staples leave a limited selection for them to choose from. I mentioned the 5-10 grams of protein that PKU patients are restricted to per day. What does that actually look like? The burden of achieving this is substantial. As you can see on the left of the slide, one banana, a bowl of rice, and a single egg already hits this threshold. To the right of the slide, you can see the traffic light system that PKU patients must live with on a daily basis. They need to stay away from things like meat, tofu, dairy, nuts, pasta. They need to monitor and limit intake of low-protein foods, including beans, potatoes, and broccoli.
They need to be cautious, more liberal consumption of certain foods like fruits and vegetables, as well as medical low-protein foods, is allowed. Protein supplements to ensure intake of essential amino acids must be taken up to three times per day. What is diet adherence like for these PKU patients? Well, let's hear directly from them.
I know that a lot of children and myself included, like in teenage years, tend to struggle with staying on diet. It can be a little bit tricky when you're trying to deal with peer pressure and just growing up in a community where everyone's just different from you. You're definitely a minority, and it's a condition that not a lot of people are familiar with.
That's why it's really important when you're younger, when your brain is developing, to have such a strict diet, because that's when your brain is developing. Now it's still important because when I have high blood levels, I have bad memory, my hands get shaky, I have brain fog, my mood is all over the place.
In discussions with patients, we have learned they have high hopes for a new therapy that can help to ease this burden. The most important driver for patients is a reduction in blood Phe to levels that can then be maintained, along with the ability to increase their protein intake without being impacted by cognitive fog. This is why the Phe tolerance data that we have shown is so important to both patients and physicians alike. Of course, they also want a drug that has a good safety profile without concerning persistent side effects. The therapy should be easy to use, preferably oral, once a day, and with easy storage. Now, let's hear from some additional physicians about their perspective on PKU. Firstly, Dr. Drago Bratkovic and secondly, Professor Nicola Longo.
There is very much a massive unmet need in PKU. The diet on its own, whilst you can get good Phe levels with it, takes a lot of work, and we do need other therapies that are easier to undertake and also maintain throughout the lifespan of a patient. You or I could probably do the diet for a few weeks. Patients with PKU have to do the diet for their whole life, and it's very exhausting. We need to have new therapies to come along to help patients maintain their levels, and their levels at a level that maintains their quality of life and their ability to function and work.
There is an unmet need for PKU patients in finding some oral medication that can really control better the midline level to allow a little bit more diet liberalization. Having the capacity to eat normal food for them is very important, and any step that we can take in this direction will help them achieve their full potential.
Similar to PKU patients, as you just heard, it is important from a physician point of view to see reduction of blood Phe and improved Phe tolerance as the most important drivers for healthcare professionals caring for these patients. They want to be able to control blood Phe levels, ease their patients' restrictive diets, and improve their overall quality of life. We asked 20 blinded healthcare professionals caring for PKU patients what they were looking for in a potential new therapy for PKU. They told us that in order to prescribe a new therapy first line, they would need to see a Phe reduction of at least 30%, but ideally closer to 50. They also told us that they would like to see a response rate across their PKU patients of at least 35%, but again, that 60% would be ideal.
This market research was conducted before we completed the Aphenity study. We now have the Aphenity results in hand. It is clear that sepiatrin has emphatically exceeded these expectations. Sepiatrin has reduced blood Phe across a broad range of patients, including classical PKU patients, and has reduced that blood Phe by 63% from baseline. In addition, we have seen a response rate of equal to or greater than 30% in 66% of patients. It is clear from the Aphenity results that sepiatrin has exceeded the expectations of the PKU community to ensure first-line usage. We are now preparing to bring this innovative therapy for PKU patients to the market and are extremely excited about the commercial opportunity. As outlined earlier, the remaining unmet need in this space, despite two therapies existing, creates a large market opportunity.
There are a number of key segments that present low-hanging fruit that we will target. First, patients who have not been trialed on Kuvan or are considered therapy naive, and this includes, as we've noted in the past, many of the classical PKU patients, where we have demonstrated benefit in both the Phase 2 and the Aphenity study. Secondly, patients who have not responded to Kuvan. In terms of these Kuvan failures, many experts who have treated patients with PKU across the world have indicated that based on the data they have seen from our Aphenity study and from their understanding of the mechanistic benefits of sepiaterin, all patients who have failed on Kuvan should be trialed on sepiaterin, and Anja noted this earlier.
Thirdly, patients who have achieved some level of blood Phe reduction from Kuvan, but are not well controlled and for whom sepiaterin may deliver a better reduction in blood Phe levels. A reduction in blood Phe that is clinically meaningful for these patients may significantly enhance their quality of life, potentially allowing them to substantially increase their protein intake and also decrease their use of formula and expensive medical foods. In summary, the potential market opportunity for sepiaterin is composed of a number of key PKU patient segments, comprising up to 15%-30% of the overall global PKU population that are targeted for treatment. As we have noted in the past, we are expecting a price range between Kuvan-branded price and Palynziq, and with this in mind, this would put us above a billion-dollar market opportunity. Turning now to the commercial pillars for success.
PKU represents a unique commercial opportunity within the rare disease space. First, as noted earlier, newborn screening is widely utilized across major markets. This means that babies born with PKU are identified immediately and hence become candidates for effective treatments to control their blood Phe levels. Second, once diagnosed, patients follow a well-understood patient journey through metabolic centers, where care is carefully managed by the pediatric metabolic specialists and or geneticists and dietitians. PTC has a good understanding of these centers and the key opinion leaders who work within them, and we have already begun to build a solid foundation of relationships with them through our clinical trials, advisory boards, and other key activities. Third, the disease pathology of PKU is well understood, with control of elevated blood Phe levels representing the primary goal of therapeutic treatments.
Finally, the patient advocacy community is extremely active and well-coordinated in the PKU space. PTC is not pioneering the pathway here. We're not trying to understand and decipher complex endpoints or build a natural history program from scratch. For PKU, it's a well-trodden path to success, with the blood-based biomarker of Phe reduction being recognized by physicians, regulatory agencies, and payers alike. PTC is well positioned for a successful commercial launch of sepiaterin. PTC is an expert in developing and delivering life-changing therapies to people living with rare diseases, and we have a proven track record in commercializing these therapies globally. We work closely with our stakeholders to understand the needs of the patients we provide therapies for, and we have a comprehensive working knowledge of the different complexities of the rare disease, regulatory, and payer landscape in each of the different regions and countries.
We have developed a global commercial infrastructure with an established footprint in over 50 countries around the world. This footprint has an in-depth understanding of the specific needs of each of these countries, including the different access pathways and, in particular, early access pathways. Hence, we are well-placed to ensure that the launch of sepiaterin is a success, and that we can reach the maximum number of PKU patients who can benefit from this new therapeutic treatment. Let me now turn to the cross-functional team at PKU clinics globally that will be called upon by our customer-facing teams. After newborn screening, as noted, geneticists or pediatric metabolic specialists, depending on the country, are the first PKU specialists that see patients. These physicians confirm the diagnosis and begin initial treatment.
After a patient's diagnosis has been confirmed, they are referred also to a dietitian, who will work hand-in-hand with the parents and the geneticist or metabolic specialist. The dietitian's primary roles are providing a set diet and plan, along with recipes and information regarding medical formulas. The dietitian remains one of the primary healthcare professionals throughout a patient's lifetime and generally is the closest to their care, hence they are also extremely important. Nurse practitioners are also important prescribers, and endocrinologists may also assist with diet management and prescription of treatment for PKU patients. Neurologists, while they do support cognitive assessments, do not generally prescribe treatments. Importantly, PKU clinics are well defined, and we are aware of the key treatment centers across the regions globally and the key opinion leaders within each treatment center. Over the last 3 years, we have built strong relationships with the PKU community.
We not only know where the PKU treatment centers are, but we also have a deep understanding of the PKU prescribers and how to reach them. Specifically in the U.S., we know who is writing Kuvan for patients, who is writing Palynziq for patients, and the specifics of their prescribing patterns. This will allow a rapid and highly targeted focus on key customers at launch. In addition, for the U.S., we know the healthcare professionals that have patients who have lapsed from treatment. We can precisely identify those lapsed on both Kuvan and Palynziq using this real-world evidence to target patients who have failed or who are unsatisfied with the current therapies. Insights from U.S. clinicians indicate clearly that many PKU patients are treading water, and they deserve better.
In addition to this, we have established important collaborations with key global PKU networks, including a number of different scientific associations that are seen here. The dietician and nutritionist communities, as noted, are also critical in the PKU patient care, we are collaborating with a number of these associations as well. Finally, of course, the PKU patient community is extremely active, and we are working closely with many of the global associations. Overall, we are now well integrated into the PKU community and have developed a comprehensive understanding of the networks required for rapid dissemination of information and advocacy. As we prepare for our commercial launch, we are setting the stage to bring sepiaterin to the majority of PKU patients.
As Anja stated earlier, the Aphenity results are extremely convincing. We will now focus on sharing this data broadly to build the confidence in the efficacy of sepiaterin beyond our clinical trial investigators. We will focus on the differentiated mechanism of action that has generated these results and the quality-of-life benefits that this will bring to patients. We will engage with the PKU community to ensure they are informed and ready to initiate treatment with sepiaterin upon approval. We will also differentiate sepiaterin with our data package and mechanistic advantages. We will also differentiate our product through the support we provide the PKU community of patients and their caregivers. We have a roadmap for achieving this, initially starting in the U.S. with our PTC Cares team.
PTC Cares is our support program, designed specifically to help patients and their caregivers get started on different PTC medications and provide personalized support throughout their entire treatment journey. Market access is always critical. We are currently heavily focused on our pricing and reimbursement strategy in early access programs. This will continue throughout launch and beyond. Sepiapterin represents a potential game-changing therapy for PKU patients and a significant commercial opportunity for PTC. The team is extremely excited to bring this therapy to PKU patients in need. With these strong data in hand, our next step is to request pre-submission meetings with regulatory authorities, which we will do so as soon as possible, and as Matthew noted earlier. Based on agency feedback, we plan to move forward with the NDA and MAA submissions, to name a few.
We are initiating our launch preparations as laid out today to achieve the potential $1 billion market opportunity. With that, we will now turn back to the operator for Q&A. Operator?
We will now open the line for questions and answers with Matthew and Kylie. One moment for our first question. Our first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your question, please.
Hi, everyone. Great presentation, and thanks for providing us with these details. First question I had is how you're thinking about the cadence of a potential launch. I guess perhaps it's really not your typical rare disease launch, as you already have a pretty detailed map here about identifying patients. Of the pillars of unmet need you flagged, wondering if you expect one of these target markets to initially gain more traction over others initially?
Yeah, thanks, Kristen. We, Kristen, we appreciate the question. Starting with your first question around the cadence, I think, as you noted, it is a pretty untraditional launch for a rare disease. As you highlighted, newborn screening allows us to ensure that we have the patients identified, the treatment centers of excellence, identified, and we've already begun working with them. We have a clear understanding of disease pathology, which allows us a smooth and efficient discussions from the payer side, and we're already engaged with a well-connected and coordinated patient advocacy community.
From our perspective, we see it as really around differentiation, about ensuring that upon approval, both physicians and patients have a clear understanding of the advantages, both from a mechanistic point of view and also how that pulls through with the Aphenity data in why this treatment will bring benefit to PKU patients, both on the aspect of Phe reduction as well as increased protein intake from a Phe tolerance point of view. Overall, we expect this to see a lot more rapid uptake, particularly in the U.S., being our first market and a concentrated market, than you would traditionally see with rare disease. Obviously, we're moving ahead with European markets and a number of other countries as we progress outside of the U.S.
The second question you had around the market segments and whether or not we see that differentiating in different regions. I think one of the things that I would probably highlight is just, you know, the difference between the U.S., and ex-U.S., As we've talked about in the past, I think ex-U.S., is a little bit more untapped. There are more therapy-naive patients, more patients that haven't been able to access Kuvan, I think we might see a faster uptake in the therapy-naive space outside of the U.S., versus in the U.S., Other than that, I expect it to be fairly consistent across the board.
Okay, thanks. Last question from me is, what your expectation on therapy, how much room there will be for diets to be liberalized? Then, despite these patients understanding the strictness of this diet, how often are there mistakes or bumps that a therapy like this gives them some comfort room in making these errors when they underestimate the protein intake? Thanks again.
Yeah, absolutely. On the first question, around diet liberalization, I think one of the things that we're gonna learn a lot from is exactly the Phe tolerance aspect of the long-term extension study. Obviously, as patients come within those, target Phe levels and then are able to increase their Phe intake, making sure that we monitor that ability to maintain those Phe levels over time is really important. In addition to that, obviously, as we shared, our initial data looks really great, and we expect that to continue as we continue to have the patients enrolled throughout the 50 as we've highlighted, and then release data in the coming months. The second question around, will there be bumps in the road?
I think that's exactly the job of the dietician and the nutritionist at the clinic, very tightly managed alongside the patient. They have clear diet plans in place, clear recipes that the dieticians work with the patients on. Obviously, patients are humans like all of us, so there will be some bumps in the road. I think that the close alignment between the dietician and the patient is what makes this limited bumps in the road.
Thank you. One moment for our next question. Our next question comes from the line of Kelly Shi from Jefferies. Your question, please.
Thank you for taking my question, sir. On one of the slides, you mentioned targeting 15%-30% of the overall patients. Do you have to understand what the split of mild to classic patient population?
Yeah, I think, you know, from that perspective, Kelly, I think that was for modeling purposes to help you understand how we get to the billion-dollar plus opportunity. I think what's important is that classical PKU versus mild and moderate PKU differs from geography to geography, region to region. In some cases, classical PKU represents 15%, and in other geographies, up to 50%. With that split, it's very hard to provide an average across the full globe. From that perspective, we haven't broken it out per the different segments. Obviously, I think we believe that we have an ability to achieve a lot higher than that 15%-30%. We're just giving that as modeling purposes to achieve the billion plus.
As we transition to launch, we'll be able to provide a lot more clarity on the patient segments that we're seeing through the treated patients.
Okay, terrific. I also have a follow-up. You have shown pretty impressive Phe reduction in both mild and a classic PKU patient population. I'm curious, based on the physician feedback, what kind of a treatment outcome over time on the increasing of patients' dietary to, you know, tolerance, for sapropterin, in each group? Would they feel, like, comfortable to adopt it as a mainstay drug for treating both patient groups? I mean, are there, like, a different standard for each group in terms of improving a dietary tolerance?
Thanks, Kelly, for the question. It's Matthew. I think one of the encouraging things we're seeing in the data are a very strong magnitude of effect in terms of Phe lowering, regardless if you're mild, moderate, and regardless if you're severe. In the data we are seeing in the Phe tolerance, included in the Phe tolerance data we've shared, there are classical PKU patients there. Again, we're seeing the ability to liberalize patients from the Phe tolerance protocol to beyond the RDA for phenylalanine and still maintaining control. I think this very much gives us confidence that we can achieve liberalization regardless of the severity. Obviously, Phe intake is managed in close collaboration, as Kylie said, with the nutritionist, and it's tightly managed based on age, sex, and also severity.
Again, what's so encouraging here is we're seeing uniformity of strong response regardless of any of those individual patient or disease factors.
Thank you. Super helpful.
Thank you. One moment for our next question. Our next question comes from the line of Eric Joseph from J.P. Morgan. Your question, please.
Hi, this is Billy on for Eric. Thanks for taking our question. Just wanted to ask a little bit about sort of the proportion of classical PKU patients who would see a benefit from using a BH4 mimetic. Kind of following on from that, like, what proportion of classical patients do you think have the residual PAH enzyme activity to make use of a therapy such as this? Thanks.
Yeah. Thank you very much, Billy, for the call. You know, I think, again, one of the things that were very impressive in these data were the proportion of classical PKU patients in whom we registered a greater than a 30% reduction in baseline phenylalanine levels. Again, while there are, of course, patients who are homozygous for the null mutation and have virtually no enzymatic function, there are actually very few of these patients, and clearly a cofactor and also a chaperone effect is likely to be less impactful on them. That's not the case for the vast majority of patients who are categorized as classical.
I would add, in addition to that, the classical PKU prevalence, as I mentioned, varies across geography. I think one of the things that's well accepted, and Anja mentioned this in her prepared remarks, is there is a huge unmet medical need in these patients. They're frustrated, and they're looking for additional therapies. While in some cases this represents about 15% of patients, in other geographies it can represent up to 50%.
Thanks. Just following on a little bit from there, do you think that there'd be any sort of labeling implications from this or no?
Billy, I think typically, the way the label for these therapies goes is for the treatment of hyperphenylalaninemia. There's not a, from a regulatory standpoint, a binning of patients as classical, as moderate and mild. Rather, it's the treatment of elevated hyperphenylalanine due to phenylketonuria. So there's no discerning based on severity. Obviously, we have the data to support the treatment of all PKU patients, regardless of age, regardless of severity, and therefore, would expect to have a broad label.
Okay. Thanks for taking our question.
Thank you. One moment for our next question. Our next question comes from the line of Tessa Romero from William Blair. Your question, please.
Hi, thanks for taking my question. I guess I was curious, obviously, sepiapterin has a better therapeutic profile compared to Kuvan, but since Kuvan only achieved about $500 million in peak sales, what factors do you think are going to be most important in achieving that $1 billion-plus opportunity? I was wondering if you could provide any color on variability of responses in that Phe-tolerance study, given there's no error bars there.
Yeah, absolutely. Thanks, Sami. Just starting with the opportunity, I think there's 2 main factors that we look at for Kuvan peaking at half a billion dollars as to why we think we can get to multiples of that. I think first and foremost is the ability for us to treat a broader patient population. As Anja talked about in her presentation today, not only are we targeting those that have tried and failed Kuvan, those that are not well controlled on Kuvan, but also therapy-naive patients. This is a broader patient population than Kuvan was able to treat. In addition to that, the second part of why we see PTC being able to achieve the multiples of Kuvan revenue is also because we see a somewhat untapped ex-U.S., opportunity.
There are a number of markets that PTC has a proven track record in and has a strong global commercial infrastructure in, that Kuvan has either not reached or has struggled with pricing and reimbursement. We see with the data that we have in hand, coupled with the Phe-tolerance data that we're collecting through the long-term extension, an ability to secure favorable pricing and reimbursement in these ex-U.S., markets. It's twofold. It's the broader patient population and the ability to tap ex-U.S., markets.
With regard to your second question, Sami, obviously these are early data, but we're seeing pretty consistent, pretty consistently across these subjects, that their phenylalanine levels are staying below that 360 micromole per liter threshold. In fact, that's how the entire Phe-tolerance protocol works. The patients only move forward in the protocol if they're maintaining control, which is defined as less than 360 micromolar per liter, with increasing Phe intake. We're seeing very consistently strong results across those patients.
Great. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Robyn Karnauskas from Truist Securities. Your question, please.
Oh, I'm hearing an echo. All right, I have a few. Let me just start with a general question. I guess in your market research that you've done since you've had this data, what is the latest thoughts on, like, how payers will view having to step through Kuvan? Second question is, you know, you talk about efficacy in classical patients. A lot of these patients are at centers, and some get lost to follow up. Like, have you done some research as to, you know, especially in the classical world, like, how many patients are lost that you may not get back? Because Biogen will often talk about that. The third question is following up on just the last question.
You had 12 patients, you know, in the beginning and then 4 in the end for the OLE. Just how many patients are actually reaching that point where they can actually get to that low diet, and what does that mean for them? Can they have 2 eggs and a chicken? Like, put it in perspective for us as far as, like, what kind of diet they can actually have as they get off this drug. Thank you.
Robyn, I'll take the third question, and I'll let Kylie take the first two. I think the important thing to focus on here... Well, two points. One is the 12 to the 4 is more representative of just the point in time the subjects were at when we did the data cut, which was obviously back a few months ago. They are able to stick through this protocol. The important thing to point out here in terms of understanding what that liberalization can mean is the fact that they're surpassing the RDA for protein in the diet. That tells you that if you're getting above an RDA, you're coming closer in line with, a less restricted diet and more what would be a typical diet that would meet the RDA thresholds for men and women.
Robyn, I'll pick up on your 1st 2 questions. I think just in addition to what Matthew said, the dieticians will obviously help guide what that means from a fee intake point of view. If you remember the traffic light I touched on earlier, it allows them to move a little bit into the more yellow phases, but that's managed very closely with the dieticians. On your 1st question around the opportunity, sorry, your 1st question around step-throughs. From a step-through perspective, I think if we look at the U.S., we've had a number of different conversations with U.S. payers, we've also had a number of conversations with ex-U.S. payers as well around what the data means and what the treatment algorithm will look like.
I think first and foremost, with the you know, if we look at a market where there's a number of patients that have already been trialed on Kuvan and have failed, or have been trialed on Kuvan and are not well controlled over time, so either come off the drug, considering that there's medical documentation that has been established for that step-through. Even in the worst case scenario, if a payer did expect them to have reinitiated medical documentation, in that case, it, again, it's a blood test. The patient would need to go on treatment for, say, a week. A blood test would be completed, and then they would assess therapy effect. It, it's not a complex process.
Robyn, you compare that to all of the work that the PTC Cares team has been doing for step-throughs from prednisone to Emflaza, this is a lot less complex, a lot more streamlined, and we don't see a hurdle around that. On the therapy-naive side, especially with classical PKU patients, where there's been no benefit demonstrated previously, we don't expect step-throughs because there is no benefit there. ex-U.S., I think what differs there a little bit is the importance of Phe tolerance data. ex-U.S., as you know, medical foods and formulas are reimbursed, being able to liberalize that diet is so important from a payer point of view, to help limit the cost that comes to managing that diet.
Again, in that case, being able to demonstrate to payers ex-U.S., the importance of Phe reduction alongside increase of Phe tolerance, is the data, the package that we expect that it will allow us favorable pricing and reimbursement.
That's super helpful.
Okay.
That's super helpful. Let me ask one follow-up, because it's relevant to what you just mentioned. When you're talking to, when you're dealing with patients and the thought about trying something new, you know, what are your thoughts? I guess, let me just take a step back. The key questions I get from investors are, I guess, when will we actually get the next OLE data set? When will we get the genotypes of the patients that are classical? Because I think there's some people that are just skeptical that they may be the more, they may have the genotype that may be more willing to be responsive to this drug. This is really more of a catalyst question.
You know, any insight that you can give into what the patient reception is and how aware they are of these new products. Like, I'm sure parents are, like, all over this. Then I will be quiet. Thanks.
No worries. Okay. I think starting with the OLE question and the genotyping, I think what we're seeing consistently across all the different data sets is treatment benefit in all patient severity types and ages, and I think that's really reassuring to us. There's obviously more to come, as you alluded to. We don't have a clear cadence on exactly how we will communicate that, but obviously, we'll continue to communicate through investor forums and then also medical conferences. In regards to patient awareness, I think this is a very well-connected and coordinated patient community, and our teams are engaged with patient advocacy groups, as are the physicians engaged with obviously, the parents and the patients, as you alluded to, and they're extremely excited for a new treatment option.
There's not been anything available for a number of years, and they're very excited, on the precipice of potentially having another therapy available to them, particularly one that is not only able to lower Phe, but also have the ability to potentially liberalize the diet.
Thank you so much.
Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Debjit Chatterjee from Citi. Your question, please.
Hi, thanks for taking my question. I'm Debanjana, on behalf of David Lebowitz from Citi. We were curious specifically on labeling, like, how sapropterin label might compare with Kuvan, and specifically, if the label could show the breakdown of sapropterin, benefit in classical subgroup?
Yeah, thank you for the question, Debanjana. It's probably too early to talk about label specifics. Obviously, we're moving towards the FDA interactions and the submission of the NDA. However, based on the strength of these data, certainly relative to the Kuvan label, we have a high degree of confidence that this would be a label for the full spectrum of patients with PKU of all age groups, given the fact that all age groups were enrolled and all levels of severity. As we mentioned earlier, there's not really a differentiation in a regulatory standpoint of different severities here.
It's really the treatment of hyperphenylalaninemia, which is what the Kuvan label is, and obviously, given the strength of the data in our data set on the classical patients, we have every expectation that we would have a label that would cover the full spectrum of severity in addition to age.
Thank you. Maybe I have a follow-up. Do you think the payers would want to see diet liberalization data on sapropterin prior to coverage decision?
I think particularly as we've talked about, particularly ex-U.S. payers are very interested in Phe tolerance data, specifically for the importance of the fact that medical foods and formulas are reimbursed ex-U.S. It's quite important that they see how the diet is impacted by a Phe reduction with therapy. Yes, we do expect that the Phe tolerance data will be a key component of the payer package outside of the U.S. In the U.S., however, it is a much more streamlined focus on Phe reduction and the importance of reducing Phe reduction.
Thank you so much. Thanks for helping.
Thank you. One moment for our next question. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your question, please.
for Brian. Thank you for taking our question. Just curious about whether if there's going to be any additional screening beyond what is integrated in the newborn screening that may be required before patients can be put on sepiaterin to really test their responsiveness, given that the drug can potentially show P lowering across broader range of patients. I know we already talked about reimbursement dynamics and step-throughs, but I also just wondering if the reimbursement dynamics can be potentially different between pediatric versus adult patients since Palynziq is available for that population there. Thank you.
Starting with your first question around any other requirements outside of the newborn screening, no, we don't foresee any other requirements. We see it as consistently with what is happening in the marketplace today, and we don't foresee any additional aspects being put in place for sepiapterin. In regards to your second question around payer dynamics and whether there's any difference between pediatrics and adults, no, we don't foresee that. I think there are some nuances in the label for Palynziq around baseline fee levels above 600. In that perspective, and coupled with the fact that from a pricing perspective, Palynziq is the most expensive product on the market, as well as has a number of safety concerns. We don't foresee any differences between pediatric and adult step-throughs.
That was very helpful. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Joseph Thome from TD Cowen. Your question, please.
Hi there. Good afternoon, thank you for taking our questions. Maybe just a couple on the regulatory process, with the NDA submission slated for Q4 and your meeting with the FDA coming up, it seems like you're pretty confident you have everything in hand that you need in the U.S., I guess, what kind of key outstanding questions might you have before meeting with the FDA? When we switch to Europe, kind of, I know you mentioned that part of the payer package should be the fee tolerance data. You know, when we think about regulatory requirements for Europe, is an expanded fee tolerance trial or increasing that OLE package important before you submit the MA in Europe? How are you thinking about that process? Then I have one follow-up just on patient care. Thank you.
Yeah, thanks, Joe, for the questions. We've actually already submitted a meeting request for the pre-NDA meeting. We believe we have everything in hand to have that discussion and be able to move forward with the NDA submission in Q4, which is why we provide those timelines. The EMA process, similarly, we look forward to moving forward with submission in Europe. There's a bit more complexity in the European process because obviously there's a need to realign the Committee on Medicinal Products, as well as the pediatric committee, as well then as the CHMP. There's just a few more moving parts that we're aligning, but believe we're well positioned to move forward with submission with the data package we have. No additional need for any comparison or extended fee tolerance data.
We believe the data are quite strong. As we continue the open label extension, we'll continue to bolster the durability effect and safety of sepiaterin and be able to provide all that information to the regulators.
Great. Then just as it stands right now, how often are these patients seen by their physicians? I'm kind of thinking of the conversion rate we should expect in patients that are maybe seeing a partial response to Kuvan. You know, how often does maybe switching therapy come up in over the course of a year? Then maybe when we think about where we should expect the most uptake between those Kuvan prescribers and the Palynziq prescribers, do you think it's gonna be more on the Kuvan prescribers and maybe the Palynziq prescribers have a little bit more comfort managing some of those AEs that come along with the dose titration? Kind of where do you think that the best focus should be in terms of prescribing habits? Thank you.
Yeah. Thanks, Joe. Starting with your first question around how often are these patients being seen by their physicians, I think they're being seen around three to four times per year. Quite often, if you consider, you know, in some other diseases, it's one or two times per year. I will say, obviously, that's from a pediatric metabolic specialist point of view and a geneticist. I think there's more frequent touch points with a dietician just on the need to manage the diet a lot more closely. In addition to that, obviously, there's very close alignment with patient advocacy groups. In addition to that, as we commonly see in the space we work in today, also patient-to-patient communication through social media and other aspects like that.
The answer that I just gave is also cavied a little bit with, dependent on age. If there is obviously a new therapy available and patients are interested in switching, they are likely to come into the clinic at any time. I don't think they would stay in that cadence of 3 to 4 times per year. They would easily be welcomed back into the clinic to have those discussions. Did that help with that question?
Yep, very helpful. Then maybe just in terms of the second part with the, maybe how willing or is there any difference, I guess, in willingness of Palynziq prescribers versus Kuvan prescribers to incorporate a new drug? Do the Palynziq prescribers, you know, like Palynziq's profile and the ability to, you know, kind of get patients to well-maintained levels over time, even if, you know, there are some AEs, are they better at managing those? Kind of what is your experience kind of shown there?
Absolutely. Our experience has shown across the board that physicians are frustrated with Palynziq. There's a number of reasons for that. First and foremost, the side effect profile with anaphylaxis and the need for a patient to carry an EpiPen, I think this is obviously a huge burden to the patient, and they constantly raise that with their physician. In addition to that, and as Anja mentioned earlier, it takes often up to 1 year to dose titrate and up to 2 years to show effect with Palynziq. That's a huge burden, not only to the patient, but also to the physician. I think it's less about the fact that they're comfortable and wouldn't be open to switching, but I think it's more the fact that they have nothing else in their armamentorium to use, and so they're leaning on Palynziq.
With the new oral therapy available that doesn't have a side effect profile and is able to reduce Phe and increase protein intake, I think they'd be very open to switching their patients across. That goes for not only Kuvan prescribers, but also Palynziq prescribers.
Perfect. Thank you very much.
Thank you, Joe.
Thank you. One moment for our next question. Our next question comes from the line of Colin Bristow from UBS. Your question, please.
Hi, this is Yihan on for Colin. Thank you so much for taking our question, congrats on the progress. We have two. The first one, could you please further elaborate the planned sales force build out you've already had? Have you already factored them into the guidance? The second question actually is on your expectation in terms of the FDA label. Do you think there might be age restriction, given your randomized trial only included children over 2 years old? Thank you so much.
Yihan, I'll take the second question first. We expect no age restrictions. The patients under two were included in the trial, but it was at the request of ethics committees and regulators to not randomize those patients, but to put those who successfully screened as being responsive directly into the long-term open-label extension. We have data in less than two-year-olds. They just were not subject to placebo due to ethical considerations. We expect no restrictions in age.
With regards to the question around the commercial infrastructure and sales force build out, as mentioned earlier, we have a very robust commercial infrastructure in place that is poised and ready to be able to commercialize sepiaterin. We don't foresee any major incremental add to the resources that we have in hand. We already have strong coverage, if we focus first on the U.S., across the specialists, and particularly with the PTC Cares team and in patient access and everything associated with that. The only small focus is to allow focus on dietitians, but this is 1 or 2 incremental resources and nothing further than that. Ex-U.S., we're in a very similar position.
Got it. Thank you so much.
Thank you. One moment for our next question. Our next question comes from the line of Jeffrey Hung from Morgan Stanley. Your question, please.
Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions. I guess, what proportion of patients with PKU exceed the recommended dietary Phe intake? Do you think a strict dietary Phe reduction will continue to be a requirement, especially for patients who stay on sepiaterin longer term? Thanks. I have a follow-up.
I think if I understood your question correctly, you were asking around how many patients are not adhering to the strict dietary requirements. Was that your question?
Yeah, that's correct.
On that perspective, it's not really clear on the aggregate how many patients are not adhering to the diet. We do know that it is onerous, it's substantial, it's painful, and it causes social isolation, depression, and anxiety. I think, you know, as Anja talked about earlier, that there are patients that represent to the clinic because of diet issues, but I would say it's hard to put a number on exactly how many aren't adhering.
No, thanks. That's helpful. Then maybe a follow-up on that, on your previous point. Based on patient perspectives, what are they most sensitive to in terms of the treatment outcome? Is it preventing neurological deterioration and the impacts on cognition and mood? Is it reducing the blood Phe levels to within treatment guidelines, or is it allowing complete Phe tolerance and dietary freedom? Thanks so much.
Interestingly, I think it's all of the above, because I think they're all very tightly linked together. I think Phe reduction is tightly linked to neurocognitive and reducing brain fog, which is so important to these patients, and then obviously increasing protein intake and Phe tolerance, which is so important from a diet management point of view. I think in regards to your earlier question around diet management, I think one of the things that's very clear is almost no patients are able to do it for life. Even though they might start out managing it appropriately, over time, it wanes and becomes very, very difficult, and that's why therapies are so important, and that's why the results in sepiaterin are so impactful.
I see. That's very helpful. Thanks so much.
Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill from Raymond James. Your question, please.
Hey, guys, this is Alex on for Danielle. Just want to drill down to an earlier question regarding the eventual NDA submission. Is there any data, i.e., safety, that you have yet to generate that is currently gating to filing? Then on the other hand, is it your hope that efficacy in the Phe tolerance study could be part of the eventual U.S., filing? Thanks.
Thanks for the questions, Alex. Obviously, we're confident that we have the data that we need to move forward with the pre-NDA discussions as well as submission. That's why we've initiated the meeting request and submitted that to the FDA. In terms of your second question was on?
Oh, just with, like, the Phe tolerance. Is that, you know, you spoke about how important that would be for the ex U.S., but I just was curious about how you are positioning that in your mind in the U.S., filing?
Absolutely. I think overall, both U.S. and ex-U.S., Alex, the Phe tolerance is really about the considerations for payers, and that's really and physician uptake, that's also really centered in Europe. From a regulatory submission standpoint, Phe tolerance is not a core part of either regulatory submission. Obviously, we'll provide the data that we have at the time because it provides further substantiation of the important meaningful benefit that is provided by sepiaterin, that's not part of the core efficacy package.
Got you. Thanks so much.
Thank you. One moment for our next question. Our next question comes from the line of Judah Frommer from Credit Suisse. Your question, please.
Yeah. Hi, guys. Thanks for taking the questions and squeezing us in. You've touched on these, but we were just hoping you could put a finer point on your expectations for compliance and duration of therapy within your internal model. Obviously, you touched on compliance issues with diet in this patient population, but our sense is that, you know, Kuvan failure rates are well documented, and patients may be less compliant on meds. What are you assuming for those two components? Thank you.
Yeah, absolutely. Let's start first with compliance adherence. I think we're expecting high compliance and adherence. I think patients are motivated when they see a Phe reduction and ability to liberalize their diet to take a therapy. Obviously, where you see compliance and adherence challenges is where they're not able to liberalize their diet. From that perspective with sepiaterin and the advantages there, we expect a high compliance and adherence. With regards to duration of therapy, I think from that perspective, we don't see any reason why patients would be dropping off or discontinuing. We expect it to be a chronic lifelong therapy, and again, having an ability to liberalize that diet does everything to motivate a patient to continue therapy.
From that perspective, we expect the high response rate and the ability to liberalize the diet in totality to ensure not only high compliance and adherence rates, but long duration of therapy.
Thanks.
Thank you. One moment for our next question. Our next question comes from the line of Joseph Schwartz from Leerink Partners. Your question, please.
Hi, thank you very much. I have a question for the company and also for Dr. Muntau. For management, how were the 15 patients in Aphenity determined to have classical PKU, and why is their Phe at baseline closer to the range that we saw in the Phase 3 trial for Kuvan than Palynziq? Do we know that they would not respond to Kuvan? Then for Dr. Muntau, can you talk about how the community typically defines classical PKU? Is the experience in the 6 patients treated with sepiaterin enough for you to feel confident that sepiaterin will be broadly applicable across the classical PKU population?
Joe, thanks for your questions. I think as we had referred to earlier, Dr. Muntau was not available for live Q&A, but she did mention in her talk that she believes the data in the classical patients, even with the sample size of classical patients, would certainly be something that would allow for broad applicability across all of our classical PKU patients. Going to your earlier question, regarding the definition of classical PKU, we used a very standard trial definition of either having it at the time of screening of greater than 1,200 micromolar per liter Phe level or a previously recorded greater than 1,200 micromolar per liter Phe level, as well as a mutation consistent with classical PKU. It's a very standard definition.
Obviously, in this era of diet control, patients with classical patients may get phenylalanine levels below 1,200, which explains the mean starting point that were in the trial, but we still had patients in this study who were randomized, who demonstrated, you know, over 30%, 40%, and even 50% reductions, who had phenylalanine levels of over 1,000 or even over 1,100. We're seeing quite a representative sample in terms of the classical patients in this study. We also had shared that patients in this study, a number of them had failed on Kuvan, that we are seeing a benefit with sepiaterin in those that failed on Kuvan.
obviously, we have the data that shows that those 27 who were on Kuvan at the time of study entry had a greater than 48% reduction in phenylalanine beyond the benefit that they had with Kuvan.
Does that answer your question?
yes. Thank you very much.
Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad from Bank of America. Your question, please?
... Hi, good afternoon. Thanks for taking my questions. Maybe can you just give some clarity on how you think about how the U.S., ramp will be relative to what you expect for EU? I think in part of your prepared remarks, you had talked about maybe the potential for more opportunity in Europe. I just wanted to clarify that. Also, can you just confirm that you've completed all of your long-term tox work for the application? Lastly, can you provide color on what type of COGS to expect for the product? Thanks.
Tiziana, I'll take the second question, I'll turn the other two over to Kylie. We've done the long-term non-human primate studies. Mammal studies are all set and gone, so that toxicity study is, those tox studies are set.
Thanks, Tiziana. I'll take question 1 and question 3. Starting with the 1st question around the ramp expected in the U.S. No, we still expect a very rapid uptake in the U.S. As we've talked about, there's a number of pillars in place to ensure that. We have the patients identified, we have the centers identified. We're working closely with them, as well as the patient community, and also we have a clear understanding of payer needs and the package that will go alongside that. We will focus on differentiation. Obviously, the difference between a U.S. uptake and an ex-U.S. uptake is that U.S. is a centralized regulatory process, and then obviously, we work with a number of payers in the U.S., but you tend to see a more unified and rapid uptake.
ex-U.S., as you know, it's a country-by-country pricing and reimbursement system. While we will be looking to all markets that have early access pathways and ensuring a rapid uptake there, it will take a little bit more time to mature the pricing and reimbursement discussion. You often see a much faster uptake in the U.S. versus ex-U.S., but that doesn't mean that there's a difference in the uptake. They are consistent in the opportunity and the uptake that we do expect. With regards to your third question around COGS, what I will say is that there's nothing particularly unusual about the COGS. This is a typical small molecule product.
Okay, thank you.
Thank you. One moment for our next question. Our next question comes from the line of Paul Choi from Goldman Sachs. Your question please.
Hi. Thank you. Good afternoon, and thanks for hosting the call. It's very informative. A few questions from us. First, with regard to the commercial strategy, can you maybe just elaborate a little more in terms of what patient support services you're gonna provide, both in the U.S., and in Europe, and how that's factoring into your pricing strategy? I think one of the questions with Kuvan was that BioMarin, you know, provided limited support in terms of the patient experience and journey. My second question is, can you just remind us what you're assuming here for orphan exclusivity for sepiapterin, how long that goes till here in the U.S., and abroad? Then third, can you just a clarification, if Professor Dr.
Muntoni did or did not participate in the Aphenity trial? Thank you.
Absolutely. Thanks, Paul. Starting with patient support, I, as I mentioned earlier, we have what we call PTC Cares team based in the U.S. They're a fantastic team, they manage patients in their journey in its entirety. Starting obviously with diagnosis, treatment, what that means, getting access to treatment, what that means for their patient journey, and helping patients get on PTC medications. Obviously, sepiapterin will be a key aspect of what patients will manage, the PTC Cares team will manage, sorry, for PTC. In addition to that, they also support step-throughs in the different access requirements and an understanding of when patients need access to medication in advance of having access cleared. That's, it's a robust program.
It's, we have received a lot of really positive feedback on that through the Emflaza rollout, and we expect to consistently receive that feedback positively in the PKU space. In addition to that, we also have a global program that focuses on, again, patient journey, patient support. From that perspective, we don't expect to have the same feedback. Then in regards to your question around orphan drug exclusivity, for, again, for base case purposes, we are expecting orphan drug exclusivity in the U.S. and ex-U.S. So in other words, that would be 7 years in the U.S. and 10 years in Europe, 10 years in Japan. As we commonly do with all of our programs, we have a very keen focus on extending patent ability and the patent estate, sepiapterin is no different to that.
We are working very heavily on trying to extend the patent life here, and we have a number of focus areas, particularly including manufacturing, which is very challenging for this product. While we are not there yet in being able to say that we have that ability to extend the patent life, we are working very hard on it and expect to come back with more information once confirmed. With regards to your third question around Dr. Muntoni being an investigator in the Aphenity study, she was, yes.
Okay, great. Thank you very much, and congratulations.
Thank you.
Thank you. This does conclude the question and answer session of today's program. I'd now like to hand the program back to Dr. Matthewhew Klein for any further remarks.
Thank you all for joining us today. We're obviously incredibly excited to move sepiapterin forward to patients with PKU worldwide. The strong data, the clear unmet medical need, represent a significant market opportunity of potentially over $1 billion, as we outlined for you today. Our global commercial teams are poised, experienced, and ready to realize this significant commercial opportunity. We'll look forward to speaking with all of you again at our upcoming earnings call. Again, thank you for joining, and have a great rest of the day.
Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.