PTC Therapeutics, Inc. (PTCT) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to the APHENITY Top Line Results Conference Call. [Operator Instructions] 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 demonstrated 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, screening subjects were treated for 2 weeks with Sepiapterin in an open label run-in phase. Those that responded to therapy with a greater than 15% reduction in blood key levels were randomized to receive Sepiapterin or placebo for 6 weeks. The primary analysis population included those subjects who had a reduction of greater than 30% from baseline and the primary endpoint in the study was reduction in blood phenylalanine levels in these patients. Before sharing placebo-controlled results, I will review the data from the run-in phase, which we have previously shared. Of the total, 156 patients in the running 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 micromole per liter, in mean absolute blood Phe reduction. Now on Slide 6, let me walk you through how we arrived at the Part II study population. As I noted earlier, of the 156 patients in Part 1, 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. One due to pregnancy, one due to a tolerability issue and one 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% to 30% and who are also randomized for Part II, but not part of the primary analysis population. Now I'll walk through Part II, 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 percent Phe reduction in Part I, greater than 30%, that being for the primary analysis population or 15% to 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 comprise the primary analysis population. Overall, 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. Now on Slide 9, the study results. Overall, Sepiapterin treatment resulted in clinically meaningful and statistically significant phenylalanine reduction. For the overall prespecified 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 Phe value of less than 0.0001. This strong magnitude of reduction is consistent with what we observed in Part I. 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 I. 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 announced population, the mean blood Phe reduction in the Sepiapterin treated group was 460 micromole per liter compared to 16 micromole per liter in placebo. For reference, in the Kuvan placebo-controlled study, the mean reduction was 239 micromole per litre. 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. As 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. Next, 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. So again, we are observing differentiated treatment benefit with Sepiapterin. One of the questions that we've gotten most often in recent months is the treatment effect of Sepiapterin in patients previously treated in Kuvan. In APHENITY, 27 patients entered the study reportedly on active or generic Kuvan. These subjects had an average phenylalanine level and study entry of 581 micromole per liter. These subjects then underwent a 7-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 2 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 micromole per liter, but represents 48% lower phenylalanine levels on Sepiapterin treatment in 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. So 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 the 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. Now let me explain how this works. Essentially, a dietitian prescribes a biweekly percent increase in Phe intake based on measured blood phenylalanine levels in the patient. We then 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 to 60 milligrams per kilogram per day and for men, it is 60 to 65 milligrams per kilogram per day, so you can see that patients in this protocol are taking greater than the recommended daily allowance of phenylalanine. On the right side, we presented 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 they are now an estimated 58,000 patients worldwide. Second, there are well-known metabolic centers of excellence for treating PKU around the world with whom we already working. Third, the disease pathology is well understood and well documented, which is very important for market access and payer discussions. And finally, the patient community is well connected and coordinated, which is very important to accessing patients. Despite there being 2 approved therapies for PKU, the vast majority of patients are not well served and is, 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, patients who have failed or not well controlled or do not tolerate existing therapies. In addition, PTC has a proven track record in commercializing rare disease drugs globally, and we plan to capitalize on our unique strength to commercialize Sepiapterin for PKU patients. We have already built the global commercial organization that we will need for a successful launch. So 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 are experienced in ensuring early access to treatment and providing patients with the support they need to patient support programs. And it will be our customer-facing teams key priority to bring Sepiapterin to PKU patients around the world as quickly as possible upon launch. Now with the strong data in hands, our next step is to request pre-submission meetings with regulatory authorities, which we will do as soon as possible and then based on agency feedback to 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 study. We expect to report results for the MOVE-FA trial of vatiquinone in May, and results from the MIT-E study of vatiquinone 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?

[Operator Instructions] And our first question coming from the line of Kristen Kluska with Cantor.

Congratulations on these really great data that you reported this morning. I just had 2 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. Now in PKU, the issue is that high phenylalanine levels are associated with cognitive defects and brain fog in particular as well as other symptoms and has been well documented that reductions in blood phenylalanine, for example, every 100 micromole per liter reduction has been associated with improved IQ. So there's a direct correlation between reduction of phenylalanine levels and patient benefits, which is why phenylalanine blood-based biomarker has been used and is accepted as an endpoint for full approval, not just an accelerated approval. So when we consider these guidelines, it's really ideal levels to get to minimize this morbidity. And I think the fact that we can on treatment get the vast majority of patients below 360 micromoles per liter, is incredibly important for their clinical benefit and really highlights the potential for Sepiapterin to have a meaningful impact in patients from all severity and all ages.

Okay. And then 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. But with this readout, you noted the 27 patients and the significant drop that we saw after treatment on for PTC. So can you talk about the validation from these data with the mechanistic differences that you see between the 2 therapies, especially now that you have these additional 27 patients.

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 and Kuvan, but those that had a Kuvan benefit had significantly larger reductions in phenylalanine on Sepiapterin relative to Kuvan. And 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 how Sepiapterin is. Obviously, those 27 subjects gave us a really unique opportunity to again do, not head-to-head, but really within patient look at what treatment effect on Kuvan look like and then what subjects are watched out and put on Sepiapterin, what greater benefit could be observed. And 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. So I think that we talked a lot about patient segments and those that we can address, including therapy naive, classical patients, Kuvan failures, but I think this also allows us to start to see the potential to deliver benefits to patients who are believed to be controlled on Kuvan.

Our next question coming from the line of Robyn Karnauskas with Truist.

Congrats on the data. This is fantastic. This is Alex on for Robyn. Two questions. Number one, with the amount of reduction that you've been able to show here compared with the Sepiapterin as compared to Kuvan, what initial feedback are you getting from provisions? And for physicians that believe that their patients are well controlled on it, do you think that this merits preference placement ahead of Kuvan? And then number two, how much LTE data will you have when you file eventually? And how many responders are going into the LTE study?

I'll take the second question first and then get your first question second. So in terms of the second question, we've had the patients who complete -- all the patients who have completed Part II have moved into the open-label extension, and we have additional, obviously, the children below age 2 who weren't randomized in that study and there's actually additional patients who were directly enrolled in the open-label extension. So 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 tolerance data that beyond what we shared today, which are quite encouraging. To your first question regarding physician feedback, look, we've seen the notes on a lot of the KOL calls and I think most people are saying over 40% will be good. But let me turn the call over to Kylie, she and her team have been really involved in presenting the market place.

Thanks, Matt. Yes, 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." 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 reduction, then that can be very clinically meaningful, particularly when you look at what physicians say that 100 micromole per liter is equal to 1-point scale on -- from a cognitive point of view. So 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. And then over time, obviously, looking at the additional Phe reduction that we're able to drive.

And our next question coming from the Brian Abrahams with RBC.

This is Joe on for Brian. Congrats on the data. I just had 2 questions as well. If you could give us a little more details on the safety. Anything you could tell us on the rate of headache or GI side effects you're seeing there, that would be super helpful. And 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?

Yes. Thank you very much, Joe. So in terms of safety, again, we were -- this was a pretty clean safety data set. As we said, the most common AEs were diarrhea and headache, they were grade 1. And 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 those the Sepiapterin and placebo group. So I think this is very strong in terms of safety profile and tolerability profile for the drug. In terms of durability of effect, the -- we were 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.

And our next question coming from the line of Eric Joseph from JPMorgan.

Congrats on these data. I guess with respect to the [ placebo ] label indication that you're going to -- that you'll see, do you anticipate being able to go as low as infants similar to the Kuvan label as well as 1 month? Or would you need to conduct a separate study to facilitate that? And I guess just on the safety front, sorry if I missed it, but I guess were there any discontinuations on study as a result of tolerability, can you just kind of clarify that?

Thank you, Eric. Thanks for the questions. The study was designed to include patients of all levels -- all ages and all levels of severity PKU with the idea that the label would support all age groups. And as we mentioned, we did -- we're able to enroll patients under the age of 2. 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.

And our next question coming from the line of Sami Corwin with William Blair.

I found the change in the intake really impressive. But obviously, it was a small end. So I was wondering if you could provide any insight into if these patients were in the control arm previously and crossed over or across driven placebo, or were they kind of were on the base 1 spectrum of disease severity or age? And then I have a follow-up question.

Yes. So just maybe -- again, Sami, thank you for the question. Let me just give a little more color on the Phe tolerance assessment. So all patients from the placebo-controlled trial, both placebo and Sepiapterin treatment groups roll into the open-label extension. And then for the first 2 weeks, all subjects are treated on Sepiapterin. And then after those first 2 weeks of open-label treatment, those that have a less than 360 micromolar per liter blood Phe level are then eligible to enroll in the Phe tolerance protocol. So the data you're seeing includes patients who were on active and on placebo and against representing the full range of severity. So 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 350, we're seeing the full spectrum of Sepiapterin-treated patients in that Phe tolerance study. So 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 what [indiscernible].

Great. That's helpful. And then I guess I noticed that only 27% of the patients were on Kuvan at study entry. So 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 have any insights there?

Yes. So the 27 patients, request the 27 of the 156 who entered the open-label run-in Part 1 space, who reported to be on active Kuvan either branded or generic Kuvan at the time of entry into that running phase. There were additional subjects who reported previous use of Kuvan or be in Kuvan failures, but we really highlighted those 27 patients because they presented that unique opportunity to be able to understand what the relative treatment benefit a Sepiapterin could be in patients who were on active Kuvan therapy.

Our next question coming from the line of Peyton Bohnsack with Cowen.

Congrats on the excellent results. I guess just kind of in a broader question, what is the required for submission in terms of safety [indiscernible]. And in general, is there anything different in the filing strategy between the U.S. and EU and kind of how you're thinking about maybe rest of the world as well?

Yes, absolutely. So we've obviously had discussions with the agency about the number of subjects that would be in a data set for approval and obviously, confident that we'll have enough patient data to -- for a submission based on this study as well as the other studies that have included patients who received Sepiapterin. So we're confident that we have a patient database that will support NDA submission. That's similar for EMA, 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. So the first priority is to align with FDA and EMA, increased submission meaning that I move as quickly as possible based on discussions of that being towards these submissions and then gradually extend to other key geographies.

Great. And 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 and -- but also given that generic Kuvan is available?

Yes, great question I believe. Again, I'll turn that over to Kylie and her team, who have been looking at that.

Yes. 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. But 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. And so 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 fully controlled.

And our next question coming from the line of Joseph Schwartz with SVB Securities.

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 2 of APHENITY, and how representative of the overall classical PKU population are these patients based on the mutations they have. And then as a follow-up, how confident are you that just 6 classical patients randomized to Sepiapterin is enough experience to gain a label in this subpopulation.

Yes, absolutely. Thanks very much for the question, Joe. So in the part -- in the first part of the study in the run-in phase, obviously, we had the patients that were randomized to 15 classical patients who were over 30%, and we had an additional 5 who were between 15% and 30%. And so 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 running phase. The responders represented really a full spectrum of classical. They had -- they -- including different baseline levels and also different indications, 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. But I think what we can say by and large, is we're seeing market response across the spectrum of classical patients. And I think, again, given the data in those classic patients from both Part 1 and Part 2, we believe they're sufficient to support treatment of classical patients in the label.

And our next question is coming from the line of Gena Wang with Barclays.

I have several questions. First is regarding the 27 patient, who -- can you hear me?

Yes, yes.

Okay, good. So 27 patients who received Kuvan wondering what is the percentage reduction before enrollment percentage of a Phe reduction before enrollment. And how many data points you collect for the baseline? And among all those 27 patients, any were classic patients, that's my first part of the question.

Yes, okay. So thank you for the question, Gena. So those 27 subjects came in, and we had a baseline measurement of those patients at screening. So it was one value measured and as we talked about, they had roughly 590 micromole per liter. They then go -- get washed out for 7 days, and we get their baseline values again after washout, so basically off therapy and that goes to about 700, which suggests that there was a roughly 100 to 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. May then go on to Sepiapterin, and we had a 48% lower level of phenylalanine in the blood relative to what that average level was on Sepiapterin, again, the either branded or generic form. So that, 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. And again, there was 1 -- specific answer to your question, it was one measurement taken on Kuvan and one measurement after washout and then the measurements that were done as part of the Part I study that gave us the blood levels on Sepiapterin.