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

Good afternoon, everyone. My name is Tessa Romero. And I'm one of the biotechnology analysts here at JPMorgan. On behalf of myself, Anupam Rama, Matt Bannon, I am pleased to welcome to the stage Aeglea. And presenting on behalf of the company is CEO Anthony Quinn. Tony?

Yes. Thank you for the kind introduction. It's great to be here. Looking forward to presenting at JPMorgan today. I will be making some forward-looking statements with risks and uncertainties. Obviously, please refer to our SEC documents. So at Aeglea, we are thinking about the science of human enzymes very differently. We're actually reimagining the potential of these natural human catalysts to address unmet medical need for patients with a range of rare genetic disorders. We have a platform that allows us to develop innovative therapeutics with unique mechanisms that can actually have the potential to truly have a differentiated therapy that changes the lives of patients. I'm going to walk you through how we're going to get there. We've got a clear vision about how -- where we're going to go, and I'm going to walk you through now how we're going to get there. So we have this unique ability to take an enzyme and to make it better, and that's the focus of our discovery effort. We have expertise and focus in genetic disease. We have a very distinctive disease selection approach. We look for diseases, whether it's a metabolite driving the complications of the disease. We use a human enzyme scaffold to manage the levels of that metabolite. The advantages of working in rare disease is the biology risk is lower because of the translatable animal models and because we're working on human enzymes that are doing natural things. That reduces the toxicology risk. We all recognize that the development and commercialization of rare disease has advantages over working in big indications. We can do smaller clinical trials. We are working on diseases with high unmet medical need, which gives us good interactions with the regulatory authorities, and we can commercialize these products with a relatively small footprint. Our pipeline illustrates our approach. Our lead program, pegzilarginase, is in Phase III for arginase-1 deficiency. We just announced on Monday that we filed the CTA for our second program for homocystinuria. We have another program in IND-enabling studies for cystinuria. And we have other research programs that are unlocking the potential of these opportunities of human enzymes to change the outcomes of patients with rare diseases. I have a team that has deep experience in discovery, development and now, with the addition of a Chief Commercial Officer, in commercial that is helping drive all of the work that we're doing. So let's move to arginase deficiency, our lead program. Arginase deficiency is a devastating disease. It presents early in life, right about 2 or 3 years, with spasticity and then progresses to severe irreversible complications. There's very high unmet medical need with no effective therapy, and most patients are dead by the age of 40. We are presenting some new data where we've been looking at the genetic prevalence of the disease instead of newborn screening, and that gives us an estimate globally of at least 2,500 patients in the major addressable markets. This is a very important slide. This shows 2 important things. Firstly, in the orange box, you can see the markedly elevated levels of plasma arginine in patients on current standard of care at baseline. The first blue box shows the effects of a single dose of pegzilarginase. The second blue box shows the marked reduction with once week 8, once-weekly repeat doses of pegzilarginase. And this is a lifelong therapy, so it's important that you can sustain that benefit. So you can see in our open-label extension study, we're maintaining our gene levels either within or just above the normal range. What's very important is this transformative ability to control plasma arginine is accompanied by a marked improvement in the clinical manifestations of the disease. We saw a 79% overall clinical responder rate after 20 doses and the clinical response is captured using 3 complementary mobility assessments, timed walk Test, a GMFM part D and GMFM part E. This is a patient who's been treated. She's 19. You can see in the pictures the marked improvement after 20 doses of pegzilarginase. She was dependent on a walker, had severe spasticity at baseline. Pegzilarginase lowered her arginine levels from 363 down to 108 micromolar. She's able to sit cross legged because of the marked improvement in her spasticity. I'm now going to show a video of this patient and a second patient showing the types of improvement we see in these patients when we're able to lower the plasma arginine levels. [Presentation]

So the first patient, this patient. She's going to perform a test that involves walking and cutting an object that tests balance; and 2 aspects of motor function, walking and holding something. You can see she is swinging from side to side. She is unsteady. She's not able to hold the ball with both hands because she's reaching out to balance. This was 8 -- after 8 doses. The second video shows her walking after 20 doses with a longer duration of arginine control. You can see her overall walking has improved. She's less unstable on her feet. She's able to complete the test, holding on with both hands with the object and successfully completes the test. We're now going to look at the same patient walking up a flight of stairs. At baseline, she was only partially able to complete the task. The video will show a comparison side-by-side of her performance after 8 doses and after 20 doses of pegzilarginase. So on the right, you can see her moving up the stairs quickly with more fluid movement after 20 doses, whereas after only 8 doses, you can see she's still struggling to manage the stairs and she's having to put a lot of thought as she tries to move one leg up from stair to stair. I'm now going to show a second patient, and she will -- we have a video of her crawling up a flight of stairs. She wasn't able to do at baseline. And you can see the difference between 8 doses and 20 doses. Again, a similar appearance. She's much more fluid on the right-hand side because of the reduction in spasticity. She's moving up the stairs quicker. She gets to the fourth stair and then she starts to come down, whereas after only 8 doses she is much slower because of the more marked spasticity. I'm now going to show a video of this patient walking up a flight of stairs. At baseline, she was unable to walk up the stairs. After 8 doses, she also couldn't walk up the stairs, and we'll show the video of her after 20 doses. Now walking up the stairs is important for these children because what happens is, as they lose mobility -- we know of cases where families have had to move house because the kid has been no longer able to manage stairs. So at baseline not able to do it, 8 doses not able to do it. And this is showing her after 20 doses with a longer duration of good plasma arginine control. So you can see she's moving up the stairs very fluidly with minimal support. She gets to stop -- top, turns around quickly and then heads down the stairs. And these assessments that I'm showing you, the assessment cutting the object, walking up the stairs, are part of the mobility assessments that we use to assess benefit. I'd obviously like to thank the patients for giving their consent to be able to show this video. Safety profile. Pegzilarginase is well tolerated. Most treatment-related adverse events were mild and treatment-related adverse events over time have been decreasing in frequency. This is an outline of our pivotal Phase III trial. We dosed the first patient in June of last year, and we expect to complete enrollment in the second half of this year. Double-blind placebo-controlled trial for 6 months. We have 20 patients on active, 10 on placebo. And then everybody will then switch on to pegzilarginase after the double-blind period. The primary end point is plasma arginine reduction. And the secondary end point, the key secondary end point, is a clinical responder assessment based on the 3 same complementary mobility assessments that we've used in the Phase I/II study. We've been looking carefully at the market opportunity. We have developed a patient identification strategy which has been highly effective at finding patients. The strategy involves conventional approaches with reaching out to physician, raising awareness at academic meetings and visiting physicians in their offices, but we've also instituted some innovative strategies that are using new DNA approaches in genetic testing to be able to identify these patients. We've developed a much better understanding of the market opportunity for arginase-1 deficiency. When we started, the only information we had was newborn screening data. Newborn screening is done in 34 to 50 states and in a small number of countries globally, so it doesn't really provide a very good geographic understanding of the disease. There are also limitations with newborn screening. There's a false negative rate. There's variability in the cutoff thresholds between different states and different countries. Using the newborn screening data, we estimated 1,000 patients in the major addressable markets. We've now done a genetic prevalence study where we look at all of the described mutations that are pathogenic in this condition. And then we look for the frequency of those mutations in exome sequencing databases that are available from a large number of subjects. Once we can work out the carrier frequency, we can then estimate the number of patients on a global basis, and that estimate gives us a market opportunity of more than 2,500 patients in the major addressable markets. The number in the states is 250 with a genetic prevalence, and in Europe 740. We are very confident about finding these patients. We've already identified more than 100 patients in the U.S., which represents 40% penetration into the genetic prevalent population. So let's just summarize quickly. We've done a Phase I/II study. We've got compelling data on the effects of arginine reduction associated with clinical benefit. That's used, been used to inform the design of a pivotal trial and it's also given us breakthrough designation. We are running our Phase III trial at the moment. We expect to complete enrollment in the second half of the year. And in parallel with that, we're ramping up our patient identification efforts. So let's move on to our second program, ACN00177, which has come out of our homocystinuria program. Homocystinuria is another devastating metabolic disease where the complications are related to the high levels of a metabolite. There's very high unmet medical need. These patients die early and they experience serious complications. They have problems with their eyes, with lens dislocation and glaucoma. They have softening of the bones and osteoporosis. They have developmental delay and intellectual disability, and then they have -- are at a risk of a catastrophic [ subnormal ] onset complication [ of ] thrombosis. And we are aware of patients with this disease developing a stroke in early childhood because of the high homocystine levels. This is a much more common rare disease indication with at least 5,000 patients in the major addressable markets. There is good natural history data available. There's a study with over 1,000 patients that was published. It establishes 2 things. First of all, it's a bad disease with mortality and serious complications. And secondly, because there are different part -- disease, there are different mutations causing different severity of the enzyme defect, we can also link the risks of mortality and other complications to the severity of the metabolic defect and the homocystine level. So patients do worse if they have a higher homocystine level. We understand the current management of these patients and the inadequacies of treatment. Current treatment is inadequate because of limited effectiveness, noncompliance and poor tolerability with the amino acid supplements and the betaine. There are 3 key areas of unmet medical need: therapy-resistant patients, patients who are at high risk of noncompliance and at risk of catastrophic complications and patients who are intolerable of available adjunctive therapies. We have -- this is the biochemical aspect of the disease. The red box shows the accumulating homocystine. Homocystine, when it accumulates in the blood, it binds to itself to form homocysteine. We've designed an enzyme that is able to break down both homocystine and homocysteine because we believe that will give us the best control of plasma homocystine levels. We took that molecule into a mouse model of homocystinuria, and you can see the reduction in homocystine levels. We then looked at it in a knockout model of homocystinuria. If you look at the graph on the -- it shows you in the red line the high mortality of these animals without treatment. We looked at 3 doses, a low, medium and high dose. We saw survival benefit with all 3 doses and 100% survival with the medium and high doses. And then on the right-hand side: This is important. We are lowering the homocystine levels in the plasma, but what you can see is that the abnormalities in the liver are corrected by that effect. So the liver is very abnormal at baseline, and after treatment, we normalize the liver by lowering the plasma homocystine levels. So this is a very translatable model, and it gave us confidence to move forward into the clinic. We've now filed the CTA. We've laid out the design here for our Phase I/II study. It's a study that will focus initially on IV dosing in a single cohort. We then will have 3 cohorts of escalating subcutaneous doses, with 4 subjects per cohort. We'll focus on safety, tolerability and pharmacokinetics, but because we're looking at the patients, we can actually look at the level of homocystine, so that's going to allow us to establish proof of concept. So let's move on to our next program, cystinuria. So cystinuria, again, is another disease with high unmet medical need. It's a kidney stone disease characterized by frequent recurrent kidney stones from an early age. These patients get serious complications, multiple episodes of abdominal pain, multiple admissions to a hospital, frequent surgical interventions and frequent procedures. They're also at high risk of chronic kidney disease and hypertension. This is a very much bigger rare disease indication. It's believed that there's at least 10,000 patients in the major addressable markets. Again, we've mapped out the current standard of care. It's really based on drinking large amounts of fluid. These patients have to drink 3.5 to 5 liters a day, modifying their diet, taking tablets to alkalize the urine and also to try and improve solubility. Again, treatments are inadequate. And the key areas of unmet medical need are therapy-resistant patients, patients who can't take current adjunctive therapies. And then the other area is many patient circumstances mean that drinking 3.5 to 5 liters of -- a day is not practical. As that's the mainstay of current treatments, it's very problematic for these patients. So this is the rationale for the approach, so let me just spend a little time walking you through this. So in normal people, cystine is filtered in the kidney into the urine and then it's re-pulled back out of the urine by a transporter. And that keeps the levels of cystine lower in the urine. In cystinuria patients, the cystine cannot be pulled back out of the urine. This leads to high concentrations of cystine and they develop stones. We came up with the idea that if we could lower cystine levels in the blood, we should be able to lower the amount filtered in the kidney and that should inhibit stone formation. So on this slide, this looks at 2 things. First of all, we took a human enzyme that doesn't normally metabolize cystine, and we made it metabolize cystine with some targeted changes. We then took that enzyme as a single dose into the mouse model of cystinuria, and it did exactly what we expected. So the first graph in the middle shows lowering of the plasma cystine levels. The next scatter plot shows that those -- that lowering of plasma cystine levels lowers urine cystine levels. And you can see in the black-and-white pictures, by lowering the urine cystine levels, we inhibit crystal formation with a single dose of therapy. So the key thing is, does this reduce stone formation? So if you look at the scatter plot on the right-hand side, these cystinuria mouse model, they do not have many stones, around about 5 to 6 years of age. When we actually restrict them slightly with fluid, they have a marked increase in stone formation. We can prevent that increase in stone formation using our cystine-degrading therapy. And the reason that we can do that is because we lower urine cystine levels and inhibit the ability of stones to form. So this study is -- this program is also in IND-enabling studies now and moving forward towards the clinic. So I've shown you our 3 programs which illustrate the power of an approach and what we are continuing to do is to unlock additional opportunities using our research platform. So what -- this is another metabolic disease with at least 5,000 patients in the major addressable markets. There is a metabolite that drives the complications of the disease. We've designed an enzyme that lowers the level of that metabolite. And you can see in the picture of the mouse the mouse without treatment has -- it looks sick, with an abnormal hair pattern on its back. And you can see that with treatment the mouse looks much more normal because we've been -- used this enzyme that reduces the metabolite. So we've had a very successful 2019, which has given us really great momentum as we come into 2020. We obviously -- we have breakthrough designation. We have our Phase III trial running. We are eligible for the pediatric voucher. We anticipate completing enrollment of the pivotal trial in the second half, with top line data in Q1 2021. For our homocystinuria program, we've advanced that rapidly through IND-enabling studies. And we've just filed the CTA, and we expect to initiate a clinical trial in the second quarter, with top line data in Q1 2021. And then for cystinuria, that program is moving forward with IND-enabling studies. So I'm very confident, as we move into 2020, that -- of delivering further success with our programs because of the characteristics of the lead assets that we have and because of all of the work that we've done in 2019. So let me leave you with some key takeaways from this. Very confident where we are at the moment about delivering on our milestones moving forward through 2020. We continue to look for -- defying conventional expectations and looking beyond the conventional for enzyme solutions for diseases with high unmet medical need because we recognize that many patients have diseases that have not historically been considered amenable for enzyme replacement therapy. And finally, we are pursuing our vision to become the premier human enzyme company by redefining the potential of human enzymes so that we can deliver disruptive solutions to many more diseases than we are at present. Thank you for your time.