Arcturus Therapeutics Holdings Inc. (ARCT) Earnings Call Transcript & Summary

Greetings, and welcome to the Arcturus Therapeutics Key Opinion Leader KOL presentation to discuss ARCT-810 Phase II interim data for OTC deficiency. [Operator Instructions] It is now my pleasure to introduce Neda Safarzadeh, Vice President, Head of Investor Relations, Public Relations and Marketing.

Thank you, operator. Good afternoon, and welcome to Arcturus Therapeutics Key Opinion Leader KOL presentation to discuss ARCT-810 Phase II interim data for OTC deficiency. Today's call will be led by Joe Payne, our President and CEO; Juergen Froehlich, our CMO; and two key opinion leaders, Dr. Marshall Summar and Professor Johannes Häberle. Before we begin, please note that today's call may contain forward-looking statements. Such statements are based on current expectations and assumptions, and actual results may differ. Please refer to our filings made with the SEC, including the risk factors contained therein for more information. We undertake no obligation to update any forward-looking statement. And with that, I will now turn the call over to Joe.

Thank you, Neda, and hello, everyone, on the call today. On behalf of the company, thank you for joining today's call as we share exciting new Phase II interim clinical data. As a founder of Arcturus, I know that days like these do not just happen. It takes a lot of innovation, effort and persistence to achieve data sets like this. So a big thank you to our team here at Arcturus and also to the OTC deficiency community for their support. We are working hard for you and are excited to share today's data, especially with all of you. And finally, I want to sincerely thank our KOLs, Dr. Summar and Professor Häberle for taking time out of their very busy schedules to provide their independent evaluation of these new data. Next. Arcturus is a commercial mRNA medicines company headquartered in San Diego. Today's call will be focusing on one of our flagship assets in our mRNA therapeutics pipeline called ARCT-810. This is an mRNA clinical candidate to treat a rare liver disease called ornithine transcarbamylase deficiency. Next. OTC deficiency is the most common urea cycle disorder, wherein there is significant unmet medical need. However, ARCT-810 is different from the other treatments. It is an mRNA therapeutic that aims to replace the dysfunctional OTC enzyme with a new OTC enzyme and improve urea cycle activity in the liver, detoxify ammonia, prevent neurological damage and potentially remove the need for liver transplantation. Next. There are many reasons why we are having a Phase II data call today for ARCT-810, but I want to emphasize a particularly key reason and what is different about ARCT-810 from all of the previous attempts in the field. ARCT-810 uses Arcturus' proprietary LUNAR delivery platform to deliver that OTC mRNA to hepatocytes. That is the key technology, the key difference. ARCT-810 has the potential to be the first and best mRNA therapeutic to treat OTC deficiency. Next. And as a quick reminder, before I pass the call over to our Chief Medical Officer, ARCT-810 has received orphan drug designation, orphan medicinal product designation, Fast Track designation, rare pediatric disease designation and received a positive opinion on our pediatric investigational plan. These regulatory designations provide several meaningful benefits that may help accelerate the development of this program. And with that, I will now pass the call to Dr. Juergen Froehlich. Chief Medical Officer of Arcturus.

Thank you, Joe. I'm excited to share with you meaningful biomarker changes based on interim data from the U.S. and final data from the European Phase II studies. Following my short presentation, our two OTC deficiency key opinion leaders, Dr. Summar and Professor Häberle will further elucidate the scientific rationale and why we are so excited about these results. Both Phase II studies were designed to enroll OTC deficient adolescents and adults with history of hyperammonemia crisis for multiple dosing with biweekly IV infusions. Endpoints are safety, tolerability and biomarker assessments of plasma glutamine and ammonia and ureagenesis. We have final data from the European study in patients with stable disease receiving up to six infusions dosed at 0.3 milligrams per kilogram. The U.S. Phase II study enrolled patients with more severe and active disease and has optimized time points for biomarker assessment and utilized a new and improved N15 assay for ureagenesis function. We have interim data from the first three participants in the U.S. study after completing five infusions at 0.3 or 0.5 milligram per kilogram. Next. Let me now focus on plasma glutamine. Before ammonia levels rise in OTC deficiency, excess nitrogen is incorporated into glutamine. Glutamine is a more stable and predictive biomarker for monitoring metabolic control in stable OTC deficiency patients and normal glutamine levels are an indicator of efficient urea cycle function. Glutamine levels exhibit significantly lower intra-subject variability as compared to ammonia and are more efficient for monitoring of OTC deficient patients. This slide shows the interim data for glutamine in each of the Phase II studies. In the European study, mean glutamine levels decreased from high to normal during the treatment course and began to rise again more than four weeks after completion of dosing. In the U.S. Phase II study, elevated glutamine normalized after three administrations of ARCT-810 and remained normal for approximately 20 days after last dose. Next. An exploratory statistical analysis using the linear mixed effects model or LMM, provides statistical evidence that glutamine levels decreased over time in the individual and combined analysis of both studies. Next, the new and optimized N15 ureagenesis assay used in the U.S. Phase II study was recently published. It measures relative ureagenesis function or RUF, has low intra-subject variability and is not impacted by ammonia scavengers. It is substantially less variable than the C13 assay we used in previous studies. The assay was validated across normal controls and OTC deficient patients with different severe degrades of disease. The results indicated that RUF values of 50% or higher are typically observed in asymptomatic patients and are considered clinically meaningful by our KOL. Professor Häberle will provide more details of this assay, which promises to become a useful clinical biomarker for monitoring improvements of urea cycle function during treatment with ARCT-810. Next. In three patients that completed ARCT-810 dosing, mean RUF increased significantly within 28 days post fifth dose by absolute 14.7%. The exploratory LMM analysis provides a positive p-value of 0.026. Of note, two subjects achieved RUF levels of more than 50%, which reflects the range of asymptomatic patients. These data are very encouraging. They indicate that multiple administrations progressively increase functional OTC enzyme and lend additional support and confidence to the meaningfulness of the favorable glutamine reductions. Next. This slide shows ammonia levels in both the European and U.S. Phase II studies. Ammonia remains stable and within normal range after two administrations and for approximately 28 days following completion of dosing. These data add further robustness to the favorable glutamine and ureagenesis data. Next. I'm now providing the safety information. The safety database includes 40 participants and indicates that ARCT-810 was generally safe and well tolerated. It includes 20 OTC deficiency participants, of which nine received up to six IV infusions. The early studies enabled the company to improve the dosing regimen without corticosteroids as pretreatment. With a 3-hour infusion used for both Phase II protocols, no serious infusion-related reactions or IRRs were reported. Two participants in the European Phase II study, one randomized to placebo and one to ARCT-810 reported a hyperammonemia event defined as ammonia equal to more than 100 micromoles per liter. Four weeks after the last dose, the participant receiving ARCT-810 was prescribed an oral corticosteroid to treat an asymptomatic transaminase elevation. This was an isolated laboratory serious adverse event, not meeting high low criteria. Subsequently, transaminase levels returned to the normal range. The event was considered related to the corticosteroid treatment. Next. And now my presentation will be followed by our two KOLs, Dr. Summar and Professor Häberle. Both are internationally renowned experts in the urinary cycle disorders and have contributed with the clinical and scientific work to substantial advances in understanding the genotypic nature as well as the clinical and metabolic phenotypes of OTC deficiency. Handing over to Dr. Summar now.

Thanks, Juergen. Hi, everyone. I'm Dr. Marshall Summar, and I'm going to talk about glutamine trends and ureagenesis in urea cycle patients treated with an ornithine transcarbamylase messenger RNA therapy. Next. I've been active in this field since the 1980s, working with urea cycle disorders. I've had over four decades of research, patient care and policy leadership. I've led and worked on a lot of the treatment protocol work groups for taking care of patients with urea cycle disorders. I'm a founding member of the National Institute of Health Urea Cycle Disorders Consortium and served for over 20 years on the Scientific Advisory Board of the National Urea Cycle Disorders Foundation. To date, I've authored over 40 publications on urea cycle disorders, including the gene reviews guidelines for treating patients as well as a number of multinational natural history studies. I have patients on ammonia -- I have patents on ammonia diagnostics, urea cycle disorder-related technologies and other things. Also in the field of rare diseases, I was privileged to receive NORD's Lifetime Achievement Award for the work I've done around the urea cycle and other rare diseases. Next, I'm certain you're already familiar with the urea cycle, but just a quick review. The urea cycle is the human pathway for clearing waste nitrogen. Without this pathway, it builds up toxic ammonia, which is lethal. Ornithine transcarbamylase is the second enzyme in this pathway, but it's the most common one we see as a defect because it's on the X chromosome. So we see a high incidence of affected males. While carrier females may have little or no symptoms, they still can have symptoms. Restoration of activity can also restore the critical nitrogen clearance, which removes that life-threatening ammonia as well as some of the synthetic functions for the things needed downstream from ornithine transcarbamylase. Next. One of the things we focus on, on the urea cycle function is the amino acid glutamine. Now why do we do that? Well, for one thing, ammonia is typically normal in a urea cycle patient unless they're in crisis, and the focus is on trying to keep them out of crisis. The body uses the amino acid glutamine as a nitrogen storage pool or buffer, so the glutamine levels go up before ammonia levels go up. Glutamine transports nitrogen all over the body, but it also carries waste nitrogen from the muscles from the breakdown of proteins as well as some of the dietary nitrogen that comes in and it takes it to the liver. It drops its nitrogen directly into the urea cycle through ammonia, changing itself to glutamate in the process, which is then processed through the rest of the urea cycle. Glutamine will go up in a patient who may otherwise look just fine, but it tells us that their urea cycle is not doing its job and that waste nitrogen is building up. It's become a very good predictor when patients are about to get into trouble. The glutamine itself as it gets higher, has its own toxicity. It can cause some of the brain swelling we see in urea cycle disorders as well as mitochondrial dysfunction and microglial cell death or apoptosis. It can also interfere with nitric oxide and cyclic GMP pathway. So as glutamine gets higher and higher, it can have its own toxicity. Next. So why would we use glutamine in ureagenesis, which is the stable isotope clearance of ammonia through this cycle to test for efficacy for an ornithine transcarbamylase mRNA therapy. For one thing, glutamine is an early warning system in OTC deficiency as we just discussed, and it also reflects the nitrogen load before the patient gets into crisis. It's not only a good predictor, but it also serves as a nitrogen buffer, offering a more stable indicator of urea cycle stress than ammonia. It's used as a routine clinical measure in managing urea cycle disorder patients. In our clinical practice, we look at the glutamine levels to see if they're high before adjusting the current scavenger medications and other parts of therapy. If we get to the point where the ammonia is really high, we've already waited too long. So glutamine is what we actually use in the clinic. It also has a lower variability of about 15% intrasubject as opposed to 56% for ammonia according to a study done by Dr. Uta Lichter-Konecki back in 2016. Now why ureagenesis? It's a direct measure of the urea cycle's ability to take ammonia and convert it into urea. As the protocol developed by Dr. Häberle, he'll talk about in a minute, we put a stable isotope 15N tracer in ammonia and then the patient takes it orally. It's then processed through the liver, and then we look to see how much of that comes out as urea with the 15N label from the ammonia. We can track the processing of the urea cycle in a very sensitive way. This is a very sensitive method to actually see if we're increasing the urea cycle capacity in women who are carriers of OTC with very mild symptoms. In conclusion, with glutamine and ureagenesis, we cannot only look at the inputs to the urea cycle and see if it's backing up, but we can also look at the outputs of the urea cycle and see if they're increasing. So that's why it's such a great way to measure improvements from therapy in the urea cycle. Next. So what's our hypothesis here? Our hypothesis is the infusion of a lipid nanoparticle containing ornithine transcarbamylase messenger RNA targeted at the liver will restore enough function that it will affect the glutamine levels in the plasma and urea genesis as measured by the 15N labeled ammonia to 15N labeled urea. We have two tests we're looking at here. The idea is the OTC mRNA is actually increasing urea cycle function. We tested plasma glutamine levels for the presence of a declining slope from baseline. In other words, glutamine was going down. The N15 urea genesis is measured for a positive slope to see if urea cycle function was going up. Our methods include treating patients with molecularly proven ornithine transcarbamylase deficiency who have been on some form of therapy and are on a stable diet. We then measured glutamine and ureagenesis at intervals and after the last dose, and I won't bother reading off all the days here. Next. We used two statistical methods to measure the effect. One is a very simple chi-square test to see if things were what you expected or if they were random. In other words, there was no effect on glutamine or did you see it skewed towards the negative slope, which means glutamine was going down. didn't change or went up. It's a very standard statistical test. The other test we use is what's called a linear mixed effects model. It's a really good test for looking at a lot of patients who are different from each other because in genetics, you rarely get the same defect in the same gene. Measured values like glutamine or ureagenesis would be different from the different patients. Overall, you could look at the trends and compare them over time. We're looking to see if glutamine levels are decreasing in each patient. We also use this for the ureagenesis study to see if urea cycle function was increasing. Next, this slide shows some of the slopes from the direction that glutamine was going in. You can see all of them had a downward trend except one who starting glutamine interesting was normal, which goes along with our hypothesis that if OTC messenger RNA is working, then we should see the downward trend in glutamine. Next, here are the slides you've been waiting for. These are the results of the chi-square analysis. We saw in the combined 03 and 04 study that there are seven patients that showed a decreasing trend in glutamine and only one that showed a very mild increase. So seven down and up, which doesn't seem random. In fact, that gives us a p-value of 0.017. If we look at Study 4, its chi-square value was also significant at 0.042, and Study 3 was also approaching that. It's very encouraging to see the patients that are all trending towards decreased glutamine levels. Next, in our linear mixed model analysis, the results were even more striking. We fitted the data from the glutamine levels over time and determine the slopes for each patient in the two studies. In both the 03 and 04 study, they were separately significant with p-values well below 0.05. This shows that glutamine had a downward slope and a downward trend. In the 04 study, the slope was even more negative, showing a really robust effect and creating a confirmation cohort to the 03 study. The linear mixed model shows strong evidence that glutamine is going down, either in each study independently or in the combined two studies with a significant p-value. We also did a sensitivity test to see if taking out a patient or changing the model is going to knock it out of the statistically significant range. It did not, stood up very well. Next. We did the ureagenesis assay in three patients in the 04 study. While the first patient bounced around up and down, the other two patients showed a really nice increase in ureagenesis function over the course of the study. Even though this is a very small statistical group to work with and actually did achieve a p-value of 0.026 using the linear mixed model statistics. As we increase the number of the patients, I suspect it will become even stronger. This also confirms the findings we had from the glutamine levels. So at this point, I'd like to turn over the presentation to my colleague, Dr. Johannes Häberle.

Thanks, Dr. Summar. Good afternoon, everyone. My name is Johannes Häberle. I'm working at the Division of Metabolism at the University Children's Hospital in Zurich, Switzerland. I'm a trained pediatrician and also certified in neonatology and intensive care. I've worked in metabolic medicine for over 25 years in different roles in clinic and research, including serving as the Chair of the European working group for urea cycle disorder guidelines. More recently, I was appointed as Director of the newly established urea cycle Disorders Translational Center of the University of Zurich. Next. The reason I'm speaking here today is to report on some of our work in the field of urea cycle defects and specifically on the possibility to measure the flux of metabolites through the urea cycle. Urea cycle in our body is the only pathway for ammonia removal in which one molecule, ammonia or NH4, which is highly toxic to the brain goes in and another molecule, urea, which is nontoxic, goes out to be excreted in urine. A key player in the urea cycle is ornithine transcarbamylase or short OTC, which is a mitochondrial enzyme and defects in this enzyme are the most common cause of urea cycle disorders. Next. If OTC is not working, we have a diagnostic toolbox in which we find several metabolites that can -- we can measure in blood. For instance, we can measure ammonia. Ammonia will increase in case of OTC deficiency. We may also find increased glutamine in blood. Next. The analysis of those metabolites will, however, benefit from additional functional studies in which the entire pathway, in this case, the entire urea cycle is measured. We believe this to be especially useful for monitoring the benefit of a novel intervention. For this reason, we have developed a ureagenesis assay, which quantifies the total flux in the urea cycle. In other words, it shows how fast ammonia goes in and how fast urea is produced. There are, in principle, two ways to measure urea cycle flux as shown in the following. Next, here is a comparison of two different tracers, 15NH4CL or ammonium chloride and 13C acetate, which were introduced by different laboratories. There are substantial differences between the two tracers, of which the difference in hepatic first pass is the most important. Hepatic first pass is an indication how much of the tracer goes directly into the liver. In the case of ammonium chloride, this is more than 50% of the given dose, while it is less than 1% in the case of 13C acetate. Mainly for this reason, we developed this test using ammonium chloride. Next. The principle of ureagenesis quantification, we give to patients an oral tracer, ammonium chloride that is labeled with a stable isotope at the position of nitrogen, hence 15N. This stable isotope depicted on this slide as a small red sphere travels through the urea cycle. It goes into the cycle at the level of the first enzyme, is then metabolized through OTC into citrulline and so forth until it reaches the final metabolite urea. Urea will then be labeled with this stable isotope. The difference in weight, although very small, can be analyzed using modern technology called high-resolution mass spectrometry. We developed this test both for research in the preclinical setting and for humans. Next. This method for human subjects was recently published... [Technical Difficulty]

One moment, please.

Professor Häberle's phone has dropped. We're patiently waiting for him to call back in.

Neda, this is Dr. Summar. Do you want me to pick up Johannes' script?

Yes, sir, please go ahead.

All right. Which slide were we on for him?

We are on the Slide #34.

Slide 34, paper, correct?

Yes, correct. Thank you.

Okay. I can pick it up from there. Hang on 1 second. Let me queue up. While I'm queuing up, what I can say is this is a paper everyone in the field has been waiting for a while because it's a very, very strong way to measure ureagenesis and it's kind of becoming the standard of care. So Dr. Häberle recently published this paper on the characterization. Next. This first slide shows relative ureagenesis function or RUF and short recording severity, presence and absence of symptoms. And one of the nice things about this slide is it shows kind of the first time the ability to separate asymptomatic from symptomatic patients with a much greater degree of accuracy. On the very left, you can see the group of patients with severe neonatal. Obviously, they have the lowest, and they all have an RUF that is close to zero. It's not only significantly different from controls at the very right of the graph, but also from symptomatic as well as asymptomatic patients. In the latter two groups, you can see a wide variation in rough values, which reflects the genetic heterogeneity and how we know these patients are different. Next, on this slide, it shows the results that were obtained in OTC females. These are interesting because some OTC females have typical and severe symptoms of urea cycle defect, but some of them really don't. So it's also a group of patients that do carry a mutation in the OTC chain. But for those of you who may not remember, you turn off one copy of your X chromosome. And if that one is the one with the mutation, that's why you may have symptoms. But some of the patients will show symptoms and some are not. And the test can actually distinguish the symptomatic from the asymptomatic patients, which is a really great step in the field. Next. Last slide shows the urea enrichment that corresponds to the labeling of urea, as explained before by Dr. Häberle. And then looking at the patients from the Arcturus trial. Patients are named 002, 003 and 004. If you look at the RUF values for these patients, you can see it has decreased at baseline in comparison to controls for all three patients, 21%, 39% and 27% from the baseline. So these are patients who definitely have OTC functional problems. In the Arcturus trial, we did the ureagenesis test 4 times after the baseline while patients were on treatment and then after they were off treatment. And you can see that there was no change for patient 2 on day 71 and day 85 However, this patient had a different enrichment amount of citrine, which is a metabolite within the urea cycle, indicating there may have been some actually side shunting from urea production. In patients 003 and 004, there was an increase in the RUF values to about 50% to 60%, respectively, which is a significant increase in their urea cycle function. So while there was no change in the rough in patient 2, there was an improvement in citrine enrichment in this patient. So the tracer is going through the cycle, but instead of going into urea going into citrulline, which is a necessary product of the urea cycle and as well as arginine. In patients 03 and 04 who both showed a significant increase in urea cycle flux after five doses of the intervention as quantified. And as we showed before, that was a statistically significant increase on that. And given that, I will now pass this back to Joe.

Thank you, Dr. Summar for stepping in for Professor Häberle, and we thank him for his thoughtful presentation as well. And also for your independent perspectives and the statistical analysis of these data. At Arcturus, our summary of this new data set is clear. ARCT-810 has achieved strong biological effects in both Phase II studies, including significant consistent reduction and normalization of glutamine and a statistically significant increase in 15N urea genesis. Further supporting the favorable glutamine and urea genesis data, patients in both Phase II studies maintained ammonia levels within the normal range. And ARCT-810 continues to be generally safe and well tolerated at all tested dose levels in Phase II multiple administration studies. So what is next? Well, first, Arcturus will share these new clinical data with the OTCD community. As for next catalysts, we want to complete our Phase II trial and get alignment with regulatory agencies on a multi-biomarker-driven pivotal study design, which will be important. Further guidance can be provided on our next quarterly call. So thank you for your attention, and we will now pass the call to the operator for Q&A.

[Operator Instructions] Our first question is from Lili Nsongo with Leerink Partners.

Can you hear me?

Yes, we can hear you great, Lili.

Congratulations on the data [indiscernible] the update. A few questions here. So first, can you give us maybe a little more color on the baseline characteristics, especially as it relates to the U.S. study? Those two patients that had the most significant improvement, were they the patients that had the most crisis before going on to study? Or were the other characteristics for those two patients specifically? And then as a follow-up, how should we think about enrollment cadence and then time to next readout in the U.S. study and then whether you expect to add additional sites for patient recruitment? And then separately, one question for the KOLs as to what do they see as the most important outcomes for both regulatory but also clinical uptake of the medication? Is it still kind of the scavenger removal and the diet normalization? Or are there new ways of looking at the trial? So multilevel question.

Yes. So there's three. You asked about baseline characteristics. I'll defer to Dr. Summar here shortly. With respect to enrollment cadence, I think that's a fair question. But typically, in rare diseases, and I would expect OTC deficiency to be no different, that as this new fresh and positive and exciting data distributes within the community that, that may impact enrollment cadence, of course. And that's one of the first things we intend to do. But with respect to baseline characteristics and the early adopter question as for which type of patient would be most interested in this type of therapeutic, I'll defer that to Dr. Summar.

All right. Let me tackle both of those fairly quickly. In the characteristics of the patient, the 02 patient was the mildest and was also on an advanced scavenger glycerol phenylbutyrate. So that patient had fewer symptoms and was more at a steady state from that standpoint. The 03 and 04 patients from the -- sorry, the 3 and 4 patients from the 04 study, both had more significant disease. They came from a background where they were not exposed to the more advanced scavengers, had more reports of elevations in ammonia, hospitalizations for that. So they definitely had a more significant clinical course for that. Both patients reported subjective improvements in how they felt during the course. These were unsolicited actual observations from both the patients and their caregivers as well, too. The next would be who would I see as the early adopters? So I just actually returned from a liver transplant meeting in London. And to be honest, frankly, these mRNA therapies are viewed as an excellent way to either hold off or even prevent having to go to liver transplant because there, you're treating one disease for another and not completely fixing the first one. So these mRNAs for OTC would be viewed as a really good way to avoid having to do transplant in our most severe patients. So starting them very early in the course in that -- almost that infant period of time, which I believe the company is heading toward eventually from dosing after making sure everything is safe in the older patients. After that, I would say the patients who presented early on, but have had an unsteady course. In other words, between combination of diet and scavengers have not really had as high a quality of life as one would hope for. And I also think the patients, though, who are on scavengers and diet would like a chance at a more normal diet. If the -- if we demonstrate very clearly that you can go on basically a normal diet with using the mRNA therapy, I think the patients would be willing to come in for an every 2-week or longer if possible infusion from that standpoint. So did I answer your questions?

Yes. Maybe I guess just a little bit of a follow-up. Do you still view diet normalization as well as scavenger removal as the bar for success in the field?

All right. So let me rephrase and make sure I understood. I view diet normalization and the need for no scavengers is normalization of the patient. Is that what you're asking me?

Yes. Do you still see that as the bar for success in OTC?

Yes. Yes, I would.

Our next question is from Yasmeen Rahimi with Piper Sandler.

This is [ Dominic ] on for Yasmeen Rahimi. Congrats on the great data. So we have a couple of questions here for management. How does this data look across glutamine and 15N at an individual patient level? And then for our KOLs, how does this data compare to other OTC approved therapies or other therapies in development?

Well, more than happy to get our KOLs view on this as well. But mRNA therapeutics are definitely different from other options that are being advanced in the clinic and definitely different than ammonia scavengers. We're in the business of fundamentally or functionally curing the disorder with protein replacement with a healthy ornithine transcarbamylase deficiency. But more than happy to hear from our KOLs, Dr. Summar. Yes?

So it's definitely a different way to go. So most of my career, gene therapy for OTC was one of the holy grails back in the '90s and the 2000s and never quite played out. And to be honest, frankly, until we had these mRNA therapies, I haven't seen anything with this consistently stronger response. The scavengers suppress symptoms. So one of the things the scavengers don't do is they don't restore urea cycle function. So glycerol phenylbutyrate, which is probably the most widely used in the United States, actually just scavenges glutamine from the system. It does nothing for urea cycle function which is one of the goals is by restoring function, not only do you have less toxic nitrogen to deal with as ammonia, but also some of those downstream things such as the production of citrulline, arginine, polyamines and a number of things because the urea cycle is one of the oldest described pathways is at the center of a number of biochemical processes. So it's far superior to restore function to the cycle than it is to just kind of siphon off some of the toxic byproducts that you do with the scavengers and diet. Obviously, diet has got a huge problem because when you're restricting protein, particularly in these younger patients in peak growth phases, that can have significant impact on brain development, skeletal growth, everything else. So normalization of diet is one of those things that we really try to achieve, but we have to balance that against the toxic metabolites that can build up. So actually increasing the urea cycle function is kind of the answer to that, which is what these mRNA therapies do.

Our next question is from Seamus Fernandez with Guggenheim.

This is Evan Wang on for Seamus. Thanks for question. Then pretty exciting data. For Arcturus management, can you just walk through some of the next steps here and whether you plan to fully exploit the dose range with the higher 0.7 mg per kg dose or kind of next steps here? And then for Dr. Summar, can you highlight, I guess, in the clinic, would you be comfortable with drawing these patients or kind of going towards that liberalization or removal am scavenger? And then where do you see mRNA therapies in ARCT-810 fitting in within emerging treatment landscape, I guess, whether that's adults, infants and some of the more severe neonatal patients?

Sure. Well, before Dr. Summar can address the mRNA versus gene therapy type question, Juergen, can you address next steps in terms of what we're going to do next on Phase II?

Yes, sure. We are definitely planning to complete the ongoing Phase II U.S. study. We wanted to complete the 0.3 milligram and 0.5 milligram kilogram doses. We need to talk with the FDA. This is our next step, and we will initiate the FDA interactions already with the interim data. And we will discuss -- we are planning to discuss with the FDA a multi-biomarker-driven pivotal trial. And the multi-biomarkers are the trifacta of glutamine ammonia as well as ureagenesis that we consider the most important biomarkers for these patients to define in the study. Does that answer your question?

Yes. And Dr. Summar, please.

Okay. I believe the first question you asked was, would I be comfortable adjusting the patient's scavengers and diet using an mRNA therapy. Am I correct there? I want to make sure I heard you properly.

Yes.

Yes, I absolutely would. The nice thing is those are such good markers, particularly using glutamine as a marker for that, that we're very -- actually, that's how we normally adjust them. We will go up or down on scavengers or diet based on that. If we're able to restore ureagenesis and urea cycle function from that, we'll see those markers go down and would make adjustments accordingly. And we try to get the patients off the drugs if we possibly can just because there's a burden from those as well, too. Glycerol phenylbutyrate actually in high-dose concentrations can result in phenylacetate accumulation, which has its own toxicity. So we have a therapeutic window there we have to try to work within. So being able to drop that would be, I think, viewed as a plus from that standpoint. Now can you restate your last question a little bit on mRNA therapies versus gene therapy? Is that what you're asking me?

I guess where do you see the kind of amongst some of the emerging therapies with gene therapy, gene editing, I guess where do you see ARCT-810 and [indiscernible] kind of fitting in and the most unmet need would be adults symptomatic kind of PAs or some of the more severe neonatal patients.

Yes. So I've actually given a lot of thought to this question. Interestingly enough, the patient who got the gene editor a few weeks ago was actually -- had the gene that I actually originally described way back in the 1990s. So I've been following that field very closely. First off, we found that the AAV therapies for the most severe urea cycle patients wear off with time. And that's been -- we've seen that. We've seen very mixed results. I've been part of some of those trials as well, too. So what I see the mRNA therapy is actually becoming kind of the bullwork of how we treat these patients right now. And for instance, we could prevent having to do a liver transplant in the very young patients, that's a huge win because those kids -- I don't know if you follow the liver transplant, but you're treating one disease for another. Those patients often have to have retransplant, immunosuppression for lifetime, all kinds of different problems just from that standpoint. So being able to avoid a liver transplant in those sickest newborn patients in early years patients would be a huge plus for us. Then you talk about, okay, are the gene therapy editors there yet. They're actually not. the patient who got the CPS1 editor treatment actually is still requiring drug and dietary, and they're actually doing it as a bridge to liver transplant. So it wasn't a fix. It's very promising data, but I have a feeling those things still need a lot of work before we're routinely using them. mRNA therapy is definitely, if not, in some ways, a better substitute, but nothing else a long-term bridge for those things ever become available. The other thing to remember is since editors are based on a patient's individual genetic defect, some patients don't have a defect that actually is amenable to an editor. So in that case, mRNA therapy would be the long-term therapy. But even in patients that have those kind of changes, they have to build that editor for that patient under specific conditions, and that can take a long time. If you look at the number of people involved in that recent case. I mean, there were probably dozens to maybe over 100 people involved in getting that ready for the patient, which is great for that one patient, but not a sustainable model, whereas the mRNA therapies actually can be rolled out very quickly. They're not mutation-specific. And so you can use those while the dust settles on all of these other things. So -- and if I had to pick patients in general, I would say the very young patients who have the most severe, then the childhood and stability patients and then adults who are having trouble. And there actually may even be instances where an otherwise stable adult would need treatment. We've lost a number of patients in the past during pregnancy labor and delivery, patients who have another severe illness or would be, say, undergoing treatment for cancer, things like that, all things that can trigger urea cycle instability. So even in your most stable patients, there may be instances in adulthood where you'd still use an mRNA therapy. But consistently, definitely, those very sick young patients those patients that are consistently having problems in childhood because you want to maximize diet, you want to minimize the use of scavengers if you possibly can. And then the adult patients who are having symptoms and then the choice then becomes diet scavenger versus mRNA and how often do they do that. And I suspect there'll be more developments around the mRNA therapy. Does that answer your question?

Our next question is from Myles Minter with William Blair.

Thanks for the very comprehensive presentation. I appreciate it. I actually had a question on just the range of the ureagenesis test data that we could possibly see. I was just looking at the Allegri 2025 paper, and it appeared to me that some patients that are in the symptomatic cohort in that paper actually had pretty high ureagenesis test data that if they weren't symptomatic, you'd actually probably put them in the asymptomatic range. So the question is more about the variability of the data and how much we can trust that, that 50% bar is correct. And maybe as part of that for the company, how many males versus females are presented in today's data because I do know that there's sex differences.

Dr. Häberle, why don't you address that question?

Okay. I'm happy to answer the first part of the question. Well spotted. We included in the symptomatic patient group in our paper, patients that had any form of symptom throughout their life. So take a 60-year-old OTC male that had a single hyperammonemic episode at any point in life, we would put this patient into the OTC symptomatic patients. Only those that never ever had any form of disease, clinical form of disease symptoms were in the asymptomatic group. And that resulted, in fact, in some patients, OTC patients in the symptomatic group that had rough values in the normal range but we had an 81-year-old patient in our cohort with exactly the situation, and he had throughout his life, never ever any symptoms. And then in the course of an intercurrent illness, he had some mild signs of neurological disease, slight hyperammonemia was noticed, and he went into the symptomatic group. And that results in what you rightly observed that the OTC symptomatic males sometimes may in the range of the controls. I think the important thing from the ureagenesis assay data is the 15% that you see over the three patients that we investigated and the -- in two of the patients, 003 and 004, what I would say, a clear increase from baseline to the 50% and 60%. And I'm pretty sure that above 50% is a makes the individual a healthy individual. So I think clearly, these ureagenesis data, they are meaningful, clinically meaningful. And I pass back for the second part on the question.

Yes, the relative percentages of male and female, Dr. Summar, do you want to address that?

In the 04 study, all three patients were female. For the 03 study, Juergen, you're going to have to help me on that one.

Or were you speaking generally like of the population that's remaining? Myles, were you speaking general percentages of male, female?

Not. Current trial, and the data that was presented today.

There's a survivor bias in that because since we have to start with adults and then go to adolescents and given that early days, the death rate was quite high in the OTC males, it's gotten much better, fortunately. But even so, the patients have definitely a higher morbidity risk there. So for the age ranges we're looking at, that's about all we have left, unfortunately.

Okay. And then maybe my last one is just on safety. Was there any sort of indication of pyrexia, myalgia, any indications that there was or potentially will be a febrile reaction just given it is repeat dose mRNA?

Yes, Juergen, go ahead.

Yes, sure. In our early studies, we were able to modify our infusion regimen. And please keep in mind that we cannot take any steroids as pretreatment because this would make OTC patients worse. And we modified our regimen, and we are using improved regimen in the Phase II studies. It's a 3-hour infusion regimen. We have seen no serious adverse events with this infusion regimen. And we think we have a good handle now on the safety related IRRs, and I think you're referring to the infusion-related reactions.

Our next question is from Whitney Ijem with Canaccord Genuity.

Just a clarification question on the dosing. And I'm sorry if I missed this, but in the U.S. study, three patients, but some -- one got 0.3, I think, and one got 0.5, so -- but you still want to go back and dose 0.3, I think. So can you just walk us through what was the dosing cohorts or cadence or kind of what was happening there?

Go ahead, Juergen.

Yes. The U.S. study is designed in a two scopes of 0.3 and 0.5 milligrams and if both are completed considering a higher dose. Our data and monitoring board after seeing the 03 data allowed us to start also enrolling patients in the 0.5 milligram per kilogram group. And this is why you see a mix of both groups in our U.S. study, but we are planning to complete both dose groups before we continue in the other dose groups.

Got it. Okay. And then I guess what was driving -- were there different baseline criteria, enrollment criteria, something for patients who have gotten to the 0.5 mg dose instead of the 0.3 mg dose for the patients so far?

No. There were no -- we decided -- since they allowed us to do the 0.5 that the first patient that comes and is eligible would be on the 0.5 milligram per kilogram group. And then we would enroll -- we look for other patients in the 0.3 milligram per kilogram group, but there's no baseline characteristics that would make them any different. So we did not select specific patients for specific dose groups.

Got it. Okay. That's helpful. And then what are the next steps or things that you need to do to move into the younger patients? And is that something that could happen in the current Phase II? Or would that be a separate study or happening in a pivotal? Or how do you think about that?

We're doing that in parallel, but Juergen you want to comment further.

Yes. Our protocol is flexible. It might allow us to go on the younger patients if we want it, but we would like to share these data with the FDA. And as you heard from Joe earlier, we have severe pediatric disease designation in the United States. So we will be talking to the FDA to allow us to go to the younger patient population as early as possible. And we hope that the current data might actually convince them already to do that..

Our next question is from Pete Stavropoulos with Cantor Fitzgerald.

Thanks for the presentation. Dr. Summar, can you discuss some of the behavioral and neurological symptoms of OTC deficiency? Are they mainly driven by ammonia levels? Or are there other metabolites involved? And what I'm really asking is what other products the disrupted urea cycle do you believe need to be normalized in order to impact behavioral and neurological symptoms?

All right. Let's -- boy, you just asked a PhD dissertation level question. Congratulations. Fortunately, I worked with one of the PhDs that did that. So here we go. There's a number of things that cause neurotoxicity in urea cycle disorders. Baseline mild elevations in ammonia, even though they're not really detectable much in the plasma are one of those things. There's sort of an ammonia trapping conundrum in the brain that can do that. The glutamine levels actually can play into that. So the cells, first off, don't function as well. So for instance, if you had a baseline elevated in ammonia, and I actually measured neurologic conduction from a tone pulse in your ear to recognition in the frontal cortex normally, they take about 300 milliseconds. Actually, with baseline disruption in ammonia and glutamine, that can take upwards to 1,000 milliseconds. So imagine what that does to cognitive processing behavioral just everyday function. So it's hard to maintain focus, hard to maintain train of thought, things like that. In the classic urea cycle, we see effects on neurocognition at a couple of levels. The first one is from the initial presentation. If the brain swelling, which affects the aquaporins and the microglial cells, which causes them to swell and push on the brain, you will see what almost looks like an ischemic damage to portions of the brain. It can be fairly global, but can definitely impact both neuromuscular as well as cognitive functions and that usually is permanent. So dead brain cells, unfortunately, dead brain cells. Then there's the ongoing, what I would say, and I'll ask Johannes to add on top of this in a second. But in the ongoing things like the glutamine, the ammonia and then probably some of these side chain things like the polyamines, like citrulline and arginine, which are involved in neuronal nitric oxide synthase have sort of a cumulative effect on the brain. So you'll have patients who just kind of generally feel a malaise or not quite as healthy as they should be. When we first noticed that when we started doing liver transplants in older patients, what we noticed was kind of a before-after effect when we kind of relieved a lot of that. Like I said, it's -- you're using a very severe procedure to try to relieve that, but the risks were very high otherwise. And what we noticed is those patients seem -- I hate to use these terms because they're not scientific, but brighter, more engaged. The learning curves, obviously, permanently lost capacity didn't come back, but the patients actually did with the capacity left, did seem to exhibit some accelerations in learning, things like that. Neuropsychologically, depression, just kind of generalized malaise also seem to reverse from that. So it's a complex picture. Johannes, do you want to add anything on top of that?

No, Marshall. I think you very comprehensively described the situation. I think what you also said is multifactorial, but clear is that we need to avoid hyperammonemia, so an elevation of ammonia at any time and also clear is that we should bring glutamine as low as possible or as close as possible to the normal range or into the normal range.

Yes. And I'll just throw a story on top of that at the end. I followed a patient for 18 years who has had severe urea cycle disorder. It was CPS1 deficiency. And the patient was getting a little unstable, didn't feel well, things like that. And after 18 years, thought we knew exactly what we were doing. Patient came in to see me in clinic, caught a respiratory virus and was dead 24 hours later after 18 years with his family doing everything possible to keep him going. So when you don't have that functional urea cycle, then you're always at risk for an overwhelming hyperammonemia. So that's just kind of the one thing to keep in mind.

And just one follow-up for the company. When you -- have you looked at the presence of bonus in these patients? And do you see clearance or accumulation of the lipids? And I ask because these are biodegradable, but wondering has this added to the safety profile, specifically ALT increase.

Yes. Yes, we've completed the evaluation of ARCT-810 intravenously dosed. And in dozens of humans now, including in our Phase I trials, and we've confirmed that the lipids are unmeasurable after just a couple of days, any sort of circulating or plasma-related lipids. So we're very confident that this is a biodegradable delivery technology that's nonaccumulating.

And then one last clarifying question. Do you need to meet with the agency? Or does the agency need to see the data before you move to the next dose level?

No. If there's any sort of dose elevation, we have the flexibility to do that. But we may just complete the two dose levels that we're at right now in Phase II. And as Dr. Froehlich mentioned, we're going to have that conversation with the FDA about next steps.

Great questions. Our next question is from Tom Shrader with BTIG.

Thanks for all the nice detail. I understand if you take a patient with 30% rough and bring them to 55%, it's transformational. What about much lower numbers? Is a patient that goes from 15 to 25 benefit, how meaningful would that be? And then a follow-up for the company. You had some transfection efficiencies from your preclinical data. Are they tracking about online with humans? Is your ability to get the mRNA in animals predictive of what you're seeing in humans? Are they very different? Do you have any data there?

Yes. We've completed a considerable amount of preclinical data and toxicology data in nonclinical models because it give us a lot of confidence that we're not wasting any dose levels here. With respect to would a 10% to 25% or 10% to 30% change in ureagenesis be meaningful, I'd defer to Professor Häberle.

Okay. Thank you for the question. 15% to 25% increase, if it's a true increase in the flux through the cycle is meaningful because you come from a still very severe situation into a not normal situation, but much less impacted situation. So I would expect this patient to benefit from the treatment from the increase to 25% by having a higher dietary allowance for protein, by having less risk of decompensations, by having maybe less need for the nitrogen scavengers. So yes, definitely, I would expect 15% to 25% already making a difference to the patient, not a cure, but a difference. For the rest, I hand back.

Our next question is from Yigal Nochomovitz with Citi.

I think you had mentioned the -- you mentioned the citrulline levels for patient 2. Can you provide any more detail in terms of the specific numbers in terms of the benefit there and whether you also observed the benefit with citrulline in the patients 3 and 4?

Juergen, why don't you address that?

I think Professor Häberle is doing all these analysis. I would like to ask Dr. Häberle to respond to that, please.

Okay...

I'm happy to comment on that. So we didn't -- I didn't present the data itself, but just mentioned the increase in citrulline. Our assay includes the metabolites of the urea cycle, not just the urea, but also the metabolites, amino acids that run through the urea cycle. Most interesting for OTC deficient patients is citrulline because that's the product of OTC. If we see an increase in the labeled citrulline 15, 30 minutes after the tracer has been given, it clearly indicates an improved function of OTC because that's the only way the citrulline, label citrulline can be produced through OTC. And this was the case for all three patients. So in that study. And it was the case for 002, and that's why I mentioned it in the absence of a measure of an improved rough value. And we believe, in fact, that the enrichment in citrulline for the OTC deficient patient is probably not as meaningful as the total urea production. It's just more difficult to explain if we are talking about the entire flux through the cycle. But that's why we included it in the presentation. The improved citrulline enrichment clearly indicates that OTC function in that patient was better. I hand back.

Okay. I just had another question. So -- just a different way to ask the variability question. In the 15 nitrogen paper with the new assay, I believe it was about a 3% to 7% intra-patient variability on RUF. And I'm just wondering if there was any correlation between the degree of variability in the assay and the degree of severity of the clinical situation with the patient.

Yes, Professor. Go ahead.

Thank you for the question. That's -- I think it's a high-level question, which I'd like to answer. We found about 20% intra-individual variability in the rough values when we repeated the test in single subjects on different occasions. And I think that doesn't reflect any impreciseness of the test itself or any problem of the technology we are using, but it just reflects the fact that we are all humans. Our biological system is not the same today and tomorrow and yesterday. So that's just the normal intraperson variability. It's about 20%. So if you take a patient with a 10% rough value, 10% next day may be 8%, may also be 12%. So there's always a range. If you take a 50% patient, this is to say that this patient may well be next day 40% and next day 60%. And it's important to your question because if you now with that information, look at the numbers, you will see that an increase of about 20% to about 50% is beyond that intrapersonal variability. It goes statistically clearly above what we expect from a normal biological variability of this biological functional assay in a human being.

This is Marshall Summar too. Let me throw something on top of that. One of the things we did in the statistical analysis is we looked at the slope for those patients across multiple time points. So as opposed to which actually is going to correct some degree for that variability intra-patient.

Our next question is from Yanan Zhu with Wells Fargo.

Thanks for taking our question and for those thorough discussion so far. I do have questions about the data itself. But if I may start with two questions on other personal perspective. For the question and also the KOL, what do you think about these biomarkers and their potential to be used for -- to support accelerated approval path down the road for the company on safety, just on the ALT elevation, I was wondering whether it's Grade 3 or Grade 4. And the timing of it, 28 days after the last dose, what does that signify or tell us about the potential mechanism? And then I have a follow-up on the data itself.

Yes. So to restate the question, thanks, Yanan. Will glutamine be a nice biomarker driver for a pivotal study and will the regulatory agencies align with that? And with respect to the temporary ALT elevation that we observed early in the clinical trial. Juergen, do you want to start there and defer as needed?

Yes, sure. I can start there. The several -- many OTC patients have actually transient elevation in LFTs and Professor Häberle or Dr. Summar can provide us some more detail...

Yes, I'm happy to weigh in on that. Yes.

But on the other hand, let me just -- these patients were all asymptomatic. So they had only these increases in transaminases and no other signs or symptoms. Dr. Summar, could you please provide your perspective?

There's really good literature that patients with OTC and urea cycle disorders have periodic elevations in transaminases. Since these are at least OTC/CPS or intra mitochondrial that can actually disrupt mitochondrial function, mitochondrial membrane function. We don't know the exact mechanism. Renata Gallagher reported a few years back about 40% to 50% of the patients will have evidence of either hepatitis or elevations in transaminases, and that's been repeated in a couple of other papers as well, too. So from that standpoint, particularly given the fact that the functional aspects of the liver, bilirubin clearance production of clotting factors, things like that was not affected at all. We felt that, at least in my opinion, that, that was consistent with what we should see as part of the baseline in OTC patients. So in other words, the fact that it's fairly remote from the last dose, to me actually suggests that it's much more likely part of the pathology of the disease rather than anything related to the treatment. Johannes, would you agree with that or have a contra opinion?

So I would agree with that. And the data from Renata Gallagher were exactly replicated by data from European centers. So OTC deficient patient, as Marshall Summar just has said, they occasionally have slight increases of the transaminases. And I agree also with the time between the last dose and the increase of ALT that likely there -- or we should consider the possibility of other courses than the intervention. I hand it back.

What was the other question?

Great. So that's very reassuring. Maybe a couple -- two questions on the ureagenesis data. I was curious because the improvement in RUF seems to be slower during the dosing period. And after the last dose, it seems to have substantial improvement after that. So I was just wondering the KOLs take on that kinetics and whether there are any thoughts there? And if I may ask an additional question here. patient 002 who didn't respond in this ureagenesis assay, it seems like that patient did respond to the on the glutamine biomarker. Could you speak to the underlying mechanism? And does that mean that patient benefited or not benefited from expression of OTC?

Johannes, do you mind if I start with that one?

Okay. I'm happy to do so. I think it's a very good question. The patient 002, you asked whether he benefited from treatment. I would say, yes, based on two things. As you said, glutamine decrease and the second thing is the increased enrichment of citrulline. I mentioned before that this increase in the glutamine labeling can only come from an improved OTC function. Why that didn't translate into an improved rough, I cannot answer. For the other question for the fact that the rough values stayed improved 14 and 28 days after the last dose. That's true. That's only 4 time points, and I don't know exactly how long that effect will last. It will surely decline with more time. And I think -- I hope we understand that better if we investigate more patients. I hand back to Marshall.

Yes. Let me speculate on this one for a second, and I am engaging in speculation here. But all of these patients are protein restricted. And that also means the flow through the cycle, which was not going into the production of citrulline and arginine can result in relative deficiencies of some of those amino acids as well as others. So what's possible is you had to fill up those bath tubs first before you started sending things all the way to the end of the cycle to make urea. So in other words, you may have had a certain amount of arginine and citrine, which kind of goes along with Johannes' observation of incorporation into citrulline, which you are using for other things, other biological purposes. So it may be that you had to kind of satisfy those needs beforehand. And so that may have taken quite a while to do because these patients typically do come in, they're slightly protein malnourished, everything else. So suddenly by restoring that -- it's like first sort of first one at the line may have been citrulline polyamines, may have been arginine production. And then after that's been satisfied in the urea cycle. So like I said, this is a cycle that's at the middle of a large biochemical pathway. So I suspect that's the case. And I do think patient 02 benefited and she reported that subjectively as well.

Just to add to that. Yanan, just to add to that is what we saw preclinically is exactly what we've seen clinically in this program. So preclinically, we saw that OTC building was accretive over multiple doses. And you're seeing the same effect in human beings. In Phase I, we did not see any biological impact after a single administration. But at some point, whether it's 2, 3, 4, 5 doses, you see a threshold being crossed and you're seeing more significant biological impact as the OTC protein is getting built. So it was good to see that consistency between the human trials and the preclinical studies.

Our next question is from Greg Harrison with Scotiabank.

Congratulations on the great data update. Just a couple on the optimized IV infusion. for the KOLs, maybe how willing do you think most patients would be to undergo this treatment every two weeks? And if you could maybe estimate the proportion of patients that would be willing to undergo that level of treatment burden. And then for management, thinking about the future commercial plans, is there any plan to look at other formulations that could have the potential for at-home use or extended dosing?

Go ahead, Professor...

Yes, this is Marshall. I'll go first. So for the newborns, no question, they would do the every two week because the alternative is not really pretty. For the sick children, the ones who don't -- haven't been transplanted yet, but they're still having symptoms, I think the same issue there. If you look across -- I also work with patients with lysosomal storage disorders, things like that. And that has not proved to be a huge block to treatment is getting a regular infusion from that standpoint. And given the fact that we won't see as much of the immunologic issues, that's actually even a better prospect from there. For the adult patients, adults are screwy. Some of them are going to be really happy with where they are. And even if there's a benefit for them, they just decide to stay on what they are because we've seen that with other diseases. I think for patients where the diet is restrictive, and they are not stable, which we see in a lot of the adults with OTC and other things, the patients don't like the diet because they're just mild enough where they get a taste of protein, but then they're told not to have any. I think there would be a drive in that direction to do that. Having said that, adults are unpredictable sometimes.

And then from the commercial-related question, first of all, with the platform, this data, of course, opens the door to other UCDs and dozens of other hepatocyte-based proteins of pharmaceutical interest. So it's very meaningful from a platform perspective. From a commercial opportunity, yes, this is -- you've heard from our KOLs and that this is an exciting new therapeutic option that's unfolding. And there's no current therapy that adequately prevents crises or prevents or addresses the underlying cause of the disease. So given that this is the first messenger RNA therapeutic in line, I think it's a great opportunity for us. And I do remind people, too, that our patent life extends past into 2040. So thanks for the question, Greg.

Thank you. There are no further questions at this time. I'd like to hand the floor back over to Joe for any closing comments.

Yes. Thank you to everyone participating on the call again to our KOLs. And if there's any remaining questions, don't hesitate, as always, to reach out to our team, and we'll get back to you as soon as we can. Bye for now.

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