Ladies and gentlemen, thank you for standing by. Welcome to the APHENITY Top Line Results Conference Call. At this time, all participants are on a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will hear an automatic message advising your hand is raised. Please be advised that today's conference is being recorded. I will now hand the conference over to your speaker host, Dr. Matthew Klein. Please go ahead.
Thank you all for joining this morning's call. We are excited to share the positive top line results of Aphenity, the phase III trial of sepiapterin in patients with phenylketonuria. 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. We are thrilled to announce that we met the primary endpoint of blood phenylalanine reduction in the Aphenity study with highly statistically significant and clinically meaningful results. Sepiapterin substantial Phe reduction 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 key levels in line with United States guidelines of less than 360 micromoles per liter.
Importantly, sepiapterin was also well tolerated with no serious adverse events. Before I go into more detail on the top line results, I will review the design of the Aphenity trial here on slide 4. Aphenity was a global placebo-controlled registration directed trial of sepiapterin in pediatric and adult patients with PKU. In order to enrich the randomized population for likely sepiapterin responders, screen subjects were treated for two weeks with sepiapterin in an open label run-in phase. Those that responded to therapy with a greater than 15% reduction in blood Phe levels were randomized to receive sepiapterin or placebo for six weeks. The primary analysis population included those subjects who had a reduction of greater than 30% from baseline, and the primary endpoint of the study was reduction in blood phenylalanine levels in these patients.
Before sharing placebo-controlled results, I'll review the data from the run-in phase which we have previously shared. Of the total 156 patients in the run-in phase, 103 patients, or 66%, had a 30% or greater mean reduction in blood phenylalanine levels, the criterion for the primary analysis population of the placebo-controlled study. These 103 patients had an average blood Phe reduction of 66%, or 464 micromoles per liter. Of those 103 patients, 16 patients were part of the classical PKU patient subset, and these classical PKU patients had a mean reduction in blood Phe of 60% or 586 micromoles per liter in mean absolute blood Phe reduction. On slide 6, let me walk you through how we arrived at the part two study population.
As I noted earlier, of the 156 patients in part one, 103 had Phe reductions of equal to or greater than 30%. Per the study protocol, patients younger than 2 years of age were enrolled directly into the long term extension study and not randomized. An additional 3 patients withdrew from the study and were not randomized, 1 due to pregnancy, 1 due to a tolerability issue, and 1 due to family reasons. Thus, there were 98 patients randomized as part of the primary analysis population. In addition, there were 12 patients who had Phe reductions of 15%-30% and who are also randomized for part two, but not part of the primary analysis population. Now I walk through part two, the placebo-controlled portion of the study.
In order to balance the sepiapterin and placebo groups for key disease factors, randomization was stratified both by % Phe reduction in part 1 greater than 30%, that being for the primary analysis population or 15%-30%, and also by baseline Phe level greater than or less than 600 micromoles per liter. Here on slide 8 are the baseline characteristics of the 98 subjects who comprised the primary analysis population. The sepiapterin and placebo groups were well matched in terms of age and baseline Phe level. You also see the distribution of classical PKU subjects with slightly more in the placebo than in the active sepiapterin treatment group. On slide 9, the study results. Sepiapterin treatment resulted in clinically meaningful and statistically significant phenylalanine reductions.
For the overall pre-specified primary analysis population, the mean blood phenylalanine reduction in the sepiapterin treatment 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. This strong magnitude of reduction is consistent with what we observed in part 1. In the subset of classical PKU patients, the sepiapterin treated group demonstrated a 69% mean blood Phe reduction, again with minimal change in placebo group. This level of reduction in classical PKU patients was better than that recorded in part 1. These are outstanding results and clearly differentiate sepiapterin for the treatment of PKU patients of all ages and severity.
In terms of absolute Phe reduction in the overall primary analysis population, the mean blood Phe reduction in the sepiapterin-treated group was 460 micromole per liter compared to 16 micromole per liter in the placebo group. For reference, in the KUVAN placebo-controlled study, the mean reduction was 239 micromole per liter. In the subset of classical PKU patients, the mean absolute Phe reduction was 523 micromole per liter. Results in both the overall primary analysis population and the classical PKU subset were again highly statistically significant. Part of the secondary endpoints of the trial, we looked at the important question of how many patients achieved the recommended target phenylalanine control level. First, looking at the U.S. guideline for all ages on slide 11. 84% achieved the target Phe level of less than 360 micromoles per liter.
For the European guidelines for adolescents and adults, 93% of patients achieved the target level of below 600 micromole per liter. These are really important results that substantiate, again, a meaningful broad-based treatment effect. For reference, the proportion of patients achieving target blood Phe levels in the KUVAN placebo-controlled trial was 32% for less than 360 and 54% for less than 600 micromole per liter. Again, we are observing differentiated treatment benefit with sepiapterin. One of the questions that we have gotten most often in recent months is the treatment effect of sepiapterin in patients previously treated with KUVAN. In Aphenity, 27 patients entered the study reportedly on active or generic KUVAN. These subjects had an average phenylalanine level at study entry of 581 micromole per liter.
These subjects then underwent a seven-day washout, after which their average Phe level was at 691 micromoles per liter. We were then able to determine the relative effect of sepiapterin treatment on these patients in the run-in phase. After two weeks of sepiapterin treatment, the mean phenylalanine level in this group was 304, which is not only below the U.S. guideline target of 360 micromoles per liter, but represents 48% lower phenylalanine levels on sepiapterin treatment than those receiving KUVAN at study entry. From a safety perspective, sepiapterin demonstrated a favorable profile. First, there were no serious adverse events reported in the study. The related adverse event frequency for treatment-related adverse events was similar between sepiapterin and placebo groups. The main adverse events reported in the sepiapterin-treated patients were headache and diarrhea, and the majority of those were grade 1.
Overall, in addition to the very strong efficacy signal in the trial, sepiapterin was found to be well tolerated. Following the placebo-controlled study, patients were eligible to enroll in a long-term open label study, which is still ongoing. This study has several objectives, including assessment of long-term safety and durability of sepiapterin treatment, as well as to assess Phe tolerance. The Phe tolerance assessment looks at the ability of sepiapterin to control phenylalanine following a regimented increase in Phe intake. In the open label extension study, patients who reached a Phe level of below 360 micromole per liter on treatment were eligible to enroll in the Phe tolerance protocol. Let me explain how this works. Essentially, a dietician prescribes a biweekly % increase in Phe intake based on measured blood phenylalanine levels in the patient.
We measure the changes in blood phenylalanine levels with this regimented increase in phenylalanine intake. The graph on the left side of this slide demonstrates the average biweekly prescribed Phe intake for the first group of 12 subjects who are participating in the Phe tolerance protocol. Of note, the recommended Phe intake for adult women is about 55-60 mgs per kg per day, and for men it is 60-65 mgs per kg per day. You can see that patients in this protocol are taking greater than the recommended daily allowance of phenylalanine. On the right side, we present the corresponding mean phenylalanine levels of the Phe tolerance patients at each time point.
As you can see, in the face of increased Phe intake, even beyond the recommended daily allowance, phenylalanine levels have remained relatively stable and below the 360 micromole per liter target level. These are, of course, preliminary data, as only 4 patients have reached the end of the protocol, but the data are nonetheless 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. As we have previously discussed, PKU represents a unique commercial opportunity because unlike in many other rare diseases. The commercial pillars for success are already well established. First, newborn screening for PKU has been in place in most major markets for decades, and there are now an estimated 58,000 patients worldwide.
There are well-known metabolic centers of excellence for treating PKU around the world with whom we already work. The disease pathology is well understood and well documented, which is very important for market access and payer discussions. Finally, the patient community is well connected and coordinated, which is very important to accessing patients. Despite there being two approved therapies for PKU, the vast majority of patients are not well served, and there's therefore a large potential market opportunity. We believe these Aphenity results position sepiapterin to address the persistent large unmet need across all PKU segments. This includes therapy-naive patients, including classical PKU patients who have failed, are not well controlled, or do not tolerate existing therapies.
In addition, PTC has a proven track record in commercializing rare disease drugs globally, we plan to capitalize on our unique strengths to commercialize sepiapterin for PKU patients. We have already built the global commercial organization that we will need for a successful launch, this opportunity will really be plug-and-play. We already have built strong relationships with PKU patients, patient advocacy groups, physicians, including key opinion leaders and payers. We have experience in ensuring early access to treatment and providing patients with the support they need through patient support programs. It will be our customer-facing team's key priority to bring sepiapterin to PKU patients around the world as quickly as possible upon launch. Now, with these strong data in hand, our next step is to request pre-submission meetings with regulatory authorities, which we will do as soon as possible.
Based on agency feedback, move forward with NDA and MAA submissions. Before I turn the call over to the operator, I want to update the timing of results from our other studies. We expect to report results from the MOVE-FA trial of ticagrelor in May and results from the MIGHTY study of ticagrelor and interim data from the PIVOT-HD study of PTC518 in Huntington's disease patients in June. I will now turn the call over to the operator for Q&A. Operator?
Thank you. Ladies and gentlemen, 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, press star one one again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Kristen Kluska with Canaccord Genuity. Line is open.
Hi. Good morning, everybody. Congratulations on these really great data that you reported this morning. I just had two questions. The first one is, can you remind us what these blood Phe levels and coming within the guideline targets really means for patients from the perspective of symptomology of this indication and other factors related to PKU?
Sure, Kristen. Thank you so much for your question and for the guidelines are really set up to give patients a guide of where they need to really get so that obviously, as you point out, disease morbidity can be minimized. In PKU, the issue is that high phenylalanine levels are associated with cognitive defects and brain fog in particular, as well as other symptoms. It's been well documented that reductions in blood phenylalanine, for example, every 100 micromole per liter reduction has been associated with improved IQ. There's a direct correlation between reduction of phenylalanine levels and patient benefits, which is why phenylalanine as a blood-based biomarker has been used and is accepted as an endpoint for full approval, not just an accelerated approval.
When we consider these guidelines, it's really ideal levels to get to minimize this morbidity. I think the fact that we can, on treatment, get the vast majority of patients below 360 micromole per liter is incredibly important for their clinical benefit and really highlights the potential for sepiapterin to have a meaningful impact in patients of all severities and all ages.
Okay. Thank you for that. Second question, I know you've done a lot of work on understanding the mechanistic differences between KUVAN, and you have the head-to-head study. With this readout, you noted the 27 patients and the significant drop that we saw after treatment for PTC. You know, can you talk about the validation from these data with the mechanistic differences that you see between the two therapies, especially now that you have these additional 27 patients? Thank you.
Yeah. Great question, Kristen. as you alluded to, we conducted a phase II study where we compared sepiapterin head-to-head with KUVAN and demonstrated not only that 50% more patients had significant benefit from sepiapterin than KUVAN, but those that had a KUVAN benefit had significantly larger reductions in phenylalanine on sepiapterin relative to KUVAN. as you rightly pointed out, the data from this trial really validate what we observed in phase II. They really continue to demonstrate exactly what you'd expect to see if you had a more bioavailable and potent cofactor therapy, as sepiapterin is.Obviously, those 27 subjects gave us a really unique opportunity to again do not a head-to-head, but really a within-patient look at what treatment effects on KUVAN look like. then when what subjects are washed out and put on sepiapterin, what greater could be observed.
Obviously, that 48% reduction on blood phenylalanine levels on sepiapterin relative to KUVAN, again, really speaks to the ability to deliver significant benefit to patients who are on KUVAN. I think that, you know, we've talked a lot about patient segments and those that we can address, including therapy naive, classical patients, KUVAN failures. I think this also allows us to start to see the potential to deliver benefit to patients who are believed to be controlled on KUVAN.
Thank you. One moment for our next question. Our next question coming from the line of Robyn Karnauskas with Truist. Your line is open.
Hi. Congrats on the data. This is fantastic. This alex for Robin. Two questions. Number one, with the amount of reduction that you've been able to show here, compare it with sepiapterin as compared to KUVAN, what initial feedback are you getting from physicians? For physicians that believe that their patients are well controlled on it, you know, do you think that this merits preferential placement ahead of KUVAN? Number two, how much LTE data will you have when you file eventually, and how many responders are going into the LTE study? Thank you.
Thanks, Alex. I'll take your second question first and then get your first question second. In terms of the second question, we've had all the patients who have completed part 2 have moved into the open label extension. We have additional, obviously, the children below age 2 who weren't randomized during that study. There's actually additional patients who were directly enrolled in the open label extension. Taken together, we believe we'll have a strong data package of both long-term durability of effect as well as safety at time of NDA submission. Of course, we'll also have additional Phe tolerance data that beyond what we shared today, which is quite encouraging. To your first question regarding physician feedback.
Look, we've seen the notes, of a lot of the KOL calls, and I think most people are saying over 40% will be good. Let me turn the call over to Kylie. She and her team have been really involved in presetting the marketplace.
Thanks, Matt. Yeah. I think from everything that we're hearing across the board with physicians is despite the huge unmet need in patients that aren't well controlled on KUVAN, quote unquote, there's still an opportunity to drive a need in that patient population, in the sense that if you're having an ability to drive additional Phe reductions, then that can be very clinically meaningful. Particularly when you look at what physicians say that 100 micromolar per liter is equal to 1 point scale from a cognitive point of view. I think across the board, if you look at the different patient segments that Matt laid out, we see a substantial opportunity, particularly in those that are therapy naive, particularly in those that are failing on current therapies and then are poorly controlled on current therapies.
Over time, obviously looking at the additional fee reductions that we're able to drive.
Makes sense. Well, congrats again. It's great news.
Thank you. Our next question coming from the line of Brian Abrahams with RBC. Your line is open.
Hi, this is Joe in for Brian. Congrats on the data. I just had two questions as well. If you could give us a little more detail on the safety, anything you could tell us on the rates of headache or GI side effects you're seeing there, that would be super helpful. Could I also ask, how consistent the Phe reduction levels were at the individual levels? If you can tell us anything about if there has been any outliers among the classical PKU patients. Thank you.
Yeah. Thank you very much, Joe. In terms of safety, again, this was a pretty clean safety data set. As we said, the most common AEs were diarrhea and headache. They were grade 1. I think overall there were 6 patients who had these AEs on the highest level of sepiapterin. The other important thing is that when you look at the frequency of related adverse events, they were similar from both the sepiapterin and placebo groups. I think this is very strong in terms of safety profile and tolerability profile for the drug. In terms of durability of effect, we're seeing very good durability over patients as they leave the placebo-controlled study and move into the long-term open label study, which is obviously very encouraging.
That was helpful. Thanks so much. Congrats on the data again.
Thank you.
Thank you. Our next question coming from the line of Eric Joseph from JP Morgan. Your line is open.
Hi. Thanks for taking the questions and congrats on these data. I guess with respect to the breadth of the label indication that you'll seek, do you anticipate being able to go as low as infants, similar to the KUVAN label, as low as one month? Would you need to conduct a separate study to facilitate that? I guess just on the safety front, sorry if I missed it, but I guess, were there any discontinuations on the study as a result of tolerability? If you could just kind of clarify that. Thank you.
Yeah. Thank you, Eric. Thanks for the questions. The study was designed to include patients of all ages and all levels of severity of PKU with the idea that the label would support all age groups. As we mentioned, we did. We're able to enroll patients under the age of two, so we fully expect to have a label that can cover all age groups of patients based on this study and obviously data from the open label extension that we would submit as part of the NDA. To your question about tolerability, there were no discontinuations in the placebo-controlled study due to tolerability issues.
Okay, great. Thanks for taking the questions.
Thank you. Our next question coming from the line of Sami Corwin with William Blair. Your line is open.
Good morning. Thank you for taking my question. I found the change in the intake really impressive, but obviously it was a small end. I was wondering if you could provide any insight into if these patients were in the control arm previously and crossed over, or crossed over from placebo, or were they on the baseline spectrum of disease severity or age. I have a follow-up question.
Yes, thank you. Just maybe, Sammy, thank you for the question. Let me just give a little more color on the Phe tolerance assessment. All patients from the placebo-controlled trial, both placebo and sepiapterin treatment groups, roll into the open label extension. For the first two weeks, all subjects are treated on sepiapterin. After those first two weeks of open label treatment, those that have a less than 360 micromolar per liter bloodstream level are then eligible to enroll in the Phe tolerance protocol. The data you're seeing includes patients who were on active and on placebo and again, representing the full range of severity. As we did have patients who had higher baseline Phe levels of over 600 and sometimes over 1,000.
In the active part that got under 360, we're seeing the full spectrum of sepiapterin-treated patients in that Phe tolerance study. Again, as you pointed out, these data are really compelling, not only in terms of treatment effect, but in terms of the drug's ability to really restore an important aspect of quality of life, which is liberalized diet.
Great. That's helpful. Then I guess I noticed that only 27% of the patients were on KUVAN at study entry. I guess I was curious about the other patients, if they were just being managed by a Phe restricted diet or if they had previously tried KUVAN in the past. I was just curious if you had any insight there.
Yeah. The 27 patients reflects the 27 of the 156 who entered the open label run-in part one phase who reported to be on active KUVAN, either branded or generic KUVAN at the time of entry into that run-in phase. There were additional subjects who reported previous use of KUVAN or being KUVAN failures. We really highlighted those 27 patients because they presented that unique opportunity to be able to understand what the relative treatment benefit of sepiapterin could be in patients who were on active KUVAN therapy.
Great. Thank you so much, and congrats again.
Thank you. Our next question coming from the line of Séhithen Bunsak with Cowen. Your line is open.
Hi. Congrats on the excellent results, and thanks for taking our questions. I guess just kind of in a broader question, what is still required for a submission in terms of safety, PMC? In general, is there anything different from the filing strategy between the U.S. and E.U. and kind of how you're thinking about maybe the rest of the world as well?
Yeah, absolutely. We've obviously had discussions with the agency about the number of subjects that would be in a dataset for approval. Obviously, we're confident that we'll have enough patient data for the submission based on this study as well as the other studies that have included patients who received sepiapterin. We're confident that we have a patient database that will support an NDA submission. That's similar for EMA. You know, typically from a regulatory standpoint, we prioritize first going to FDA and EMA, which is what we'll plan to do, and then obviously we will go to additional markets after that.
The first priority is to align with FDA and EMA in pre-submission meetings, and then move as quickly as possible based on discussions of that meeting towards these submissions and then gradually extend to other key geographies.
Great. Then I guess kind of, the second follow-on question is how are you in general thinking about price range, given the very impressive impact on classical patients but also given that generic KUVAN is available?
Yeah, great question. Again, I'll turn that over to Kylie. Her team have been looking at that.
Yeah. Thanks, Matt, and thanks for the question. I think obviously as we commonly do, we have not set price at this point. We like to look as we progress further with regulatory discussions at the label to understand the true value proposition. What I will say is we continue to believe the price point will fit between KUVAN-branded price and Palynziq. I think obviously as we've talked about today, this data is extremely strong and provides an opportunity across the huge unmet need that exists in PKU. We continue to believe in the value proposition, not just for therapy-naive patients, but also those that are looking for additional Phe reduction across KUVAN failures and KUVAN poly controls.
Great. Thanks so much for answering our questions, and congrats again on the awesome data.
Thank you.
Thank you. Our next question coming from the line of Joseph Schwartz with SVB Securities. Your line is open.
Hi, congrats on the results. I was wondering if you can tell us how many classical PKU patients were screened in order to arrive at the 15 patients who were analyzed in part two of Aphenity, and how representative of the overall classical PKU population are these patients based on the mutations they have? As a follow-up, how confident are you that just six classical patients randomized to sepiapterin is enough, experience to gain a label in this subpopulation? Thanks.
Yeah, absolutely. Thanks, very much for the question, Joe. In the first part of the study, in the run-in phase, obviously we had the patients that were randomized, the 15 classical patients who were over 30%, and we had an additional 5 who were between 15% and 30%. We had a total of 20 that had a 15% or greater reduction, and that represented about 50% of all those classical patients who were in the run-in phase. The responders represented really the full spectrum of classical. They included different baseline levels and also different mutations. Of course, in a disease like PKU where there's been at least 950 different genetic variants, it's hard to exactly map genotype, phenotype responses in this data set.
I think what we can say by and large is we're seeing market response across the spectrum of classical patients. You know, I think again, given the data in those classical patients from both part one and part two, we believe they're sufficient to support treatment of classical patients in the label.
Thank you. Our next question coming from the line of Gena Wang with Barclays. Your line is open.
Thank you for taking my questions. I have several questions. First is regarding the 27 patient who. Can you hear me?
Yes, Gena.
Okay, good. 27 patient who received KUVAN, wondering what is the % of reduction before enrollment, % of a Phe reduction before enrollment, and how many data points you collect for the baseline? Among all those 27 patients, any were classic patients? This is my first part of question.
Yeah. Okay. Thank you for the question, Gena. Those 27 subjects came in, and we had a baseline measurement of those patients at screening. It was one value measured. As we talked about, they had roughly 590 micromole per liter. They then go get washed out for seven days, and we get their baseline values again on after washout, so basically off therapy. That goes to about 700, which suggests that there was a roughly 100-120 micromole per liter treatment benefit in those patients on KUVAN or either branded or generic. Sorry, I don't know where that line feedback is coming from.
They go on sepiapterin, we had a 48% lower level of phenylalanine in the blood relative to what that average level was on sapropterin, again, either branded KUVAN or generic form. That 48% is different. I don't believe any of the patients were classical. I think those, there were no classical patients in that group of 27. Again, to specifically answer your question, it was one measurement taken on KUVAN, one measurement after washout, the measurements that were done as part of the part one study, that gave us the blood levels on sepiapterin.
Okay. Thank you. Very helpful. Quickly on the classic patient, can you remind us what is the definition of a classic patient here?
The classical patients, it basically means at some point in at birth or at some point in their life, they had levels of phenylalanine at greater than or equal to 1,200 micromolar per liter. Essentially the most severe forms of the disease, typically associated obviously with a less, or a more severe mutation in the phenylalanine hydroxylase enzyme.
Okay. At the baseline, what is their Phe level when they enroll for the classic patient?
I'm sorry, when they got into the study, what was the baseline levels of the classical patients?
The classic patient. Yes.
The baseline level of the classic patients, I believe, was on the order of between 700 and 800. We can get you that exact number. Obviously many of them had had some control. Obviously, they were not all over 1,200, but they were reflecting that they did have some diet control, which led to them having obviously the phenylalanine levels below 1,200.
Okay. Thank you. My last question is regarding the safety. I think on slide 13, I'm wondering if you can share a little bit more color. I think usually when we see the safety will be percentage, you know, grade one, two, three or like the low grade percentage of the most frequent safety events. Wondering if you can give a little bit more quantitative color. I know you're putting headache and a few comments there, but, you know, what will be the quantitative color that what, you know, what percentage patient had, what are the most frequent, say grade one, grade two AEs or grade three? What are the, what is the percentage of these?
Yeah. Let me just go back to the classical patients. At baseline, there was 761 micromoles per liter in the active group and 771 in the placebo. Sorry, to more completely answer your last question. In terms of frequency of treatment, emergent adverse events, the most frequent was diarrhea. At the overall, keeping in mind this was a dose escalation in the placebo-controlled study. Overall, there was a rate of 7.1% of grade one diarrhea, and there was one grade two event, and that actually was on placebo. It turns out that on sepiapterin treatment the most common AE was diarrhea. Four subjects had diarrhea and those were all grade one. The second most frequent AE, treatment-related AE was headache.
There was one patient with a grade two headache, three patients with a grade one headache. There was one subject on placebo who had grade one headache.
Okay, very helpful. Thank you very much.
Again, yeah, you're welcome, Gena. Again, very low numbers and again, we're very pleased with the tolerability observed in this study.
Thank you.
Thank you. Our next question coming from the line of Colin Bristow with UBS. Your line is open.
Hey, good morning and congrats on the really great data. I think we've covered most of, well, what we have, but maybe just on what was the level of Phe reduction in part two for the patients who had a 15%-30% Phe reduction in part one? Sorry if I missed that. Then just thinking about sort of the commercial side of the story, what, you know, how should we be thinking about launch prep and sales force build out? Thank you.
Yeah. Absolutely. When we thank you for the question, Colin. When we look at the full analysis set of those randomized, we are seeing a mean reduction overall. When we include the 15%-30%, the mean reduction overall was about 355. And in the 355 in the overall population of those 15 and older. Again, obviously a bit lower than what we observed in the over 400 micromoles per liter observed in the treatment group. In terms of the commercial question, let me turn that over to Kylie and Erica.
Thanks, Colin. Yeah, from a commercial perspective, as we've touched upon, many of the pillars for success are already established. We're in a very unique position with PKU, when newborn screening is widespread across all major markets, and so the need for patient identification is greatly reduced. There's very well-known centers of excellence, and the team has already been engaging with these centers of excellence as well as the patient advocacy community, which is, as Matt touched on earlier, coordinated, connected, and moving in the same direction. Then the fourth important factor, from a market access perspective is the disease pathology is very well understood and documented.
This, alongside with the strong data coming out of the Aphenity study today, as well as our phase II head-to-head study and the additional data we're collecting for Phe tolerance, puts us in a very unique position for engagement across physicians, patients, and payers. We're moving in that direction and have been for a period of time. With regards to your second part of your question around sales force build-out. As we've shared, we have a very strong commercial infrastructure in place across the globe, and this is in many regions that companies tend to shy away from. We have a proven track record in commercializing rare disease drugs in many parts of the world. From that perspective, we're poised and ready to go with almost all aspects of what's needed from a commercial build-out perspective.
Any additional resources will be incremental. We have the infrastructure in place, and the team is ready to go.
That's great. Congrats again. Thank you.
Thanks, Colin.
Thank you. Our next question coming from the line of David Lebowitz with Citi. Your line is open.
Thank you very much for taking my question. Specifically on the classical PKU patients, how many of these patients actually got to a more normalized diet? I guess how do you see it from a practical standpoint of being able to move into this particular population?
Yep. Thank you. Thank you for the question, David. Obviously, we're still early in the Phe tolerance part in terms of being able to give actual numbers that get to have fully normal diets. Again, it's very impressive to see that on the four patients who have gone through this full six months of Phe tolerance, that they are reaching levels of phenylalanine protein in the diet that are above the recommended daily allowance. That's really good to see. Obviously, we'll have more data over time, including some of the classical PKU patients.
Got it. Thank you for that. I know that there were multiple doses, used in the trial at various time points. Do you have any data on that might be able to differentiate one dose versus another?
Very good question. Just as you pointed out, the part two, this placebo-controlled study was six weeks in duration and also included a dose escalation such that for the first two weeks, patients got 20 mgs per kg. The second two weeks they got, the subjects got 40 mgs per kg. In the final two weeks, patients got the full 60 mg per kg, which is what we use as the run-in dose and what we anticipated would be the clinical dose. Interestingly, the non-classical patients appeared to have similar levels of reduction at weeks three and four and weeks five and six. At 40 mg per kg and 60 mg per kg, there were similar levels of reduction, slightly higher on the higher dose.
In the classical patients, we did see a stronger signal of benefit, in at that higher dose of, 60 mgs per kg. We and again, I think what we're encouraged by is really consistent safety at both of those dose levels. I think that along with the long-term durability of Phe tolerance data sets us up, to be able to support that higher dose level.
Thanks so much for taking my question.
Thank you.
Thank you. Our next question coming from the line of Jeff Hung with Morgan Stanley. Your line is open.
Hi, this is Michael Reid on for Jeff Hung. Thank you for taking our questions, and congratulations on the compelling data. First, for the patients who received KUVAN at study entry, how has mean blood Phe looked at the end of the part two and in the OLE? Has it remained at the 300 micromole level, or has it been re-reduced even further over time?
Yeah. Thanks for the questions, Michael. I would say overall, what we're observing thus far is what patients are reaching in terms of their phenylalanine levels at that primary endpoint part of at week six. We're seeing those maintained over the course of the open label extension thus far. We're seeing that 84% of patients who achieve under 360 micromolar per liter are staying there. Obviously, as we showed in the Phe tolerance data, those that are in the Phe tolerance protocol thus far are demonstrating maintenance of below that target level of 360 micromolar per liter in the face of increasing Phe. I'll also point out that we had 11 subjects in the part two, in the placebo-controlled study, who reached levels of phenylalanine that are considered normal.
The threshold for normal is 120 micromolar per liter. We had a number of patients who were actually not only getting below the target, the therapy target guideline of 360, but actually down to normal levels below 120 micromolar per liter. That's another very impressive data point that confirms this treatment benefit we're observing can be quite substantial for patients.
Thank you. That's super helpful. Maybe just to follow up on your previous point on the Phe tolerance protocol. So we saw meaningful increases in dietary Phe intake, above what's recommended, but surprisingly blood Phe levels continued to reduce. Can you give us some expectations? Was this a result of extended duration of treatment? Maybe could you provide more color on the additional Phe tolerance data you had referenced earlier? Thanks so much.
Michael, they obviously remain on that 60 mg per kg of sepiapterin. basically, they're on that drug, and you're seeing continued drug effects. that's really durability of treatment in the face of higher phenylalanine. exactly, it confirms an important not only finding of durability, but also obviously the durability in the face of greater phenylalanine. in terms of the additional data we referenced, as we said that we had data available at this data freeze for the first 12 subjects who enrolled in that Phe tolerance protocol, and we expect to have additional data over time that we look forward to sharing.
Thanks again. Thanks guys again on the data.
Thank you.
Thank you. Our next question coming from the line of Danielle Brill with Raymond James. Your line is open.
Hey, guys. Congrats on the data. Thanks for the question. just a quick one for me. I know there's been a lot of questions on phenylalanine intake. Could you disclose what the average
... intake, was that baseline, how that varied during, the study, and if there was any variability across arms? Thank you.
Yeah, thanks for the question, Danielle. We don't have the exact numbers and average Phe intake, the important part is what you pointed out, was that ensuring that there was stable Phe intake over the course of the placebo-controlled trial in both the placebo and active groups, which is exactly what we observed. The findings that we have in the trial are, can obviously be attributed to therapy and not to change in diet, of course, which is what you'd expect given the substantial levels of Phe reduction. That was an important element in the study design to ensure that we had oversight of diet and ensuring that patients were adherent to their diets and did not confound the effects, the treatment effects of sepiapterin, or quite frankly, introduce a quote-unquote, "placebo effect" in the trial.
We were very pleased to see that at the maneuvers we took to ensure stabilization of Phe intake over the course of the placebo-controlled diet worked well.
Thank you.
Thank you. Our next question coming from the line of Paul Choi with Goldman Sachs. Your line is open.
Hi, good morning. Let me add my congratulations as well. Two questions from us, please. You provided the baseline patient baseline characteristics, the min and max ranges for the active and placebo groups. Could you maybe provide some descriptive statistics on what the range or confidence intervals look like on the primary endpoint, just to understand what sort of range of outcomes you had on the primary endpoint?
On the primary endpoint for the 95% confidence intervals in terms of micromolar production, they were at 352 to 450.9. Obviously, -352 to -450.9. Again, you're seeing very, you know, consistent, given those narrow confidence intervals, very consistent reductions across the entire treatment cohort.
Okay, great. Thank you for that, Matt. Then as a follow-up, I think you used a powder for the pediatric patients here. Can you just remind us for the, you know, commercial product in terms of the presentation, you know, have you thought about any changes on the production front for there? Do you have stability data along those lines? Then for the adult population, would you use a different presentation there, or would you also likely use a powder? Thank you very much for taking our questions.
Yeah, thank you, Paul. We're not gonna make any changes. Obviously, what this study shows is the formulation we have is highly effective, well-tolerated, and easy for patients to use in the once daily dosing. We have obviously already done the work to go from what was the clinical manufacturing to ensure that we have all the commercial scale-up processes in place so we can move forward. Obviously, having the CMC data to support NDA and MAA submission and obviously also having the supply for commercial launch.
Okay, great. Congratulations again. Thank you.
Thank you, Paul.
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. I wanna thank everyone for joining us this morning. Obviously we're incredibly excited about the Aphenity results, really matching, in some cases surpassing what we saw in the open label and then a threshold response of getting 84% of the patients below 360 micromolar per liter. The Phe tolerance findings all really substantiate the potential for sepiapterin to meet that large unmet medical need for PKU patients. We look forward to next steps, we'll keep everyone informed as we move through the necessary regulatory processes. Again, thank you everyone for joining us this morning, have a good day.
Ladies and gentlemen, that does end our conference for today. Thank you for your participation. You may now disconnect.