Spyre Therapeutics, Inc. (SYRE) Earnings Call Transcript & Summary

Greetings, and welcome to the Aeglea BioTherapeutics PEACE Phase III Topline Study Results. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Kelly Boothe, Head of Corporate Communications and Investor Relations for Aeglea BioTherapeutics. Thank you. You may begin.

Thank you, operator, and good morning, everyone. Joining me on today's call to discuss the PEACE Phase III topline results are Dr. Anthony Quinn, Chief Executive Officer; Dr. Eric Bradford, Chief Development Officer; Michael Hanley, Chief Commercial Officer; Dr. Leslie Sloan, Chief Operating Officer; and Jonathan Alspaugh, Chief Financial Officer. The Form 8-K with our press release was filed this morning and is available on the SEC's EDGAR system and on our website. I would like to remind you that various remarks that we make on this call include forward-looking statements for the purposes of the safe harbor provision of the Private Securities Litigation Reform Act of 1995 including, but not limited to, the types of statements identified as forward-looking in our periodic reports filed with the SEC and available on our website. These statements should not be relied on as predictions of future events. I'll now turn the call over to Anthony.

Good morning, everyone. I'm really pleased you're joining us today as we review the results from our PEACE Phase III clinical trial. This is a great day for Aeglea and an important day for the broader arginase-1 deficiency community. We're very excited about the results in the Phase III PEACE trial. The results we're going to discuss today represent an important step in advancing a potential treatment for arginase deficiency, where none currently exist. Before we get to the results, I would like to emphasize that today's news was made possible because of people, passion and great science. And I would be remiss if I didn't mention upfront, the many people who have made this all possible, people who have been in our corner since we began this journey, including our investors and many other stakeholders. Conducting and participating in a clinical trial requires a great deal of dedication and commitment in the best of times. And let's not forget that the majority of this trial was conducted during a global pandemic. I'd like to acknowledge the enormous contribution of the Aeglea team, past and present, whose passion, dedication and energy made this milestone possible. To our clinical trial sites that participated in the PEACE study, including the study coordinators, nurses and investigators, your conduct was nothing short of amazing. We are so grateful for the commitment, professionalism and compassion that you show for the patients you treat, and we very much appreciate the huge contribution you made to the PEACE study. And finally and importantly, a huge thank you to the patients and their families who participated. Your courage and your commitment to participate in the clinical trial, especially during a global pandemic is essential to our mission, and we cannot accomplish this without you and your heroism. Thank you. At Aeglea, we are now at a significant inflection point as a company. We have reimagined the potential of human enzyme therapeutics. And with this data in hand, we're now poised for the potential commercialization of our first innovative therapy, pegzilarginase. We're really excited and energized by the progress we've made, and we look forward to leveraging the experiences from our first Phase III clinical trial as we continue to advance our pipeline. On the call today, we plan to discuss the topline PEACE results and our next steps from a regulatory and commercial perspective. And then we'll take your questions. So let's get to the PEACE results. I will now turn the call over to Dr. Eric Bradford, who is our Chief Development Officer. Eric?

Thank you, Anthony. I am very pleased to present the topline PEACE results, which are summarized on this slide. PEACE is the first placebo-controlled study of an investigative therapy for ARG1-D, a progressive and debilitating disorder. Pegzilarginase is the first potential therapy to normalize plasma arginine levels, a previously unattainable goal in this population. Summarizing the key results. The study met the primary endpoint. Pegzilarginase statistically significantly reduced plasma arginine levels by 80%. We observed additional evidence of arginine control with over 90% of patients achieving normal plasma arginine levels, representing a significant advance for this disease. We are really excited to see that lowering plasma arginine was accompanied by a positive trend in mobility. As you may recall, impaired mobility is one of the hallmarks of this devastating disease. Additionally, we were also very pleased with the favorable safety profile. Pegzilarginase was well tolerated. The PEACE safety data were consistent with the results from previous clinical trials and there was no adverse events resulting in treatment discontinuations. Given these data and the significant unmet need in this underserved population, the pivotal data supports our plans to submit a BLA in the first half of next year. I would now like to walk through the PEACE study design in more detail. PEACE is a global, randomized, double-blind placebo-controlled study that assesses pegzilarginase compared to placebo over 24 weeks. The double-blind period is followed by a long-term extension. 32 patients, 2 years of age or older, were randomized in a 2:1 fashion to receive weekly infusions of pegzilarginase plus standard of care or placebo plus standard of care. The primary endpoint of the study is the reduction in plasma arginine levels from baseline. The key secondary endpoint, assess mobility, are requiring a statistically significant change from baseline and either the Gross Motor Function Measure Part E or the 2-minute walk test assessment. The goal of the study was twofold. One, show a reduction in arginine with treatment; and two, show that the arginine reduction leads to a concomitant clinical benefit as assessed via the key secondary endpoint. In terms of baseline characteristics, the patients enrolled in PEACE are generally consistent with our Phase I/II patient population. As expected, the patient population was predominantly a pediatric population with a mean age of 10.7 years. The majority of patients in PEACE were male and half were from the United States. In terms of baseline clinical characteristics, it is important to note that poor arginine control despite standard of care, which was also consistent with our prior study. Overall, the mean plasma arginine at baseline was 402 micromolar. Patients in the pegzilarginase arm had lower mean arginine levels at 365 micromolar compared to those in placebo at 472 micromolar. Gross Motor Function classification system, or GMFCS, assesses the degree of impairment with higher levels indicating greater impairment. The majority of patients had a GMFCS of greater than or equal to 2. The mean baseline score in Gross Motor Function Measure Part E was 48 out of a maximum score of 72, signifying meaningful impairment. There was little difference across the treatment arms. Finally, the mean distance walk at baseline for the timed walk test was 106 meters. Patients in the placebo arm were somewhat lower at baseline compared to those in pegzilarginase. These met the primary endpoint with pegzilarginase demonstrating a marked and sustained reduction in plasma arginine. On this slide, you can see the change from baseline in plasma arginine, the primary endpoint of the study. The boxes represent the 25th and 75th percentiles of plasma arginine levels. Pegzilarginase is in blue and placebo in gray. At baseline, all study participants had a very high plasma arginine level despite being on optimal standard of care. At the 12-week and 24-week time points, we observed a marked reduction in plasma arginine levels with pegzilarginase treatment. At week 24, pegzilarginase resulted in an 80% reduction in plasma arginine, which was highly statistically significant and very clinically meaningful. The mean plasma arginine level for pegzilarginase was well below 200 micromolar, which is the current clinical goal. We believe that these findings represent a potentially game-changing ability to control plasma arginine in ARG1-D. The arginine reduction we have seen is really striking. But what's more remarkable is the number of patients who reached normal plasma arginine levels between 40 and 115 micromolar. We are very excited to see that pegzilarginase resulted in over 90% of patients achieving normal levels compared to none in the placebo arm. Clinical treatment guidelines for these patients have suggested levels of plasma arginine below 200 micromolar. And treatment with pegzilarginase significantly surpassed this clinical objective. We view pegzilarginase as a potentially transformative therapy for a population with previously unachievable control of arginine. Before we review the key secondary endpoints, I would like to provide an overview of the mobility assessments used in PEACE, namely GMFM-E and the 2-minute walk test. GMFM is a tool to assess gross motor function and was originally developed for patients with cerebral palsy. GMFM-E uses 24 tasks to assess a patient's ability to walk, run or jump and is scored from 0 to 3 with a total score range of 0 to 72, lower scores indicating greater impairment. The time walk test is a common measure to assess mobility and has been utilized across a number of diseases. For PEACE, we utilized the 2-minute walk test, which measures the distance walked over a 2-minute period. Based on the learnings from the Phase I/II study, we incorporated these as the key assessments of mobility. And now I'd like to take you through the results of GMFM-E and the 2-minute walk test. Here, we see the positive trend in GMFM-E in pegzilarginase treated patients first dose in the placebo arm. On the left-hand side of the chart is pegzilarginase change from baseline at 12 and 24 weeks with placebo on the right-hand side. Pegzilarginase demonstrated a 2.9 unit improvement at 12 weeks, further increasing to 4.2 at 24 weeks. This change is consistent with the response over time that we saw in the Phase I/II study. When compared to placebo at 24 weeks, there was a 4.6 unit improvement, highlighting a positive trend with an associated p-value of 0.1087. The positive trend in GMFM-E in the PEACE trial suggests potential improvements in mobility addressing a key need given the high impact on patient quality of life and their families. In addition to GMFM-E, we also assessed the 2-minute walk test as part of the key secondary endpoint. When compared to placebo at 24 weeks, there was a 5.5-meter increase, highlighting a numerical improvement with an associated p-value of 0.5961. We are disappointed that this is not a statistically significant result. It highlights the challenges of designing a study where there has been no clinical precedent in a rare neurological disorder. I would now like to review the key safety results. Overall, treatment-emergent adverse events were mild and moderate in nature. In terms of serious adverse events, 19% of patients in the pegzilarginase arm experienced a serious adverse event versus 36% in the placebo arm. During the PEACE trial, we also looked at specific adverse events, including hypersensitivity and hyperammonemia. Less than 10% of pegzilarginase treated patients had hypersensitive adverse events compared to none in the placebo. These events were managed with routine care and did not result in treatment discontinuations. Hyperammonemia, which is part of the background disease was observed in 14% of patients in the pegzilarginase arm compared to 36% of patients in the placebo arm. Overall, pegzilarginase was well tolerated and demonstrated a favorable safety profile. There were no discontinuations due to adverse events. I've spent a lot of time interacting with physicians who treat patients with ARG1-D, and I'm aware of the challenges for this patient population. I'm extremely excited with the PEACE topline results. Pegzilarginase has the potential to be a transformative therapy in a patient population with high unmet need and limited treatment options. And now I'll turn the call back to Anthony.

Thanks, Eric. Before handing over to Mike, I want to spend a few minutes to do two things. Firstly, I want to briefly summarize the significance of the PEACE data we've reviewed today. And secondly, I want to highlight the robustness of the data package we have for our pegzilarginase program overall. We now have, in our hands, data from a well-conducted pivotal trial with meaningful results. We have a dramatic impact on plasma arginine levels, which was accompanied by improvement in a mobility assessment. The pivotal data supports our planned BLA submission in the first half of next year. Stepping back and looking more broadly at the program, we've generated a very robust data package for pegzilarginase. We have a wealth of clinical data. So the really exciting results from PEACE that we've shared with you today strengthens the data package that we previously generated with our Phase I/II open-label extension. And to remind you, this ongoing study includes 13 patients who have been on pegzilarginase for 2 to 4 years. Taken together, we've gathered significant insights on the safety, efficacy and long-term impact of pegzilarginase treatment in patients with arginase deficiency. Pegzilarginase follows a straightforward biologics manufacturing process, and the regulatory CMC path is really well understood. We're already manufacturing at commercial scale, and we've got our commercial formulation on stability in anticipation of approval and launch. We have a number of important regulatory designations, including Breakthrough Therapy and Fast Track designation. And we believe that overall, this substantially derisks our path to the successful commercial launch. So I'll now hand over the call to Mike Hanley, our Chief Commercial Officer, to highlight what this means for patients and also our approach to bring this potentially transformative therapy to the arginase deficiency community.

Thank you, Anthony. Arginase deficiency is a devastating and progressive disease, associated with the significant burden and early mortality. As PEACE demonstrated the existing standard of care consisting of protein-restricted diet, potential amino acid supplementation and nitrogen scavengers does not allow for patients to effectively manage their plasma arginine levels. From our ongoing dialogue with the ARG1-D patient community, we fully recognize the urgent need for therapies that can effectively reduce plasma arginine. Looking at ARG1-D prevalence, we estimate there to be at least 2,500 patients in global addressable markets, which are highlighted on this slide. Of that, there are at least 250 patients in the United States. If approved, we intend to commercialize pegzilarginase in the U.S. on our own with an organization that would include a small, focused field-based team in key supporting functions. Due to the highly concentrated number of specialists responsible for managing these patients, we anticipate an efficient sales force of fewer than 10 representatives. Outside the U.S., our partner, Immedica, is responsible for seeking approval for and commercializing pegzilarginase in certain countries in Europe and the Middle East. We clearly recognize the substantial unmet need and commercial opportunity in other key markets, and we continue to evaluate partnerships with like-minded organizations who can leverage their own infrastructure and relationships to apply our same launch playbook to bring pegzilarginase to patients in need in key regions throughout the world. As we've outlined in the past, we've been preparing for success with our commercial plans for pegzilarginase. We're educating key stakeholders and building the infrastructure required to ensure that patients who can benefit from this therapy will have access to it, if approved. We've built a commercial and medical team with deep ultra-rare disease experience and a patient-focused culture that places heavy emphasis on execution and urgency. We feel confident that this approach positions us well for a successful pegzilarginase launch and also serves as a strong foundation for Aeglea's future rare-disease portfolio. To sum it up, we're operating with a sense of urgency and efficiency to ensure a successful launch following regulatory approval. We recognize the significant opportunity and the significant need for a potentially transformative therapy like pegzilarginase. So now let me turn the call back over to Anthony.

Thanks, Mike. As I highlighted earlier, PEACE is an important milestone for Aeglea and for the broader arginase deficiency community. So we know that this is a disease where there's significant unmet medical need and that these patients face inexorable progression, which is thought to be due to the markedly and persistently elevated plasma arginine levels. In PEACE, we met the primary endpoint of plasma arginine reduction. We also demonstrated that more than 90% of patients achieved normalization of plasma arginine levels. And we're excited to see that the lowering plasma arginine was accompanied by a positive trend in mobility. In parallel with our clinical trial and other activities to deliver a robust data package for our BLA submission, we're continuing to prepare for a successful launch. Our success in advancing pegzilarginase from research through to Phase III topline data and our efforts to continue building our commercial capabilities sets us up well for the future. This success in our first pivotal study in a rare metabolic disease is also an important milestone for the rest of our portfolio and human enzyme engineering platform. Our second clinical program, AGLE-177, is currently being studied in a Phase I/II trial in homocystinuria. Like pegzilarginase, AGLE-177 relies on our technology platform and our specific expertise in engineering human enzymes against validated metabolite target. Homocystinuria represents an additional opportunity with the large unmet medical need. We are very excited about this program, and we look forward to sharing more on AGLE-177 and the ongoing trial in the future. Before we open the call to your questions, I would like to leave you today with a few closing comments. Today's announcement, and in addition to being important for patients with arginase deficiency, demonstrate that we have the capabilities to progress innovative enzyme therapeutics into the clinic and through registration studies and beyond. Again, I'd like to express my gratitude for everyone involved in bringing about this exciting achievement. Operator, I'd now like to open the call for questions.

[Operator Instructions] Our first question comes from the line of Ted Tenthoff with Piper Sandler.

Congratulations on positive data today. I appreciate, in particular, the reductions in arginine level and the detail that you went through with respect to improvements in performance and motor function. And I'm wondering whether or not through your conversations with various regulatory agencies, if there were any thresholds set and whether statistical significance was required on the secondary endpoints?

Yes. Thanks, Ted. Yes, so we're very excited about the data. As you know, plasma -- high levels of arginine are accompanied by these progressive neurological -- these neurological manifestations. And we have shown that statistically we can markedly lower plasma arginine levels. We're seeing an amazing 90% of patients reducing their arginine levels into the normal range. And then obviously, we'll see GMFM-E with lowering arginine level. So we see the GMFM-E level as very meaningful. And we have not [Technical Difficulty] the data that we have that is allowing us to move forward with the BLA submission.

Yes. Excellent. Good. And then are there any updates on numbers of diagnosed patients in the geographies that you shared? I always find that really helpful and appreciate the outreach that you're doing for this community. But any updates in terms of numbers of patients diagnosed in the U.S., Europe and then rest of world?

Yes. Thanks. I'd like to ask Mike and -- to address that question.

Sure. Thanks, Tony. Yes, from a patient identification perspective, this has long been a focus for Aeglea and it's a key element of our launch plan. We're tracking ahead of other ultra rare benchmarks that we've identified. And we're very confident that we'll continue finding those patients in helping drive that accurate diagnosis. Along the lines of the patient identification efforts, we're also very pleased with the insights that we've gained from profiling the patients. We have a very thorough understanding of the ARG1-D patient population, the demographics, the existing management, the clinical status and believe that the PEACE population is very representative of the broader ARG1-D patient population.

Great. Thank you for the important work you're doing.

Our next question comes from the line of Anupam Rama with JPMorgan.

Congrats on the data. Two quick ones from me. Can you talk about the baseline characteristics between the pegzilarginase arm and the placebo arm? And any impact that might have had on functional outcomes? And can you remind us how functional data trended over time in the Phase I/II as we look to the [ OLE ] from the PEACE study? That's question one. Question two is on the functional side, this was done on a continuous variable, right? So -- but I think originally, it was designed, PEACE, to a responder analysis. Just wondering how the data would have kind of turned out if you would have kept your responder analysis?

Yes. Great. Thanks, Anupam. I'd like to ask Eric to address those questions. Eric?

Okay. So Anupam, in terms of the first question regarding the baseline characteristics in the study between the two treatment arms, overall, we believe they were relatively similar. There are some slight differences in terms of age that were noted in the pegzilarginase arm versus the placebo arm, as we highlighted on our slides. Overall, we believe this is consistent with the broader ARG1-D population and relatively consistent with our Phase I/II study. So we don't really have a demonstrable impact on the overall results. We will note that we have yet to look at specific subgroups or any specificity there around that.

Okay. Anupam, in terms of your second question with regard to the Phase I/II data, just to remind people what we saw with the Phase I/II data over time is over time, we saw continued improvements in the outcome assessment measurements in terms of the GMFM-E and the timed walk test. Eric, would you like to just finish off with the continuous versus the responder analysis.

As you mentioned, we initially had a responder-based approach. We did switch that to a continuous analysis and we've discussed that publicly over the past year with that transition. And we believe the continuous analysis is a more robust approach and hence, the reason we did transition to that. We will look at individual patient level data moving forward to determine which patients met pre-specified responder criteria. But overall, we believe the continuous assessment was the appropriate approach and reflects a well-designed study.

Our next question comes from the line of Sam Slutsky with LifeSci Capital.

Appreciate the questions. I guess, first, as we think about the clinical significance of these data, just can you help us understand what a 4.6 unit relative improvement in GMFM-E score means for patients? And then observationally, what this might look like?

Yes, thanks, Sam. So let me just say something quickly and then I'm going to ask Leslie to provide a little more color on that. Yes. So there has been no previous clinical -- Phase III clinical trial in arginase deficiency. The GMFM-E was originally developed for another disease, cerebral palsy with spastic diplegia. And there is insights from that about what clinically meaningful difference is. So I'm going to ask Leslie to address that.

Thank you. So for the GMFM-E, as Tony said, it was initially developed and validated to assess patients with cerebral palsy. It has also been validated in other disease states. One of the -- there's a few publications. The one we look at mostly is -- it breaks down the sort of minimal clinical improvement that matters into groups depending on their functional abilities. And just to say that a 4-point change is meaningful at a clinical level for the most able of the patients, and it goes down from there. So we're pretty confident and feel pretty good about that 4 point, 4.5 point change.

Got it. And then second question, just I realized we're discussing small patient numbers here. But as you looked across patients, any color that you're able to provide just on the relationship between improvement in functional outcomes relative to baseline severity?

Yes. So Sam, we have -- we've just got topline data. We -- the data that we've seen at a population level with the GMFM-E, we see that as compelling, as achieving what we needed to achieve was linking arginine reduction to a clinical impact, that we have a wealth of data and we'll be looking at that data in more detail moving forward.

Our next question comes from the line of Josh Schimmer with Evercore ISI.

Maybe just to ask a very pointed one based on your conversations with regulators prior to this data, what is it about this data set and specifically the secondary endpoints that does give you confidence that this could have support approval despite missing the p-values? And then second, whether you have any early sense as to how the Phase III results might have deviated relative to your initial powering assumptions, whether you think the nonstatistical significance on secondary endpoints was a result of fewer responders, or less dramatic responders, or perhaps patients who didn't have as much a reversible component of disease as you might have expected?

Yes. Yes. Thanks, Josh. So based on the dialogue we've had with the FDA and the European regulators, we are -- we believe that we need to show statistically significant reductions in plasma arginine levels and link that arginine reduction to clinical impact. As you know that there's not been any previous controlled trials in this rare neurological disease. And we do see the trend that we've seen in GMFM-E and the magnitude of the increase, as Leslie said, with a meaningful increase of over 4, we do see that as clinically meaningful. And as we say, the entirety to the data we have, we will be moving forward with a BLA filing. The second question, I think, what you're asking about is about individual responses and responders. Those are all really good questions and important questions. And we will be looking at those -- the individual patient data for those endpoints moving forward to build a better understanding of that.

So maybe you can explain then why you deem these results to be clinically meaningful, if not statistically significant?

Well, we saw -- the difference between the placebo and the active, we believe that is a compelling trend and that -- and as I say, that's at a population level. The mean increase of the population level was more than the level that's considered clinically meaningful. And with that level.

Maybe you can elaborate on why you view this to be a compelling trend because I think for many of us, these are just numbers that don't really have much clinical meaning. So what is this kind of a benefit mean from a clinical perspective that we may be able to relate to?

Okay. So one way of looking at that is to look at our Phase I -- is to look at our Phase I/II data and where obviously, patients have been on therapy longer. And the changes that we saw in the GMFM-E in the Phase I/II study and the recognition with the physicians that the improvements that they are seeing in the patients I think, validates the fact that those magnitude of changes that we're seeing, they are meaningful. So I think you can't just look at the Phase III data in isolation. It's important that we also can look at it in the context. And what's really important there is consistency in terms of what we've seen with the GMFM-E in this study and what we saw previously in our Phase I/II.

Maybe I can ask it yet another way, what does a 5 unit improvement in GMFM-E actually imply from perhaps activities of daily living equivalent perspective?

Yes. So just as an example, one of the tests on the GMFM-E is to walk up and down a flight of stairs. So that is a set. So based -- if you -- we know that patients over time find it increasingly hard to walk up flights of stairs. So a 3-point improvement would take some degree of struggle moving up a flight of stairs to somebody who could actually move up a flight of stairs -- up and down a flight of stairs. And as you know, previously, we did show some videos of a patient who at baseline was not able to walk up a flight of stairs. So that is a GMFM-E change. That would be a change of 3 in that, and that's clearly a very meaningful thing, and we know from these families that have been able to do something like that is very clinically impactful. So just to summarize, the GMFM-E mean change that we've seen, we believe that's compelling. The magnitude of an increase at a mean level is in the order that is considered a clinically meaningful difference. And then obviously, within that population, we do have patients that are actually showing larger improvements.

Our next question comes from the line of Soumit Roy with Jones Research.

Congratulations on the robust data. One question is, when we look at the placebo arm for both the GMFM-E and 2-minute walk test, there is quite a bit of an improvement between 12 weeks and 24 weeks. Do you have any explanation why it moved so much in favor of improvement? Any color would be appreciated.

So just to -- I think you're asking a question about the improvement in the pegzilarginase arm? Or are you talking about the variability in the placebo arm? Or both?

In the placebo arm because if you look at GMFM-E, to move from negative 3.2 to almost close to baseline and then, also in the 2-minute walk test the placebo arm from between 12 to 24 weeks almost swung by like 10 meters. So why is such a dramatic improvement, which we don't see in the pegzilarginase arm, it's pretty slow improvement?

Yes. So I am going to ask Eric to address that. I'll ask Eric, our Chief Development Officer, to address that question. Eric?

Thank you, Anthony. In terms of the -- for instance, the timed walk test, we know there's some variability in the timed walk test, and this has been demonstrated across various different disease states. When we look at the placebo group, as you acknowledged at 12 weeks, there was more anticipated variability than we would had initially anticipated. At this point, we will have not looked at that level of detail, but we do plan to look into it as we further review the data in more detail. We are encouraged by the positive trend in GMFM-E. We believe that is providing a link between the arginine lowering and mobility improvements, and it supports the positive view we have on this data.

Yes. And so maybe just one other thing to just remind you about, in terms of the pegzilarginase, we see an improvement over time. That is consistent with what we saw in our Phase I/II study. So placebo, as Eric indicated, there's some variability kind of around zero. And as I say, we do expect variability in the timed walk test.

And previously, you have mentioned that you feel confident most of the clinical benefits would be seen around the 24 weeks. Do you still think it's the valid time point? Or 52 or later time points could continue to show the improvement, looking at your long-term open-label trial?

Yes. So the trial was designed based on the Phase I/II data. And the key question was, is it a placebo-controlled trial in pediatric patients with a progressed neurological disease? Based on the insights that we got, much of the improvement was occurring by 6 months. What we do know that there is a continued improvement in patients over time from our Phase I/II. But the challenge is there's a limit in terms of how far you can push things out with regard to placebo controlled duration. So that was why we used the 6-month period because we believe that captured most of the benefit, but it's an important point. Our Phase I/II data indicates that there was continued improvement over time. And just to remind you, we've got patients in the Phase I/II study who have been on a once-weekly subcutaneous injection for 2 to 4 years.

Congratulations again on the positive data.

Our next question comes from the line of Ed White with H.C. Wainwright.

Congratulations on the data. So on a regulatory standpoint, you gave us a time line that you expect for submission in the U.S. Can you give us your thoughts on Europe? And then following that, as far as regulatory goes, how much long-term extension data will you have available when you do your submissions? And how do you think that will impact the submission?

Yes. So in terms of your second question about the long-term extension data, we're really pleased that [indiscernible] one of the patients are in the long-term extension study. The focus of the call today is the topline data for the 6-month double-blind period. The long-term extension data will also be important and will be part of our regulatory filing. And then if -- your other question, I think it was to do with the timing of the regulatory approval in Europe, and I'm going to ask Leslie to address that question.

Thank you. We're working closely with our partners, Immedica, to get this file together as quickly as possible. We expect them to file in 2022 as well. Our goal is really just to, as quickly as possible, get the data together and the file together to get this drug to patients.

Our next question comes from the line of Gil Blum with Needham & Company.

Congratulations on the results. Just maybe another one on the functional improvement. Could you comment on any comparables between what you saw in the Phase I/II and what you've been seeing in the pivotal study at the same time point? Are there large differences in the kind of improvements you've been seeing in subcategories? Or are these basically in line?

Yes. So first of all, at the moment, the -- our focus has been on the topline data and the population effect and that's what we're focused on. We -- based on what we –- we know that there are variability of responses within that group. So I'm going to actually hand over to Eric and he can provide more color on that question.

Thank you, Anthony. To address the question around comparability between what we see in the PEACE study and the previous long-term extension in the Phase I/II, these are in line with what we have seen previously in terms of the timing as well as the magnitude of change. And so we're really confident in the reproducibility or the consistency of the data we're seeing between the two studies.

Maybe another question. So in the previous study, you've also shown 100% of patients reaching "the normal levels of arginine". What of those two patients that did not achieve? Are they trending downwards? Is there -- are they nonresponders? Is there something different about them?

Yes. So we're really excited about we met the primary endpoint with statistically significant differences, 80% difference. But that important point, more than 90% of patients showed normalization of plasma arginine levels. And just to remind you, that has never -- that has not been achieved previously. These patients, as you can see from our baseline, were running very, very high -- were running very high levels. So I think in the context of a double-blind placebo-controlled trial, the arginine data is very compelling and obviously builds on the initial data that we had in an open-label study.

Okay. And again, congratulations on the results.

[Operator Instructions] Our next question comes from the line of Yanan Zhu with Wells Fargo Securities.

I might have missed this in your answer to an earlier question. The audio seems to be cut off for a few seconds. But in your prior interaction with FDA, have you had a clear understanding from the agency whether statistical significance is required for at least one of the secondary functional endpoints? And then another question is given that this therapy has breakthrough designation and -- which are for frequent interactions with the agency, would you be talking to FDA about your ability to file before you make the BLA filing?

Yes. So as I said earlier, based on the dialogue that we have with the regulatory authorities, we believe that we need to show a statistically significant reduction in plasma arginine levels, and we need to be able to show that, that improvement is accompanied by a clinical improvement, and the way that we did that is using these clinical outcome assessments. That's why we are -- the GMFM-E data that we've seen in the PEACE trial, is very compelling. We know that -- I can't -- we can't predict what the FDA will do or say, but we believe that the data we have -- the package of data we have is compelling, and we'll be moving forward to file our BLA. And we -- as you've indicated, we do have an advantage in that we do have these designations, which will support dialogue with the regulators.

Thank you. Ladies and gentlemen, this concludes our question-and-answer session. I'll turn the floor back to Mr. Quinn for any final comments.

Yes. Thanks very much for joining our conference call today. We're excited about our next steps of pegzilarginase. We're committed to identifying innovative therapeutics for patients with rare and devastating metabolic diseases as we pursue our vision to be the premier human enzyme company. Thank you.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.