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

Good morning, and welcome to the Aeglea KOL webinar. [Operator Instructions] Please note this event is being recorded, and a replay will be made available for replay on the Aeglea BioTherapeutics website following the conclusion of today's event. I would now like to turn the call over to Jonathan Alspaugh, Chief Financial Officer and our first speaker. Please go ahead, Jonathan.

Thank you, Sarah, and thank you all for joining us this morning for a webinar on homocystinuria. Before we begin, please note that this webinar may include forward-looking statements under the Private Securities Litigation Reform Act. Actual results might differ materially from those projected in the forward-looking statements. Additional information concerning factors that could cause actual results to materially differ includes, but is 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, and please note the additional disclosures on this slide. So we are very delighted and grateful to have Dr. Harvey Levy join us this morning. Dr. Levy is a world-renowned expert in metabolic disease with over 50 years' experience treating patients with homocystinuria. He established the metabolic program at Boston Children's Hospital in 1978. The program and its chair appointment have recently been named in his honor. Dr. Levy diagnosed the first homocystinuria patient identified with newborn screening in the U.S., which is also one of the first worldwide and he has treated and followed many other patients with the disease since. In addition to his clinical work, Dr. Levy is the principal investigator of the Boston site for the clinical trial of an enzyme replacement therapy for homocystinuria sponsored by Travere and as a consultant to Aeglea on our clinical trial. In his presentation, Dr. Levy will discuss homocystinuria, its impact, current treatments and share case studies on the presentation and management of the disease. Later, we also have Mike Hanley, our Chief Business Officer; and Leslie Sloan, our Chief Operating Officer, provide an overview of our pegzilarginase program for homocystinuria before turning to a Q&A session. As a brief overview of Aeglea, I want to share our vision to redefine what is possible with human enzyme therapies. By pioneering bold science, we believe that we can deliver groundbreaking medicines that transform the lives of patients and families living with rare metabolic diseases, patients and families that are in need of new treatment options. While the focus of today's call is on homocystinuria, I do want to take a moment to remind you of the other programs in our pipeline. The marketing authorization application for pegzilarginase for the treatment of arginase 1 deficiency was submitted by our partner, Immedica and is currently under review by the EMA. At Aeglea, we are also continuing to engage with the FDA to identify a path forward for the ARG1-D program in the U.S. We also have a preclinical pipeline of engineered human enzymes designed to address unmet medical needs in a variety of metabolic indications. And with that, I'd now like to hand it over to Dr. Harvey Levy to walk us through his presentation on homocystinuria. Dr. Levy.

Thank you. Homocystinuria is an autosomal recessive genetic metabolic disorder with progressive, potentially debilitating complications. I can tell you that it's one of the most severe of the metabolic disorders that we deal with. It's certainly one of the best known because of its clinical phenotype. It has 4 particular areas of clinical abnormality. The first is the brain. And the brain intellectual disability is something that affects many of the metabolic disorders we deal with and certainly affects homocystinuria as well. But interestingly enough, unlike many of the other metabolic disorders, homocystinuria also affects the somatic system of the body. In other words, it affects different organ systems in the body other than the brain, for instance, the eye. The eye has a dislocated lens. In Latin, it's ectopia lentis, which you'll hear very often referred to in homocystinuria. So the lens floats freely in the eye. And as a matter of fact, because of that floating briefly -- freely, the lens does not retract -- reflect -- refract the visual stimuli that come into the lens adequately onto the retina of the lens into the visual center of the lens. So consequently, individuals with homocystinuria end up with very, very severe myopia, near-sightedness. In fact, they have visions of 20/20 or 20/40 of legal blindness. The skeletal system is involved. And so you -- and I'll show you some pictures of the external skeletal abnormalities that you see in homocystinuria. But there is not only the external abnormalities, but you see osteoporosis. So it can be very severe osteoporosis with complications such as spinal collapse or scoliosis, the vascular system of thromboembolism, thromboses, particularly stroke or pulmonary emboli. This is the pathophysiology, the metabolic problem in homocystinuria. And I direct your attention to the bottom of the right side of the slide, the metabolic methionine -- metabolic cycle. Homocysteine is the bottom of that cycle. And I direct particularly attention to Cystathionine beta-synthase, a pyridoxine vitamin B6 dependent enzyme. That is the central problem in homocystinuria. It is lack of activity of that particular enzyme, which is the major enzyme in the metabolic -- methionine metabolic cycle. Therefore, individuals with homocystinuria cannot convert homocysteine to cystathionine, a transsulfuration phenomenon, and as a result of this, homocysteine accumulates in very, very high quantities in homocystinuria. The levels of homocysteine can be anywhere from 15 to 20x higher than normal. Homocysteine is the bad actor in homocystinuria. It is the toxic element in homocystinuria, which produces the clinical problems that I just described. The homocysteine binds to sustained residues and certain proteins and thereby inhibits the function of those proteins. Those proteins include proteins that are the eye is specifically the zonular ligament that anchors the lens of the eye to the ciliary body of the eye. And therefore, that zonular ligament and brays and eventually breaks, when it breaks the lens float freely in the eye and you have what's called ectopia lentis. And so no longer does the eye refract normally and you end up with very, very severe visual impairment. It affects the proteins of the cartilaginous system, which are responsible for the formation of bone. So consequently, you have the skeletal abnormalities, you have the severe osteoporosis. It affects the proteins of the intima of the vascular system. So you have an irregularity of the vascular system, which leads to emboli or the thromboses that we see in homocystinuria. How it affects the brain, we don't know. But it definitely affects the brain. So you end up with intellectual disability in the vast majority of cases with homocystinuria. If I direct your attention to the right side of the pathway, you can see that methionine is transmethylated to homocysteine, and that's how homocysteine comes to be. Homocysteine and all other metabolites within the methionine metabolic pathway are not protein-containing. Methionine is the only amino acid, the only metabolite in the methionine metabolic cycle, which is contained in protein. And so consequently, individuals with homocystinuria ingest dietary protein. They get the methionine in their body. On the right side, the transmethylate that is they removed the terminal metal from methionine to lead to homocysteine. Homocysteine, is really just demethylated methionine. It's methionine, which lacks the terminal methyl group. So the methyl group is removed, you end up with homocysteine. Homocysteine can be remethylated back to methionine by the addition of that terminal methyl group. There are 2 pathways in which remethylation occurs. The first is the pathway mediated by a folic acid derivative called M -- 5-methyltetrahydrofolate, which lends its methyl group to homocysteine to re-methylate to methionine or a method B12 it's a form of B12, which has a methyl group, which can be added to homocysteine and there's an alternate pathway in which betaine can add a methyl group to homocysteine to re-methylate to methionine. But unfortunately, the remethylation capability is not nearly sufficient to reduce the homocysteine to below toxic levels. It will reduce the homocysteine to some extent, but certainly not nearly sufficiently prevent the toxicity of homocysteine from occurring. It does, however, raise the mine level. And so the 2 major metabolites in homocystinuria are an elevated homocysteine and elevated methionine. You also get -- at the bottom of the slide, you'll also get a reduction in cystathionine because that's a transsulfuration product from homocysteine which is not made in normal quantities, of course, because of the enzymatic -- lack of enzymatic activity and SYSTANE which is a product that's released from cystathionine. And so that is the pathophysiology and the pathophysiology, which is -- which alternative therapies are directed to. The -- There are 2 forms of homocystinuria. You may remember that the cystathionine beta-synthase enzyme is a pyridoxine vitamin B6-dependent enzyme. And so there are 2 forms. There's a vitamin -- pyridoxine vitamin B6 or pyridoxine responsive form, and there is a pyridoxine vitamin B6 nonresponsive form. The majority of patients with homocystinuria are nonresponsive to vitamin B6, pyridoxine. Some are -- the remaining patients are responsive to pyridoxine. So they can -- the homocysteine can be somewhat reduced, though not dramatically reduced by giving them supplemental form of vitamin B6. But the majority of patients are nonresponsive to pyridoxine. And those that are nonresponse to pyridoxine have a more severe phenotype than those who are responsive. For instance, the elevation of homocysteine is much more severe in the nonresponders than it is in the responders. Lens dislocation occurs at an earlier age in the nonresponders than it does in the responders. The IQ is lower in those who don't respond to vitamin B6. The chances of thrombosis by age 15 are higher in those who are nonresponsive and death by the age of 30, occurs in a much higher percentage of those who are nonresponsive than those who are responsive. But the death is the same. And so in either case, their -- the death is going to be due to a thromboembolism. It's going to be either a stroke or it's going to be a pulmonary embolus. The current guidelines call for the reduction of the homocysteine level to below 100 micromoles per liter. And now this is much lower than the level of homocysteine in the untreated or the noncompliant patient, which is 120 to 250. But I can tell you that there are patients that I've seen with -- who are untreated with homocystinuria whose levels have been even higher than 250. They've been up to 275 and even higher than 300. So 100 is a stretch for many of these patients. The recommended level for safety in homocystinuria for those who appeared actually responsive according to the guidelines, is less than 50. But this is really just passing phenomenon. It only has to do with the fact that one can reduce the level of a pyridoxine responsive homocystinuria to below 50 easier than you can to a nonresponder. But basically, they both need to have levels that are less than 100. But I can tell you that in our clinic and in most clinics in the United States, we feel much more comfortable if the homocysteine level is below 80 or below 70, then -- so I'm not so sure that even getting a little below 100 is going to be totally preventive of complications or is going to be preventive of the continuing and extension of complications in homocystinuria. So we feel as if the level should be below 80 or below 70. But nevertheless, the guidelines are below 100. How those guidelines were developed is purely almost a flip of the coin. It's based upon empiric information from case reports and sometimes from personal information. But it doesn't -- it's not certainly an absolute level of safety for sure. Like all metabolic disorders, homocystinurics are better off if they're diagnosed in newborn screening, and they're put on treatment from the very earliest stages. That is true for phenylketonuria. It's true for maple syrup urine disease, it's true for all metabolic disorders and certainly is true for homocystinuria. The newborn screening for homocystinuria was one of the first of the metabolic solutions to be added to newborn screening when they first began in the 1960s with PKU screening exclusively. So that homocystinuria, maple syrup urine disease, galactosemia were among the very first that were added only a few years after PKU screening began. The marker for the identification of homocystinuria in newborn period is an elevated methionine. And you'll remember that the re-methylation from homocysteine to methionine does result in an elevation of methane from the pathway that I showed you earlier. So methionine does elevate in some individuals with homocystinuria within the first or second day of life when the newborn blood specimen is obtained. And therefore, they're -- they -- with an elevated methionine are identified as possibly homocystinuric. They are referred to a clinic, such as ours and other clinics throughout the United States, where a plasma amino acid analysis is performed and the elevated methionine is confirmed, a plasma homocysteine level is obtained and they have an elevated homocysteine. And so the combination of the elevated methionine, elevated homocysteine gives them a presumptive diagnosis of homocystinuria at which point, we put them on dietary therapy, which I'll describe in just a few moments. In addition, we obtained molecular genetic testing of the cystine beta-synthase gene, to identify the 2 variants in the gene. It's an autosomal recessive disorder. So you have 2 variants, 1 from each parent. The 2 variants and the gene that will identify them and confirm that they have homocystinuria. Enzymatic activity, as mentioned from skin fibroblasts, many years ago is very rarely performed today simply because we have molecular genetic testing. The problem with newborn screening is that the majority of people with homocystinuria do not get identified in the newborn period. Those with B6 responsive homocystinuria don't get identified because they raised their methionine after the second or third day of life, which is when the blood specimen is taken. They usually don't elevate their methionine until they're almost a week of age, which is long after newborn screening. So they universally are not identified by newborn screening. And a fair number of individuals with the most severe form of homocystinuria, B6 nonresponsive homocystinuria, also do not elevate their methionine within the first or second day with the newborn blood specimen is obtained. Because remember, methionine is a secondary elevation to homocystinuria. The primary elevation is homocysteine and then it must be re-methylated to methionine. That may not occur on the first, second, or third day of life. It may take several more days for that to occur, and that's after newborn screening. And so consequently, individuals with homocystinuria are missed. In fact, probably the majority of individuals with homocystinuria are missed in newborn screening. And this is a major, major problem in newborn screening. At the moment, there is no adequate test for homocysteine in the newborn investment, which would, of course, be the better of the 2 tests, but there is no method yet developed that would apply to newborn screening. So I'm showing you a plate. This is the original bacterial assay of newborn screening. You can see at the top of the plate of bacterial growth around a specimen indicating that, that newborn has an elevation of methionine. They are blood specimens throughout the plate, which do not have elevations, do not have bacterial growth, which indicates that they're normal. The role of the of blood specimens in the center, just are there to make sure the plate is working adequately. And so consequently, individuals with homocystinuria are missed in newborn screening, they grow without they go up and develop without the diagnosis of homocystinuria, and they develop a skeletal appearance which resembles an autosomal dominant disorder called Marfan syndrome. When a physician sees a patient with that appearance, he immediately diagnoses the patient as having Marfan syndrome. This young lady on the left-hand side, as you look at the screen is a patient with homocystinuria. She is tall and thin. She has long arms and long legs. She has dislocated lens of her eyes. And the gentleman on the right is patient with Marfan syndrome who is also tall and thin and has long arms, long legs and also has dislocated lens, ectopia lentis. And so consequently, superficially both, they look exactly alike. And the physician sees this, but he knows Marfan syndrome. He knows Marfan syndrome because the frequency of Marfan syndrome is 1 in 5,000 as compared to the frequency of homocystinuria, which is 1 in 200,000. So he's much more familiar with Marfan. In fact he may not even know about homocystinuria. So immediately diagnoses the patient as Marfan syndrome, and that is the diagnosis the patient is carried with for a number of years. The ectopia lentis is the same in both disorders. There's tall stature and the long arms and long legs of both disorders, skeletal abnormalities is the same in both disorders. They're different in terms of intellectual disability. Homocystinurics are intellectually disabled the most part. Those with Marfan syndrome are not. Homocystinuric individuals have thromboembolism, vascular inclusions, those with Marfan syndrome do not, but Marfan syndrome have mitral valve prolapses, but homocystinurics do not, they aortic root dilatation, also that homocystinuric do not. So they're different, but superficially, they look alike. So therefore, they carry the misdiagnosis of Marfan syndrome for a number of years. I'm going to give you 2 case histories of individuals, homocystinuria to illustrate some of the problems that we find clinically. First of all, there's a male patient who I've seen who was not ascertained through newborn screening. He dislocated his lens with severe myopia, again, legal blindness by the time it was 8 years of age. He was tall and thin with the long arms and long legs of what is called the marfanoid habitus, which, of course, applies not only to Marfan syndrome, but homocystinuria. He was developmentally delayed, but he was carried with the misdiagnosed as Marfan syndrome until he was 23 years of age when he had a pulmonary embolism, at which point was hospitalized, resident in the hospital of homocystinuria and so obtained plasma homocysteine level. It was 230 far, far above the upper limit of 15 micromoles per liter, which is normal. And so we just put on dietary restriction, which I'll describe in a moment and a medication called Betaine. But his homocysteine levels never, never became lower than the magic 100 toxicity level. They were 120 to 170, never getting out of the toxicity level. And so he's at great risk for new pulmonary emboli or stroke. Now the mainstay of therapy is severe protein restriction plus a formula plus supplementation with Betaine. And when I say severe protein restriction, it is severe. It's the most severe protein restriction of any of the metabolic treatments that we have. They can eat virtually no protein, and so constantly, they would become protein and nutritionally deficient very quickly if this were all that they had in the diet. So they have to have a formula, this is composed of elemental amino acids, not including methionine, of course. But the elemental amino acid is mostly essential amino acids, some nonessential amino acids with some minerals, vitamins and some carbohydrate thrown in, which supplements them because of -- and gives them the protein equivalents in terms of amino acids that allows them to avoid nutritional and protein deprivation. They are also supplemented with Betaine. You'll remember the alternative pathway for re-methylation was the transfer of methyl group and Betaine to homocysteine. So if they're giving Betaine, they can stimulate that pathway to some extent, therefore, increase re-methylation back to methionine and thereby reducing the homocysteine level to a small extent, but certainly only to a small extent in and of itself, not sufficient to -- so they need the total diet, they need the formula, they need the Betaine. And they're monitored with -- their eyes are monitored and examined periodically. Their development cognition is examined. Their bone density, through DEXA, is obtained every several years. And the goal, of course, is to maintain normal nutrition and prevent the serious complications. The problem is, and this is why alternative therapies are necessary -- is that dietary restriction is extremely difficult to maintain. It's virtually impossible as they get older to maintain the severe protein restrictions that they have to maintain. And so there's -- they'll be cheating. They will be even protein that they shouldn't be eating and therefore taking excess of protein. The formula is unpalatable. It tastes bad, and so consequently, they have to take it 3 times a day, and they have to drink quite a bit of formula each time. And so consequently become basically poorly compliant, maybe even noncompliant on formula. Many patients as they get along, will take not 3 time -- drink the formula 3 times, they'll drink the formula twice a day, they'll drink 1/2 of the formula 3 times a day or maybe they'll drink the formula once a day or maybe sometimes they stop drinking the formula. So compliance with diet becomes an extremely difficult problem as patients age. Betaine is practically unpalatable because of its gastrointestinal side effects. So Betaine is irritating to the mouth, and it also produces a lot of gastrointestinal irritation. And they don't -- and they have to take a lot of Betaine. They have to day Betaine 3 times a day. And so consequently, that becomes a major problem and many, many, many parents -- patients stop taking Betaine as they get along. So inadequate control, which results, of course, in an increase in homocysteine into the toxic levels is associated with the greater risk of pulmonary embolus, stroke, increased osteoporosis complications and psychiatric and psychological difficulties, depression, anxiety and frank psychiatric complications such as paranoia. And we've seen this in individuals with homocystinuria. The next case is that of a female patient who was ascertained through renewable and screening, but had poor homocysteine control as we see in many patients with homocystinuria. She was put on diet at age 8 when her homocystinuria was confirmed in the clinic, and Betaine was added when she was about 2 years of age. Her homocysteine levels through the first few years of life were not terribly bad. They certainly were above normal, but they were probably below the frank severe toxic area, 35 to 70 micromoles per liter. But over time, as she became an older child and then certainly into her adolescent years and into adult years, her homocysteine, she became basically poorly compliant and then noncompliant with diet and her homocysteine levels began to increase up to 115 micromoles per liter as an adolescent and then as an adult, she never had levels that would have been below 120 to 180 micromoles per liter. And the complications have included severe myopia. So while she hasn't dislocated her lens because she was treated early, her lens has wobbled and so consequently, she is severely nearsighted. She has some degree of developmental intellectual delay. She has psychological problems, executive dysfunction, she can't keep track of things, she can't organize herself. This has severely affected her school work and fairly affected her work and beyond school, and she's suffered from anxiety. It's affected her social life. She has severe osteoporosis. And she suffered a stroke when she was 45 years of age, which has left her with marked right-sided weakness. So she's since moved into Connecticut, but I keep track of her. She cannot live independently. She has to rely on a caregiver. So it's a very unfortunate result of what we see all too commonly in homocystinuria. So the burden of disease is very severe in homocystinuria. The long-term consequences include the health burden that I mentioned, decreased quality of life for sure. The consequences and outcome worse with the more severe homocysteine elevations. And the -- there's a high medication burden because they do have problems, and so consequently, they have to be on many medications, many of them very expensive medications. They have increased hospitalization. And of course, as I've said, a very restricted diet is extremely burdensome for patients and caregivers. And so they simply become noncompliant. So they suffer vascular disease and risk of thromboembolism and stroke. They have cognitive decline, dementia. They have osteoporosis, which, of course, can lead to fractures, and as I said, collapse of spinal vertebra and problems of that nature. They have psychiatric, psychological difficulties, including depression, anxiety and other kinds of things. So it's a very, very severe outcome. So the therapeutic need is great. Suboptimal control of homocysteine is associated with certainly more severe disease and poorer outcomes. Patients with classical homocystinuria experience significant disease burden and the risk of permanent morbidity. So new and effective therapies addressing clinical outcomes for patients with classical homocystinuria are very, very sorely needed.

Thank you, Dr. Levy for sharing your insights and knowledge about the disease and its impact. I'd like to spend some time now walking through what we view as the patient population with the potential to benefit from pegzilarginase and the unmet need our treatment may address. So as Dr. Levy explained, pyridoxine or Vitamin B6 responsiveness is a critical concept in the management of classical homocystinuria. And it's also very helpful to view the unmet medical need and the potential for pegzilarginase through that same lens. Let me take a second to define the different treatment categories of responsiveness referenced on the left side of the slide. Patients are classified as B6 responsive, if they're able to achieve a total homocysteine level, less than 50 micromolar with vitamin B6 alone. Less than 20% of patients fall into the categories of extreme and full responders with the remaining 80-plus percent classified as either partially responsive or nonresponsive. Partial responders are patients who can achieve at least a 20% reduction, but are unable to achieve total homocysteine levels of less than 50 micromolar with B6 alone. Partial responders represent another 20% of the population. And nonresponders are unable to achieve a reduction of at least 20% in total homocysteine levels on B6. Many of these patients are unable to achieve levels below 100 and typically manage the disease with a low-methionine diet and/or Betaine. This subset makes up more than 60% of the patient population. So that's over 80% of patients with classical homocystinuria who don't adequately respond to B6. We view those roughly 25,000 patients as likely candidates for pegzilarginase due to the challenges they face in effectively managing homocysteine levels. To provide further context to Dr. Levy's presentation, the inability to manage homocysteine levels is a big reason why this disease is so devastating. Dr. Levy mentioned earlier, the disease severity is highly correlated with B6 responsiveness. The less responsive a patient is to B6, the more severe the disease. As you can see on the slide, nonresponders and partial responders are typically diagnosed earlier than others. But unfortunately, that diagnosis typically follows the onset of symptoms by several years. In fact, nonresponders and partial responders, almost 80% have already experienced a lens dislocation and 30% of thromboembolic complication before receiving that diagnosis. Another reason why classical homocystinuria is so devastating -- can we switch the slide, please? Thank you -- is related to the challenges associated with existing treatment options. Dr. Levy mentioned this, we've already highlighted that only a small proportion of patients respond adequately to vitamin B6. The remaining patients are limited to that lifeline regimen that includes a highly restrictive low-protein, low-methionine diet and amino acid supplementation. We've talked to a lot of patients, families, physicians, and it's really hard to put into words just how challenging and frustrating it is for them to comply with this over the course of a lifetime. The other treatment option that Dr. Levy mentioned is Betaine. Betaine a prescription drug works by pushing homocysteine back up the metabolic pathway by re-methylation to methionine. As Dr. Levy referenced, Betaine's mechanism results in marginal efficacy, and the product has quite a challenging dosing safety side effect profile. However, due to the limitations of B6 and diet, Betaine currently prescribed for many of those patients who don't adequately respond to V6. So without effective easy-to-use therapies, patients with classical homocystinuria remain at risk for serious life-threatening complications. We believe pegtarviliase has the potential to radically change this equation for so many patients and families who are living with this disease. So I'll now hand over the call to Leslie to share some more about pegtarviliase, our innovative enzyme approach to lowering homocysteine levels, Leslie?

Thank you, Mike. I'd like to start by walking you through the therapeutic approach we're taking to try to treat homocystinuria. As Dr. Levy and Mike both mentioned, patients with homocystinuria experience a buildup of a toxic level homocysteine, which is what drives the serious disease complications. The concept that a patient has high levels of total homocysteine and we designed an enzyme to lower those levels is fairly simple. However, as you can see on the slide, there's a bit more detail involved, and I'd like to take a minute to dive a bit deeper into the mechanism with you. So on the left side of the slide, you can see the metabolic cycle of homocysteine as it occurs in the cell and the impact of a deficient CBS protein. Current standard of care as mentioned before, protein restriction, Betaine and B6 supplementation all impact different aspects of this cycle, but none of them directly affect the toxic driver of the disease, homocysteine. Moving to the right side, you can see that once homocysteine moves to the plasma, it exists in 3 forms in equilibrium, which represents what we call total homocysteine. It is important to note that the flux of dietary protein can continue to drive intracellular accumulation and this, in turn, will drive high levels of total homocysteine in the plasma and other tissues. Although in plasma, a large amount of homocysteine is in the protein bound form, the remaining is nearly all in the dimer form, it's only about 1% in the monomer form. Our therapy candidate, pegtarviliase, was engineered from the Cystathionine gamma-lyase scaffold with enhanced stability in plasma and the ability to metabolize the dimer form and the reduced monomer form into endogenous metabolites. This ability to metabolize both monomer and dimer means that pegtarviliase acts on all the accessible forms of total homocysteine that exists in the blood as depicted in the simplified diagram on this line. As these forms are degraded, accumulated homocysteine in cells and tissues as well as protein-bound homocysteine equilibrate, leading to additional opportunities for metabolism and systemic reduction of total homocysteine. While the different forms of homocysteine exist in equilibrium, our belief is that the faster you can reduce homocysteine in the plasma, the greater likelihood that you can sustainably lower homocysteine levels systematically. So in summary, accumulation of toxic homocysteine leads to systematic exposure and increased risk for disease manifestations and quickly and sustainably lowering plasma total homocysteine can lead to a reduction of these risks, and we believe that our engineered enzyme, pegtarviliase, represents a unique mechanism of action targeted at quickly clearing the key driver of the disease. We are currently enrolling and dosing in cohort 3 of our Phase I/II trial. This trial, as you can see on the diagram, is a standard dose escalation study with once weekly dosing for 4 weeks. The primary endpoint is safety and tolerability, and we'll be gathering additional information on the pharmacokinetics and effects on plasma homocysteine levels. We are enrolling patients with classical homocystinuria aged 12 and older in the U.K. and Australia and 18 and older in the United States. After an additional IV cohort, cohort 1 at the dose of 0.15 mgs per kg, we switched to subcutaneous dosing for our dose escalation cohorts and Cohort 2 was dosed at 0.45 mg per kg, and Cohort 3 is currently dosing out 1.35 mg/kg once weekly. After the completion of the first mover, we announced all patients showed homocysteine reduction, indicating to us that we had scaled appropriately from our preclinical models and we were on the dose response curve. Dose-dependent reduction in homocysteine would establish proof of concept and set us up for discussions with regulators on registrational study requirements. We look forward to sharing interim clinical data from this trial later this year. I'll turn it back over to Jonathan.

Thank you, Leslie. So in summary, we believe that pegtarviliase has the potential to be a best-in-class therapy that addresses a significant unmet need for homocystinuria patients. We're excited about the homocysteine lowering we saw in the first cohort, and we believe that once weekly dosing will be appealing to patients who are currently managing a burdensome daily standard of care. In addition to the progress we made in our clinical trial, we've worked hard to advance many other elements of the program. We have made significant progress on toxicology studies, manufacturing and regulatory work. We believe we have all the pieces in place to move into a registration study should the results from our Phase I/II trial to support the potential we believe that pegtarviliase has. We're about the progress we have made with this program across multiple fronts, and look forward to sharing clinical data later this year. Thank you. Leslie and Mike providing that overview of the pegtarviliase program. And again, thank you, Dr. Levy for sharing your insights on homocystinuria. I'd now like to turn the call over to Sarah, who will open the Q&A session.

[Operator Instructions] With that, we'll go ahead and take the first question from to Edward Tenthoff at Piper Sandler.

I'm trying to get a sense for how large the potential registrational problem might be? And what kind of effect size do you think would be necessary to appreciating the massive unmet medical needs?

Thanks, Ted. Really good question. I think one thing to note, we are still working to produce the data in the Phase I to establish that dose response -- and with that data, we anticipate that we'll be able to take the program forward, engage the FDA and discussions on a pivotal design. We do think that in that pivotal, the important thing will not just be the percent reduction of total homocysteine, but as we discussed and as Dr. Levy had discussed in his presentation as well that dosing in these patients that maintains total homocysteine levels below these clinically meaningful thresholds is going to be very important. So as far as specific sizing of the study, that's ongoing work. Part of that is going to be a function of the results that we get from the Phase I/II. But I'm going to ask Leslie to add anything that I may have missed on that point.

Yes. So I think I would just add that it kind of depends on exactly the design when you do your power calculations and what size you end up with. So we'll reserve those final decisions for after we have a conversation with the regulatory bodies.

The next question will come from Soumit Roy at JonesTrading.

Thank you, Dr. Levy, for giving the comprehensive understanding of the landscape. Possibly the first question for Dr. Levy, what would be your inclination for prescribing a drug that lowers the homocystinuria level to between 80 and 100 and doesn’t really push it down all the way down to 50 and 60. Would the respective toxicity profile and those things would weigh in more than the possible clinical benefit?

Yes. I mean I think we'd have to take both into consideration. If, for instance, you needed a sufficient amount of drug in order to push the homocysteine level down to, let's say, 60 or so that might produce some toxicity, then I think that would be a clinical decision. You'd have to weigh the benefit of pushing a drug down that, pushing the homocysteine level down that low with the possibility of side effects. On the other hand, you may not have to get that low. It may very well be that well, it may turn out that less than 100 is okay. And over a period of time, we may find that patients who maintain levels that are 90 or so are doing as well as patients who maintain levels that are lower than that, or we may find that it may take a little bit lower. That's going to be really a decision that will have to come after a certain amount of time and using drugs that lower the homocysteine level. So I think at this point, we really can't say whether or not you need to have a level that's significantly that much below 100 as -- and whether they'll have toxicity.

And in your opinion, like what do you think would be the compliance of taking the drug if beyond the first year? How well the compliance would be for the drug. And for maybe a question for Jon or Leslie, have you seen any antidrug antibody being developed so far yet?

Well, as far as compliance is concerned, I would say that the vast majority of patients that I know with homocystinuria who are on diet and -- or maybe not complying with diet, but need diet, would welcome a drug taken once a week and having to take year in and year out. So I don't see that as a limiting factor at all in compliance with the drug. Of course, it would depend upon whether or not there were side effects. That's a major, major issue, of course, with all patients. So if there were no side effects or limited or minor side effects, then I would say the compliance would be pretty good.

Thanks, Dr. Levy. And Soumit, your other question was on ADAs. We will be looking at ADAs to both the PEGylation and the enzyme protein, but we haven't disclosed any information on that yet.

The next question comes from Sam Slutsky of LifeSci Capital.