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

Welcome, everyone, to the annual -- 40th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Caleb Smith, Malcolm Kuno and Priyanka Grover from the team. Our next presenting company is Aeglea. And presenting on behalf of the company, we have CEO, Tony Quinn. I just want to remind folks that there is an Ask A Question feature in the portal. And if you would like me to ask you -- ask a question on your behalf, put it in the portal and I'd be happy to do so. With that, Tony, take it away.

Great. Thanks very much, Anupam. Good morning, everyone. I'm very pleased to join you at this year's JPMorgan Healthcare Conference, albeit virtually. Last year was a really important year for Aeglea with positive top line data from our Phase III study in arginase deficiency and advancement of our second innovative enzyme therapy into the clinic. So building on these achievements this year has the potential to be a transformative 1 for the company, and I'm looking forward to walking you through these exciting developments today, so let's get started. So please note I may be making some forward-looking statements. At Aeglea, we're thinking really differently about the science of human enzymes. We are reimagining the potential of enzyme therapies to address the imbalances that are found in rare metabolic diseases. We believe that by engineering a small change in a human enzyme, we can have a big impact, benefiting patients and their families who are living with rare and devastating metabolic diseases where there's limited treatment options. 2021 was a year of significant accomplishments for Aeglea, particularly regarding our lead program, pegzilarginase for the treatment of arginase deficiency. So in addition to delivering positive top line data, which I'll cover in more detail later in the presentation, we made significant progress in our commercial preparations. We signed a license and supply agreement with Immedica to commercialize pegzilarginase in Europe and certain countries in the Middle East, and we continue to progress the key objectives in preparing for the potential U.S. launch. So these activities, this set us up for a transformational 2022, including the planned filing of the U.S. BLA Americas planned to file the MAA in Europe, continuing the preparations for potential approval and launch and progressing our scientific communication strategy by leveraging the important data from our clinical program as we continue to build disease awareness with our key stakeholders. For our second program, AGLE-177 in homocystinuria, we began dosing and generating clinical data in 2021. And today, I'm going to share some important advancements we've made in the program, and I look forward to sharing initial clinical data later this year. So in addition, I'd also like to call out our cystinuria program. We haven't shared much about this program, but we've been really hard at work, and we now have a new candidate that we've advanced through lead optimization, and it's got the attributes that we believe will support an attractive clinical dosing schedule. The plan is to advance it through our IND-enabling studies this year as we prepare for our third innovative enzyme to enter clinical development. All our investigational medicines are designed to address metabolic imbalances found in rare diseases that have limited or no effective therapies. So this model allows us to apply our innovative human enzyme science to disease areas where there's limited competition and to take advantage of the complementary manufacturing and commercial infrastructure and that gives us multiple exciting opportunities in our pipe yard. So beyond the clinical programs, we've got a strong preclinical pipeline of yet to be disclosed programs that we are generating from our human enzyme engine platform. So I'd now like to get to our most advanced program, pegzilarginase, on Slide 7. Arginase deficiency is a rare debilitating progressive disease, there's early mortality and very high unmet medical need due to a genetic disorder of arginine metabolism. So the hallmark of the disease is high arginine levels, and that's the key cause of many of the severe disease manifestations, including a really characteristic spasticity, which begins in early childhood. Now disease progression, that leads to increasing mobility challenges with many patients as the disease progresses, requiring walking aids and eventually becoming wheelchair bound. And in addition, patients experienced developmental delays, intellectual disability and seizures. The current tax out of the care is challenging to maintain. And even if patients comply, it has limited effectiveness. So what does that mean? That means that these patients are not able to control the plasma arginine levels, the disease continues to progress, and that leads to increasing disability, severe disease manifestations and poor outcomes. The therapy that we're developing to treat arginase deficiency is pegzilarginase. It's an engineered human enzyme. It's designed to lower arginine levels in the blood. We've conducted the first clinical program for arginase deficiency, including the first-ever placebo-controlled trial and the largest prospectively studied cohort of arginase 1 deficiency patients. We've generated very compelling data, and we're really excited about the opportunity in front of us with this program. So based on the genetic prevalence work we've done, we believe that there's over 2,500 patients in global addressable markets and there's a huge need for a therapy that addresses the high arginine levels. So we plan to file our BLA with the FDA in the first half of the year, and we're very excited for the potential approval and launch for what we believe is a therapy that can change the lives of these patients and their families. So Slide 9 shows the trial design of PEACE, a 6-month double-blind, placebo-controlled trial, which is followed by a long-term extension. The top line results in the double-blind portion were announced in December 2021. The primary endpoint was plasma arginine reduction and the secondary endpoint looked at improvement in GMFM-E and/or the timed walk test to assess a functional benefit. We enrolled 32 patients in the study and all 31 patients that completed the double-blind portion continued into the long-term extension. So let's first look at the safety results. pegzilarginase was well tolerated and demonstrated a favorable safety profile. Overall, the adverse events were mild and moderate in nature. There were no discontinuations due to treatment-emergent adverse events, hypersensitivity reactions were infrequent and they were managed with routine medical care. So we're really pleased with the safety data from PEACE. It aligns from -- with the results from our previous Phase I/II trial and it should support a strong commercial uptake. So as I mentioned, the primary endpoint of PEACE was reduction of plasma arginine levels at 24 weeks compared to placebo. This was met with high statistical significance with a p-value less than 0.001. You can see at baseline, all of the participants have really high levels of plasma arginine despite being on optimal standard of care. At week 24, pegzilarginase resulted in an 80% reduction in plasma arginine. The mean arginine level for pegzilarginase was well below 200 micromolar, which is the current clinical goal. So we believe that these findings, they represent a game-changing ability to control plasma arginine level in arginase 1 deficiency. And I'd like to dive a little deeper into that in the next slide. So the arginine reduction we have seen is really striking, but what's even more remarkable is the number of patients who reached normal plasma arginine levels between 40 and 150 micromolar. Over 90% of patients achieved normal levels compared to none in the placebo arm. It's really important to remind everyone that achieving normalization of plasma arginine, that was not a treatment goal that was even considered feasible with currently available treatments. To achieve this in such a high proportion of patients, we believe, is a very clinically meaningful result and it highlights the potential of pegzilarginase to be a potentially transformative therapy for a patient population with previously unachievable control of plasma arginine. Slide 13 shows the results of the GMFM-E and the 2 Minute Walk Test, the 2 mobility assessments that made up our key secondary endpoint. So if you look at the left-hand side, we see the positive trend in GMFM-E and pegzilarginase-treated patients versus those in the placebo arm. So pegzilarginase demonstrated 2.9 unit improvement at 12 weeks, increasing to a 4.2 unit improvement at 24 weeks. The change that we saw was consistent with the response over time that we saw in our Phase I/II study. And when you compare it to placebo at 24 weeks, there was a 4.6 unit improvement, highlighting a positive trend with an associated p-value of p 0.1087. So if you want to put this in perspective, what does a 4.2 change mean in GMFM-E? So a clinical meaningful difference using GMFM-E is defined by 2.8- to 4-unit improvement depending on the severity of the disease at baseline. So we were really pleased to see that the improvement that surpassed that 4-unit improvement level. So if you now look at the 2 Minute Walk Test results on the right-hand side, so compared to placebo at 24 weeks, there was a 5.5-meter increase, highlighting a numeric improvement that did not reach statistical significance. So the positive trend in the PEACE trial suggests the potential mobility improvement, which remains a significant unmet need due to its impact on the quality of life of many patients and their families. So we believe that this effect in the context of a placebo-controlled trial, it provides evidence that links arginine reduction to mobility improvement. And that's further supported by the long-term data from our Phase I/II and open-label extension studies that I'm going to show you in the next slide. So we've continued to generate incredibly compelling data from our ongoing open-label extension study, which has had 13 patients on treatment for a duration ranging from 2 to 4 years. We've previously shared the 20- and the 56-week analysis, and what I'd like to do today is share an additional long-term data with the 104-week analysis. So as you can see, not only have we seen mobility improvements that are sustained over time in what is normally a progressive disease, but in GMFM-E specifically, that effect has actually increased with longer-term dosing. While you might not see worsening in the -- over the course of a 6-month study, over 2 years, you would expect these patients to decline. So the results that we are seeing here support the clinical benefit that we believe pegzilarginase provides to patients, and it's going to be an important part of our regulatory submission. So moving on to our planned BLA submission on Slide 15. We are very confident in the package we are putting together. We've shown impressive and clinically meaningful results, both with the normalization of arginine levels and the mobility improvement sustained over nearly 2 years. Together with the strong safety data, we feel that pegzilarginase has a very compelling risk-benefit profile and has the potential to be a life-changing therapy for arginase 1 deficiency patients and their families. So we're hard at work completing our BLA filing, which we plan to submit in the first half of the year. We're excited about the commercial opportunity that we have in front of us in a disease with a significant unmet medical need and more than 2,500 patients in addressable markets including more than 250 patients in the U.S. and another 900 patients within the territories that are covered by America. So as I mentioned earlier, this is a devastating progressive disease where the existing standard of care is ineffective and challenging to adhere to and where there are currently no FDA approved therapies that address the harmful high arginine levels that these patients are experiencing. As we prepare for commercialization, we're focused on the 4 key objectives for a successful rare disease launch: patient identification, disease education and awareness, access and reimbursement and organizational readiness. We've made significant progress across all 4 of these objectives, surpassing prelaunch benchmarks for patient identification developing deep relationships with the patient community and the healthcare providers as well as engaging with peers so we can educate them about arginase 1 deficiency and the need for new therapies. Additionally, we've built a commercial medical team that's got deep ultra rare disease experience and a patient-focused culture that places emphasis on execution and urgency. So we're confident that the commercial planning currently underway represents a strong foundation for our successful pegzilarginase launch in the near term and to support our future rare disease portfolio in the longer term. That's a nice segue we enter second clinical program, AGLE-177 which is in development for the treatment of homocystinuria. So Slide 18 provides an overview of homocystinuria. This is another debilitating progressive chronic disease with early mortality. So in addition to the disease burden, which includes a lifelong risk of sudden unpredictable thrombotic events, the current treatments, including the severe lifelong protein restriction, that has a huge adverse impact on the quality of life of the patients and their families. So homocystinuria is a more common rare metabolic disease. We estimate that at least 30,000 patients in the major addressable markets globally. These patients experience a wide range of serious disease complications, including dislocation of the lens, intellectual disabilities, developmental delay, skeletal deformities and sudden life-threatening thrombotic events like a stroke or a heart attack. So homocystinuria is well understood and the natural history demonstrates both the severity of the disease. And importantly, that there is a clear link between the risk of death and other serious complications and plasma homocystine levels. So Slide 20 shows our therapeutic approach for treating homocystinuria by focusing on controlling homocystine levels in the plasma. Now in the plasma, homocystine exists in 2 forms: as a monomer and as a dimer. And given that most of the homocystine is in the dimer form, we've designed a human enzyme that metabolizes both the monomer and the dimer as we believe that's the most effective way to control plasma homocystine levels. We are really pleased with the profile of AGLE-177 which you can see in Slide 21. So the graph on the left, it was data from a mouse model of homocystinuria. Without treatment, the mice die quickly. With treatment twice weekly, we saw a survival benefit with a total weekly dose as low as 2 mgs per kilogram per week. So this total weekly dose is 10-fold lower than what's been reported for a survival benefit with a competitor enzyme. So if you look at the right-hand side of the slide, you can see some results from our toxicology studies on the effectiveness of once-weekly dosing with 177 in lowering homocystine levels. So in Tox studies, we're using normal animals, meaning that they don't have elevated homocystine levels. So despite this, we're still able to see a clear dose-dependent reduction in homocystine levels in these animals. So this is in contrast to what's been reported in the literature with the competitor enzyme, which was not able to lower homocysteine levels in normal animals with doses in [ VAT ] 74 to 80 hours of up to 24 mg per kilogram and in [ incinos ] every 72 hours of up to 10 mg per kilogram. So the survival data in CBS [indiscernible] mice at low doses of 177 and the ability of 177 to substantially lower homocystine levels with once-weekly dosing in novel animals in our toxicology studies is consistent with our view that our enzyme is a highly effective way of controlling plasma homocystine levels. Our focus remains progressing our Phase I/II trial and generating clinical data. And this slide lays out the trial design Slide 22. So after the initial IV dosing cohort, we switched to subcutaneous dosing for our dose escalation cohorts. In addition to determining safety, tolerability and pharmacokinetics, we're going to gather insights on the effects on plasma homocystine levels. Dose-dependent reductions in homocystine that would establish proof of concept and set us up for discussions with regulators on registration study requirements. So we're excited about the data we generated for this trial, and we look forward to sharing some clinical data later this year. 177 represents an innovative approach for the treatment of homocystinuria with a number of key attributes that are important differentiators from the other enzyme therapy that's in development to treat homocystinuria. We've made significant progress in the 177 program across clinical, preclinical, manufacturing and regulatory work. We have all the pieces in place to rapidly move into a registration study. Should the results from our Phase I/II study support the potential that we believe that 177 has. We've been able to apply all of our learnings from pegzilarginase program to create an efficient, effective and scalable manufacturing process, not only for our trials, but also to be able to support the commercial opportunity that we see for 177. In addition, we're focused on moving forward with a convenient once-weekly subcutaneous injection and we already have a very promising high concentration liquid formulation available to support this. The chronic tox studies that bolsters our confidence in the potency and the safety of 177 and the potential advantage it has by degrading both the dimer and the monomer. And we have the designations to facilitate dialogue with the regulators and accelerate the process where we can. We're really energized about the potential of 177 to be a transformative treatment for homocystinuria. And the advantages that we see in the profile of 177 as we continue to advance this program. We're really excited about progress we've made with the program across multiple fronts, and we look forward to sharing clinical data later this year. Moving on to our broader human enzyme platform and our lead preclinical program for cystinuria, we believe that there is untapped potential in human enzyme therapeutics and we are working to design solutions for a range of rare diseases through our active enzyme engineering platform. So I'd like to highlight our most advanced research program, which is focused on lowering urine cystine levels in patients with cystinuria who get frequent recurrent kidney stones. So this is an example of taking an innovative approach to using human enzymes. There are no human enzymes at metabolized cystine. So we took another human enzyme that metabolizes its chemicals similar to cystine and by making some targeted changes we created a human enzyme with novel cystine metabolizing activity. By lowering cystine levels in the blood, we believe we can lower the cystine levels in the urine and therefore, reduce the inflammation. So we've presented proof of concept previously with a prototype that this novel approach work. And we've been really hard at work on this program. And what we now have is a new candidate that we've advanced through lead optimization that has the attributes that we believe would support an attractive clinical dosing schedule. So as you can see from the graphs on the right, AGLE-325 is very effective at reducing kidney stone formation with a marked reduction in the volume of stores in the treated animals. So in addition, we are also able to show that 325 it prevents the severe kidney damage that accompanies stone formation in the mouse model cystinuria. We're going to be moving 325 through IND-enabling studies this year as we prepare for our third innovative enzyme to enter clinical development. This is a really exciting opportunity, and it fits well within our strategy of developing treatments for under surgery [indiscernible] diseases. So I'd like to leave you just with a few thoughts on our recent complements and our future outlook. So in 2021, we positioned ourselves to successfully transform into a commercial stage company with positive Phase III data, a commercial partnership and advancing one objectives. We look forward to working with the FDA on our BLA filing and to work with Immedica on the MAA filing this year. So beyond pegzilarginase, there's incredible future potential for Aeglea. Our homocystinuria program is progressing nicely in both clinical and nonclinical efforts. We're excited to be laying the groundwork to advance our third therapy, AGLE-325 into the clinic for the treatment of cystinuria. We are looking beyond the conventional, to identify innovative therapeutics for patients with rare and devastating metabolic diseases as we pursue our vision to be the premier human enzyme company. To do so, we've positioned Aeglea to redefine the potential of human enzymes, deliver disruptive solutions and change the lives of patients, their families and their caregivers. Thanks very much. And let me now hand back to Anupam for the Q&A.

Tony, if you want to introduce the broader team on the line, we can get started.

Yes. So I'd like to welcome Jonathan Alspaugh, who's our CFO, joining us; and Mike Hanley, who is our Chief Commercial Officer.

And I just want to remind those who are on the line that if you have a question, please put it in the portal, and I'm happy to ask and we do actually have a question in the portal, which is in the Phase III PEACE study, all patients receive basic treatment while receiving the drug. [Technical Difficulty] Would Aeglea's enzyme replacement therapy allow patients to remove sort of background treatment? Is the question.

So our trial was designed on top of current standard of care, which is a severe protein restriction and use of ammonia scavengers. And protein restriction is used for 2 reasons. One is to lower the arginine levels and the other one is to reduce the nitrogen load, the hyperammonemia. In contrast to the other urea cycle deficiency patients, the protein restriction is much more severe in arginase deficiency because you're trying to limit the amount of arginine and precursors in the diet. And but we haven't specifically studied that at the moment. But given that -- we know what the insights from other education by UCD for this hyperammonemia, that's obviously something that may be of interest.

One of the key controversies post the PEACE data has been on sort of the functional endpoints and the benefit observed. What have regulators outlined in terms of functional assessment and the benefit needed for an approval?

So in terms of the dialogue we've had with regulators, we knew that we needed to statistically significant reductions of plasma arginine levels, preferably arginine level reductions that are clinically meaningful, which is why 90% of patients normalizing is actually important and be able to link that arginine reduction to a clinical impact. We -- this disease had not been studied previously until we embarked in this program. And we learned that the GMFM-E was a good way of capturing mobility assessments. The data we've got from our Phase III study, it's very consistent. It's a similar magnitude of improvement that we saw in the Phase I. But importantly, what we now know is what is the placebo response in that patient population. So we believe that, that data with the arginine lowering effects that we've seen is pretty compelling data, and we will be using that to move forward with discussions with the regulators.

The BLA filing is first half. What are the gating factors there? And when you think about the -- you presented a slide that showed that the function improved over time. So when you file, will it have a later data functional cutoff for data than what we saw in the top line.

Yes. So we believe at the moment, we have sufficient data that to file with. That's the long-term follow-up data from the Phase I/II the PEACE data. We've been working hard on the other activities that needed toxicology and preclinical CMC. So we don't believe that we need any additional data at the moment. It's important to recognize that we will. We've only presented the top line data from PEACE for the 24-week double-blind period and there will be additional data being generated as we move forward over the next 6 to 12 months.

We've got a couple of questions in the portal. One is, "where are you in terms of your field force build-out, what field force roles do you anticipate having?"

Yes. So I'm going to ask Mike, our Chief Commercial Officer. Mike, you can take that one. Thank you.

Sure. Sure. Thanks, Anthony. Yes, Anupam, we anticipate a very targeted approach here, right? We know from our efforts engaging with physicians that roughly 75% of the patients we've identified are seen among 30 institutions. So that sort of gives you a sense of how focus this can be. So we already have medical affairs, field-based positions in the field. We have patient affairs managers in the field. And then on top of that, we would obviously layer in salesforce closer to approval and we'd anticipate no more than 10 representatives to be able to cover both the prescribers as well as the referring specialists.

Sure. Back to the Phase III PEACE study, did you see a correlation between keeping blood arginine levels below 200 and clinical improvements?

Yes. So Anupam, here's the disadvantage of having a highly effective therapy. In our pegzilarginase largely treated patients, more than 90% of the patients where we're actually within the normal range. That's where the placebo group is very important. So in the placebo group, there was no numeric improvement in the GMFM-E at 12 weeks or 24 weeks. So that's the key -- that's why the placebo data is very important because that's the first time there's been an opportunity to look at longitudinally, what happens in the context of a placebo-controlled trial in the placebo group. And that is important because it allows us to put the GMFM-E data in context, not just for PEACE, but also for the data that we saw in our Phase I/II open-label extension.

We've got another question here in the portal, which is on 177. "What are the strategies to improve diagnostics and newborn screening in the U.S. for homocystine levels?"

Yes. Let me touch on that quickly, and then I'll get Mike to say a few words. So homocystinuria, newborn screening has been available for homocysteine urine for some time in the U.S. But what's recognized is it does have some limitations in that it doesn't identify all of the patients. So it's a little bit like a challenge we have with arginase deficiency. Arginase deficiency is available, but it misses patients. So it's nice to have that foundation for any disease moving forward. But the important thing to build on is do exactly what we've done for pegzilarginase is the importance of raising disease awareness. So I'll hand over to Mike. He'll provide a little bit more color. This is very close to -- he's very involved in this type of thing, Mike.

Sure. Anthony, I mean, it is -- there's a lot of parallels with our efforts in ARG1-D. And so the fact that newborn screening exists is fantastic, and it gives patients an opportunity to be diagnosed, but we also know patients are often missed, right? So similar to what we're doing with ARG1-D, it's really less of a challenge to accurately diagnose that the means are there. It's the awareness among the referring physicians who are treating these patients to know enough about the disease to be thinking about an underlying metabolic disorder. So those are the efforts we're really focused on in addition to newborn screening is making sure physicians are aware of the disease and looking for it quickly -- early.

Maybe I'll follow up on this. But in the U.S., specifically on Arginase 1 Deficiency, like not all states, right, have newborn screening and the testing levels, right, for Arginase 1 Deficiency like the level is not standardized, right, in the diagnosis. Like how do you kind of bridge the gap there?

Yes. Mike, do you like to...

Yes, sure. Sure. So Anupam, you're correct. We estimate that about 2/3 of the states currently have ARG1-D on their newborn screening panels. But to your point, the levels that are required to detect a positive are often different. There is inconsistencies. So our goal is, again, I mean, what I said before is to drive an early accurate diagnosis that comes through improvements in access to newborn screening, but it also gets to the point of educating those physicians who are seeing these patients who didn't have an accurate diagnosis of birth to make sure that they have awareness and access to the tools to be able to make that diagnosis as quickly as possible.

Okay. Maybe a final question for me here on 177 on the data readout from the Phase I/II later this year. You talked a little bit about the size and scope of the data we're going to be getting. And I guess what level of plasma homocystine levels are you looking for that would be kind of clinically relevant?

Yes. So Anupam, thanks for the question. So we -- you can see the preclinical data that we presented. We're really excited about that preclinical data we have. What we now know is that preclinical data translates into human data. If you can lower it in animals, you can lower it in humans, that's important. What we're really excited about is the insights that we've got in terms of survival benefit with a very low dose. And also the fact that we can see these pharmacological effects in our toxicology studies with a single dose very, very important. So our focus at the moment is continue to recruit that trial to remind people, the doses, we start at a low dose of 0.15 mg per kilogram and the top dose we're proposing is 1 mg per kilogram at once weekly and we're working to continue to generate data. We haven't given any additional guidance beyond that we will provide a clinical update this year. But I also do want to emphasize the other thing that we've been very focused on, which I highlighted in my talk, is making sure that the other building blocks that you need to be able to follow-up after discussion with the regulators, transition into a registration study that those -- that we're making good progress on those. And I'm really pleased about where we are with those at the moment.

All right. Tony and team, I want to thank you guys so much for taking a few minutes this morning and walking us through the spectrum of programs. It's been a super productive session. So thank you guys so much, and have a great rest of the conference.

That's great. Thanks, Anupam. Good to see you.

Thank you.

Thanks very much.