Thank you for standing by. My name is Tina, and I will be your conference operator today. At this time, I would like to Welcome Everyone to the Precision BioSciences AASLD Update Call. All lines have been placed on mute to prevent any background noise. After this speaker's remarks, there will be a question-and-answer session. To ask a question, simply press star followed by the number one on your telephone keypad. To withdraw your question, press star one again. Thank you. It is now my pleasure to turn the call over to Naresh Tanna, Head of Investor Relations. The floor is yours. Thank you, Tina. Good morning, everyone, and welcome to the Precision BioSciences 2025 AASLD business update. I am joined by Michael Amoroso, our President and Chief Executive Officer; Alex Kelly, our Chief Financial Officer; Dr. Cassie Gorsuch, our Chief Scientific Officer; and we are happy to welcome Dr. Mark Sulkowski, Professor of Medicine at the Johns Hopkins University School of Medicine and renowned expert in hepatic and infectious diseases, who is also serving as our Head Clinical Development Advisor. For today's presentation, you will have the opportunity to go through the slides as the speakers mention the slide number. On slide two, you will find our forward-looking statements that we may make during today's presentation. Without further ado, I would like to hand off the call to our CEO, Michael Amoroso, who will begin the business update on slide number three. Michael. Thank you, Naresh and team. Welcome to our investment community today. It's wonderful to be with you on the back of AASLD, where we just showed some of our late-breaking data at the end of day yesterday. My name is Michael Amoroso, and I'm the Chief Executive Officer, and I have the privilege to lead this team. On slide two, you will see Arcus, no longer just a vision, no longer just a preclinical platform, but a platform that is the underlying backbone of Precision BioSciences and one that is now delivering in the clinic. First, you'll see our partnered programs, iECURE 506 for the dire disease of OTC deficiency. I'll remind the investment community, the first patient treated this year on a gene insertion program, proof of gene insertion with Arcus, through our partner at iECURE, Joe Truitt and team. The first patient is now over a year and a half old in a complete response. Joe continues to give business updates of more patients being treated, and he'll tell you more about that end of the year and early into next year. We look forward next year to hopefully talking about a BLA path for these children in dire need with OTC deficiency. Immugene, our partner with the AzoCell product for cancer, is now meeting with the FDA in November of this year to discuss a pivotal path forward. More than 100 patients treated now, many long-term durable responders. Immugene believes they have the go-forward combination and dose for AzoCell. Again, examples of Arcus, the platform now delivering in the clinic. The focus of most of today's time with you, our own wholly owned organic program for chronic hepatitis B, PBGENE-HBV, and the Eliminate B trial, data that was freshly presented at the end of day yesterday at the AASLD clinic by Dr. M. F. Yuen. Next slide, please. Precision is focused on our two wholly owned organic development programs, PBGENE-HBV, and the Eliminate B trial, which Doctors Mark Sulkowski and Cassie Gorsuch will take you through today. Obviously, the PBGENE-DMD program that we went wholly owned on in 2024, and we will be starting in the clinic with that program in Q1 of 2026. This is the dual focus of Precision BioSciences, an in-the-clinic stage company delivering results for patients. You may also note that yesterday we announced the public offering where Precision brought in $75 million. The reason for doing so on the back of the incredible data was to secure our cash and operational runway for patients, our investigators, our employees to deliver all the way through phase II HBV. The Eliminate B trial is getting to a point where we think we're going to the expansion phase shortly. That will run right into phase II, about 100-150 patients. And those proceeds will also fund us all the way through DMD pivotal to BLA submission. That is the purpose for yesterday's raise to take us through 2028. Now, I will turn it over to Dr. Mark Sulkowski and Dr. Cassie Gorsuch to take you through the wonderful data presented yesterday by M. F. Yuen. Dr. Sulkowski, Mark, please. Great. Thank you, Michael. Let's go to slide four. Slide four describes the very exciting oral presentation delivered at this year's Liver Meeting by M. F. Yuen. M. F. is one of the leading international experts on chronic hepatitis B infection and leading many of the trials in this therapeutic space, including the clinical trial of PBGENE-HBV. We will take you through the data that M. F. submitted to the audience yesterday at about 5:30 P.M. Excellent presentation that was well received by the folks sitting in the room. Let's go to slide five and talk about some of the background and really the need for a novel approach in patients with chronic hepatitis B, really targeting cccDNA. On slide six, we're really at a point, a really pivotal point in the quest for hepatitis B cure. There have been a number of modalities that have been in clinical trials, and we've learned a number of things in the last 10 years in trying to develop curative therapy. The first one is that simply targeting hepatitis B surface antigen, that is lowering S antigen, is insufficient to deliver cure. Really, the group of individuals working in this disease and the patients need a different approach, and that is to target the virus itself, cccDNA. M. F. Yuen presented the findings from PBGENE-HBV. This is the first and only clinical stage trial of gene editing. He presented the three cohorts demonstrating safety, tolerability, and a dose-dependent antiviral effect. Of course, we'll talk through that in a few minutes, but first, on slide seven, I want to talk through the large unmet need for patients with hepatitis B and really kind of understand how we got there. On slide eight, we're going to get into some biology of hepatitis B. This is a complicated virus. This is something that many of my patients ask, "Why can't we have a cure like we did for hepatitis C?" The answer really lies in how this virus establishes chronic infection. The virus enters the liver cell depicted here into the nucleus depicted in blue and establishes a mini fortress or mini chromosome known as cccDNA. This is the replication template for Hep B. What you can see coming off this in the figure is pregenomic RNA that is then translated and packaged into new virions released into the bloodstream. We can measure that as DNA. In addition, the virus integrates into the human DNA, and this is not a full virus. This is a particle of the virus that can produce S antigen. S antigen in the blood comes both from cccDNA as well as integrated, but virus DNA only comes from cccDNA. That is the really heart of the infection. Let's go to slide nine. When we look at where modalities have been used to treat hepatitis B work, we've been using nucleoside nucleotide analogs since 1998, and it's really the only approved modality we have. Nucleoside analogs work at blocking the reverse transcription from RNA to DNA. As you can see on the figure at the letter A, this is a late stage of the viral life cycle. They can block DNA but have very little impact on cccDNA. Thus, it's not surprising that over time, while these can control the DNA, they really don't cure hepatitis B at high rates. At some of the other steps, blocking translation, this is really where ASOs and small interfering RNAs work. They block the production of viral proteins, but again, at a relatively late step. In addition, and on C on the figure, there are immunotherapies that are really trying to work to establish immune control of the infection. If we go to slide 10, this is really how PBG differs. This Arcus gene editing approach targets really the virus itself, targeting cccDNA to stop transcriptional activity, targeting integrated DNA. When this happens, we will see the lack of production of RNA and all the downstream effects, including viral DNA and S antigen, will be removed. The last point I want to make before handing off to Cassie is that this could lead to a complete cure. We talk about functional cure, which means there's residual cccDNA, but effective editing of cccDNA could lead to the removal of this infectious particle. With that, let me turn over to Cassie to talk you through the Eliminate B clinical trial. Thank you, Mark. On slide 11, I'm excited to share with you the data that was shared at the AASLD Liver Meeting describing the data coming out of our Eliminate B study. Moving on to slide 12, this slide depicts the study design. It's a phase I, part I, part II study. We're currently in part I, which is our multiple ascending dose escalation. The study is enrolling e-antigen negative patients enrolled on nukes, which account for about 80% to 85% of the chronic Hep B patient pool. Each cohort has three patients enrolled into it, and each patient receives three dose administrations. We've completed dosing in cohort one at 0.2 milligrams per kilogram and cohort two at 0.4 milligrams per kilogram. We've initiated dosing in cohort three with all three patients receiving their first administration and our sentinel subject receiving their second administration as well. This cohort was dosed at 0.8 milligrams per kilogram. The goal of this part one study is to identify a dosing regimen that allows us to stop nukes and demonstrate cure. Once we have that dosing paradigm identified, we can move into part two dose expansion. We are excited to share with you today that we feel the data coming out of cohort three represents a near-term path towards stopping nukes, testing for cure, and then moving into part two dose expansion. Slide 13 shows the safety profile for PBGENE-HBV. To date, we have dosed nine patients shown here across 22 dose administrations. Importantly, no dose-limiting toxicities have been observed across the 22 doses provided. On the table are patients who have experienced treatment-related adverse events. The adverse events that have been observed in the Eliminate B study have been predictable and consistent with LNP-related infusion reactions. The infusion reactions occur right after the infusion and generally resolve within about 12 hours. I want to note on the ALT AST represented on this table, those happened in the exact same patient within cohort three on the same dose administration. These data were reviewed by an independent ALT FLAIR committee that had been assembled prior to the study start. These are made up of world-renowned hepatologists comfortable with reviewing liver function data. They reviewed these data and deemed them not dose-limiting, so this participant is eligible to receive their subsequent and planned dose administrations. One final note on this slide is the hypotension, which has been observed in some patients. This occurs after the infusion and has been responsive to normal IV infusion saline. Because the investigators administered saline to help resolve the hypotension, this is what constituted it as a grade three adverse event. Overall, the safety profile for PBGENE-HBV has been manageable across global sites and was consistent with expectations for LNP-based therapies. On slide 14, we'll dig in a little bit more on the liver function test data. On the left, you can see ALT, in the middle is AST, and on the right is the bilirubin graph. What you're looking at are means for each of the three individuals within each cohort. As you can see, and as was expected after LNP administration, we see transient elevations in ALT and AST. These were not associated with any changes in bilirubin, demonstrating no evidence of Hy's law. On the bilirubin graph, the green line, I want to comment on that briefly. This is cohort one, our lowest dose cohort. It is being pulled up in the average because there was one patient in that group that had a diagnosis of Gilbert's syndrome, so had elevated bilirubin levels at baseline and throughout the study. That is why that line is a little bit higher than the other two cohorts. As you can see, no treatment-related changes in bilirubin. The transaminase elevations have been transient and resolved quickly without any changes in bilirubin, no evidence of liver dysfunction. On slide 15, to summarize the safety profile that we have observed so far with PBGENE-HBV, PBGENE-HBV has been well tolerated across all three cohorts with repeat administrations. This is important because this is the first time a gene editor has been repeat administered in this fashion in a clinical study. Establishing the safety profile of that dosing paradigm was paramount. The adverse events that have been observed have been predictable, manageable, and quickly resolved across our global site. Transaminase elevations were transient, not associated with changes in bilirubin, and resolved without intervention. We have seen minor fluctuations in platelets directly after the infusion that have resolved quickly back into the normal range and have not been associated with any symptoms. To summarize, PBGENE-HBV safety profile has been well managed across all sites. Moving now on to slide 16, we're going to get into the antiviral data. We're really excited to share with you the dose-related antiviral activity that we're seeing across our cohorts. On slide 17, starting with cohort one, this was the 0.2 mg per kg dose level. Based on non-human primate data, this dose level was not expected to be our best therapeutic dose going forward, but was chosen to establish safety for this first in-human study. What we are excited to observe was that activity was seen in all three participants within this cohort, with each of them showing substantial reductions in S antigen. Patient one, which is the thicker green line on this plot, has been reported previously and now with extended follow-up. What you can see is this patient continues to sustain a 50% reduction in S antigen, now nine months after that first dose administration. The other two patients in this cohort show a different trend where they see downward declines in S antigen, steep declines in S antigen after each dose administration. However, they also observe an increase in S antigen after each dose. What this tells us is that PBGENE-HBV is clearly active in the liver, eliminating viral DNA. However, the persistent DNA in the liver has upregulated the transcription of new S antigen transcripts and then protein. This was what we sought to overcome as we moved into the higher cohorts, to drive deeper reductions in the viral reservoirs in the liver, thus providing more durable responses in patients. On slide 18, we are looking at the data from cohort two, now at 0.4 mg per kg. We are excited to see a different trend in this cohort. What you can see is, again, clear activity in all three participants dosed and now durable responses in three out of three patients in this cohort, with all showing sustained S antigen decline from baseline. One interesting feature about these curves is that we see this decline in S antigen directly after dosing and then a muted increase in the S antigen, where it does not return all the way to baseline but settles in with some reduction from baseline. This allows us to continue to see deeper S antigen reductions with subsequent dose administrations. However, we have not, at this dose level, completely blunted the ability of the remaining viral DNA to transcriptionally increase that S antigen production. Moving into cohort three then at the 0.8 mg per kg, this is where now you can start to see the ability to overcome that transcriptional upregulation. In patient seven, you see a nice decline in S antigen from baseline after their first administration, and then that decline is held until the second dose administration where the decline further progresses. This tells us now that at this higher dose level, we are able to sustain this effect, likely due to the ability to remove more viral DNA or cccDNA within the liver. Patients eight and nine, while early, are showing promising trends similar to patient seven. On slide 20, now we can compare across all three cohorts, and these now have calculated trend lines that you can see really demonstrate dose-dependent antiviral effects and dose-dependent increases in durability as we have increased the dose from 0.2 milligrams per kilogram to 0.8 milligrams per kilogram. On slide 21, we will dive a little bit deeper into cohort three. Now we are looking at absolute S antigen levels for all three patients in cohort three. One thing to mention across all of our cohorts outside of even just cohort three is we did enroll patients with varied S antigen levels across this study all the way up to 12,000 IU per ml, and we've seen good activity independent of baseline S antigen. Here in this cohort, you can see each of these patients has exhibited a substantial decline in S antigen from baseline, all achieving relatively low levels of S antigen at their most recent blood draw. Of course, our goal is to continue to provide these patients their planned subsequent dose administrations with the goal of achieving undetectable S antigen. What's been interesting in the field of Hep B is this emerging benchmark around 100 IU per ml with S antigen. Where this benchmark comes from is from stop-nuke studies that have demonstrated that in HBV e-antigen negative patients on nukes, like our patient population, patients who have less than 100 IU per ml do well with stopping nukes and achieving cure. This tells us that all of these patients are approaching a threshold where we could consider stopping nukes with or without S antigen detectable with the goal of achieving cure. Now on slide 22, really to summarize what we've seen so far with PBGENE-HBV in the Eliminate B study. On the left, you can see the orange line indicates the goal of this study to drive deeper S antigen reductions by planned subsequent dose administrations. The blue line is patient seven, which is our sentinel subject in cohort three. You can see now this trend line is starting to follow the goal as we set out within this study. PBGENE-HBV is the first mechanism targeting cccDNA elimination that is currently being tested in humans. This S antigen reduction can only be driven by the elimination of cccDNA or inactivation of viral DNA in the liver. This is really the first time targeting this type of mechanism in chronic hep B patients. PBGENE-HBV has been well tolerated with a manageable safety profile and has shown dose-dependent activity as we've increased the dose with improved durability. As we see it, cohort three represents a near-term path towards stopping nukes, testing for cure, and then moving into the part two expansion phase of this study. On slide 23, I have one more piece of exciting data to share with you from this study, and this is very hot off the press data. This is biopsy data from our first participant in part one who's agreed to pretreatment and post-treatment paired liver biopsies. Let's talk through the biopsy data on slide 24. I want to start with revisiting a piece of data from our preclinical package. When we cut viral DNA, cccDNA in the liver across models in our preclinical package, what we found is there are two editing outcomes. One is elimination of the viral DNA sequence. The other is indel formation, or small mutations in the viral sequence that render it inactive. So indel or mutated viral DNA can no longer replicate and can no longer express S antigen. Both of these represent productive editing outcomes. Based on preclinical data, we know that the elimination outcome represents the larger fraction of editing outcome, about 60%, based on this non-human primate preclinical data shown on the slide. Indels represent about 30% of the editing outcome in the non-human primate model. Now, on the right-hand side of the slide is the clinical biopsy data. The first data coming out of this clinical biopsy analysis is the indel fraction of editing. What we found was after two administrations at 0.4 milligrams per kilogram, we observed 28% editing in the remaining viral DNA fraction. Now, we expect that the majority of the editing outcome has resulted in elimination consistent with preclinical data. We're still working on evaluating the elimination fraction of this clinical biopsy sample, and that data is pending. However, this data represents the very first proof of mechanism that PBGENE-HBV is doing exactly what it was intended to do in the liver of humans: edit viral DNA, and that editing viral DNA is resulting in S antigen reductions. On slide 25, we can now correlate the biopsy data from the liver with the serum data and the S antigen. This biopsy was taken in patient five in cohort two. As I mentioned, that post-dose biopsy was taken after two administrations of PBGENE-HBV. You can see at the time of biopsy, we observed a 44% decline in S antigen from baseline in this patient. Since that biopsy time point, this patient has received their third administration of PBGENE-HBV, now resulting in a 67% S antigen decline. This indicates further gene editing in the liver of this individual has occurred with dose three, which is consistent with cumulative editing observed in the preclinical data. On slide 26, we will talk about next steps. The next steps for the Eliminate B program are to complete dosing in cohort three. As I mentioned, each of the individuals in this cohort are now showing low S antigen levels, and all of them have additional administrations to go. Patient seven still has their third administration. Patients eight and nine have their second and third administration. We expect to continue to observe cumulative S antigen declines after repeat administration. Dosing for this cohort is expected to complete in Q1 of 2026. Assuming these patients achieve a scenario where we are comfortable stopping nukes, that would be the plan: to stop nukes and test for a cure. In order to stop nukes, the protocol requires two sustained S antigen measurements about four weeks apart. There are a few other clinical markers, including HBV RNA and core-related antigen, that we can use to inform that stopping nuke criteria, that stopping nuke decision. We're encouraged by the data in cohort three that we will achieve the ability to stop nukes and test for cure in these participants. Once we've identified a dosing regimen, potentially 0.8 mg per kg with three administrations, we will move that dosing paradigm or regimen into our part two expansion phase of the Eliminate B study. In this part of the study, we plan to enroll up to 45 individuals between part one and part two and plan to take paired liver biopsies in these participants. Our clinical operations team is planning for success and is looking for site expansion options today to allow for rapid enrollment in this part two expansion. In parallel to completing cohort three, testing for nukes, and stopping nukes and testing for cure, we also have an additional cohort looking at dosing optimization. In this cohort, we will be evaluating the 0.4 milligrams per kilogram dose at four-week dosing intervals. Given the cumulative effects we're observing in cohort two, we think this may also represent a path towards potentially stopping nukes and testing for cure. Beyond the part two expansion, what does success for Eliminate B look like? On slide 27, I want to comment quickly on an FDA guidance document that outlines the approvable efficacy endpoint. On this slide, you'll see the functional cure definition as the second bullet in this guidance document, which is sustained suppression of HBV DNA and S antigen off treatment for at least six months. There is another path that is rarely talked about because it hasn't made sense for the mechanisms that have come before. This path is sustained suppression of HBV DNA off treatment for at least six months. You'll notice there's no mention of S antigen in this definition. This path really exists for therapies like PBGENE-HBV, which eliminate viral DNA within the liver and cccDNA. In this scenario, the S antigen would only be able to be expressed from integrated HBV DNA in order to sustain this kind of an effect. We think that this is a possible path forward for PBGENE-HBV as well as the functional cure definition. As we see it, there are multiple paths forward for success. On slide 28, I want to spend a couple of minutes talking about our second wholly owned program, PBGENE-DMD. This is the first gene editing approach for the majority of patients living with Duchenne muscular dystrophy. On slide 29, this really outlines why we are developing PBGENE-DMD. PBGENE-DMD has been designed to address the limitations that exist in the Duchenne community based on their current therapy options, whether they're microdystrophins or exon skippers. In our view, an ideal therapy improves upon the treatment options that currently exist, including providing long-term durable benefit and having applicability to a broad patient population. On slide 30, this outlines the mechanism of action for PBGENE-DMD. The PBGENE-DMD is an AAV vector. It does not encode a microdystrophin. In this case, the AAV contains two Arcus nucleases. These Arcus nucleases have been designed to cut target sites in the introns surrounding exons 45 and 55. Once the Arcus nucleases create the cut, this region of the dystrophin gene between exons 45 and 55 is excised, removed from the gene. We're targeting this region for a couple of reasons. One is up to 60% of patients have pathogenic mutations in this hotspot region in the dystrophin gene. This therapeutic approach allows for broad applicability. The second reason for targeting this region of the dystrophin gene is that we know that the resulting protein that is produced is functional because it occurs in humans. It occurs in a subset of Becker muscular dystrophy patients. On slide 31, you can see the clinical presentation of a Duchenne patient on the left. I think we're all familiar with how devastating that disease presentation is. On the right is indicated the Becker muscular dystrophy patient who has the same genotype as will be created by PBGENE-DMD, this del 4555 Becker patient. We know from the literature that these patients have a pretty good prognosis. They live into their 60s or 70s. Many of them are mildly symptomatic or even asymptomatic, with normal muscle function and ambulation throughout their life. Our goal is to be able to treat a Duchenne patient and provide a protein that is similar, exactly the same actually, as what is produced in this Becker muscular dystrophy patient. It is expected, based on literature, that as little as 5% expression of this near full-length protein that is created after treatment with PBGENE-DMD would be therapeutically beneficial for patients living with Duchenne. On slide 32, I want to revisit some preclinical data in a DMD mouse model. What we've done is we've administered PBGENE-DMD one time to these DMD mice at either 3E13 or 1E14 viral genomes per kilogram. We took this study out to nine months, which represents a long-term mouse study. We evaluated in these various tissues, heart, calf, and quad, shown on the slide, we evaluated for% dystrophin protein expression. I'm happy to share that in each of these tissues, we exceeded that 5% threshold, reaching up to almost 25% dystrophin protein. This was consistent across both dose levels, indicating that with PBGENE-DMD and a gene editing approach, you may not need the same high-dose AAV as has been observed with microdystrophins. These dystrophin protein levels also resulted in functional improvements in this mouse, which is illustrated on slide 33. What we did is we measured the ability of these mice to exert force from their muscles. We measured this at three, six, and nine months. On the graph in the gray, the light gray you're looking at, this is the untreated disease model. You can see compared to the darker gray next to it, these DMD mice have deficient force output compared to healthy mice. In PBGENE-DMD treated mice, again, at either 1E14 or 3E13, you can see a significant improvement in the force output compared to the untreated DMD mice, near levels observed in healthy mice that express full-length dystrophin. These data really give us a lot of confidence that we can achieve necessary levels of dystrophin protein expression after a single administration with PBGENE-DMD. That protein that's known to have function in humans is able to restore long-term muscle function in a DMD mouse model. On slide 34, this is an outline of the planned clinical study. The next steps for this program are to file an IND by the end of this year. The team is working diligently and is on track for that goal. We plan to start the clinical study in early 2026. The goal is outlined here. The phase I/II study will be a single dose level design, no dose escalation planned. We plan to enroll between five and eight ambulatory patients across multiple clinical trial sites in 2026. Based on the regulatory path that has been paved by the microdystrophins, we expect this study to progress quickly, with 10 to 15 patients' worth of data needed for a pivotal discussion with FDA, and between 35-40 patients needed from the pivotal study to support BLA filing, which is planned in 2028. We are very excited about this novel and differentiated approach and its ability to provide long-term durable functional improvement for kids living with Duchenne muscular dystrophy. With that, I will hand it back to Alex Kelly for our last slide. Let's go to slide 34, please. Thank you, Cassie, for the thorough update on Eliminate B, but also showcasing the work that is going on right now to support the DMD IND filing later this year. I would like to just wrap things up by, number one, talking about our relentless focus on these two programs. HBV, DMD, we are executing with both of them. HBV, it's been less than a year that we've been in the clinic. We've already completed dosing patients at least one time in each of the three first cohorts of this, or the first. The cohorts. We've already generated antiviral activity and demonstrated it in every single cohort. We've also shown the very good safety profile of Arcus when administered with LNP after three administrations at these rising doses. Near-term next steps, Cassie outlined, is to continue following the data and administer the remaining doses in cohort three and get to a place where we can stop nukes, test for a cure, and then ultimately expand into part two. Ultimately, the goal is a phase II program that would be finished up in 2028. DMD, great progress by the team. The team is running hard and fast to get the IND filing in by the end of the year. We'll expect to dose first patient in the early part of 2026 and probably have data from three to five patients by the end of 2026. That is really important for us because it sets up a potential pivotal pathway to expand the trial further and to ultimately file BLA in 2028. Going back to the raise that was conducted yesterday, really great to see the participation and support from our top current shareholders and excited about the participation from new, high-quality, long-term focused investors who want to support the Arcus pathway through 2028. I think it's very important that we secure the funding at this point in time because now our team can focus on execution, knowing that we have the resources to take these programs all the way through, not their phase I data inflection points, which we're excited about, but also to give them plenty of runway to get to their phase II or their BLA inflection points, depending on the program. I think that over time, you've hopefully seen that Precision BioSciences are very good stewards of the capital that's deployed to us from our shareholders. We currently execute these programs as well as support programs going on at iECURE with one-third the people of our gene editing peer group and at one-quarter of the OpEx. We hope that you see every dollar invested in Precision BioSciences is deployed to things that generate meaningful data endpoints. These two clinical programs are the future of our company. With that, I'd be happy to open up the call for Q&A. As a reminder, to ask a question, simply press star one on your telephone keypad. We respectfully request that you limit questions to one and one follow-up. Our first question comes from the line of Soumit Roy with Jones Trading. Please go ahead. Good morning, everyone, and congratulations on the great data. It's good to see no cumulative A, but cumulative efficacy with the higher dose. If you could give us a bit of understanding on the average baseline in the real-world population, the S antigen, and what are you thinking of if the baseline is in thousands going up to 10,000, would you reduce the dosing interval, increase dosing to another higher dose cohort, or dose based on the baseline S antigen level? Yeah, I think I'll start off with that one, and then I'll ask Dr. Sulkowski to kind of qualify what I'm saying as he sees more patients in the clinic than I do, that's for sure. Soumit, good to hear your voice. Thank you so much for the thoughtful question. I'm glad you asked the question. Guys, I think it's really important we reset our mind to understand you're looking at a nascent approach for the first time ever. I've heard a lot over the years of HBV, you can't win in that disease. I'd argue we've put a lot of the same approaches. We tried to blunt S antigen downstream and turn the immune system on to eradicate the replicating virus factory cccDNA. Frankly, that hasn't worked. Our goal here, guys, I understand this is a disease where we look at S, it's the obvious serial marker in blood, and it's a lot easier to get than biopsies. S antigen in an E negative patient, E negatives are about 80%, Soumit, everybody will start E positive and unfortunately graduate to an E negative. Just because you have more or less S antigen in an E negative does not mean you have more disease. About 15-50% of all hepatocytes in an E negative patient who's been infected for years are infected. About 15-50, the literature supports. You probably have 5-10 virions in the literature in each hepatocyte, cccDNA. Your expression, as you know, comes from S, comes from cccDNA or integrated disease. And not everybody expresses exactly the same. It does not mean if you have more hepatocytes infected, for example, you have greater burden of disease with S. Now, knowing what our mechanism is, cut out that 15%-50% of viral reservoirs. The result of that will be the correct path of reducing and eliminating getting S to undetectable transcript level. If you look in the real world, and we call this very importantly a real-world study globally, we are in Moldova, New Zealand, Hong Kong, U.S. This was made to really bring in the E negative patient who walks in the door of Dr. Sulkowski, Dr. Yuen, and others every day. There's no upper limit of S antigen, but if you're controlled on nukes, if I just use the U.S. data for a moment, about 300,000 patients in the U.S., more than 90% of patients are an S level at baseline less than 3,000, and about 70% are less than 1,000. We got the question of, "Hey, you're looking great in cohort three, you're close to stopping nukes." Are those less sick patients? They are not. That represents 70% of the people who walk into Mark and others' clinic in the U.S. every day. If you look at Asia, MF's practice, over 90%, I think somewhere in the range of 95-98% have an S level at baseline less than 3,000, and about 75-78% are less than 1,000. If you look at our one outlier patient who was over 10,000, 11, 12,000, the hepatologist at first thought, "Are we sure that's an E negative? Could that be an E positive?" The thought process was we confirmed it, and maybe someone who just came out of E positive disease and has settled into becoming an E negative. Remember, when they first get the disease, that's when you see the higher S levels. The goal here, we may cut out one or two logs, and if you start under 1,000, Soumit, you may not have to cut out the logs. The idea here is eradicate with this mechanism, eradicate S and all viral transcripts by eliminating the viral reservoirs, the 15%-50% permanently. Therefore, when you stop after the finite course, nukes, HBV DNA will come back. Obviously, if you cut out, eliminated the cccDNA and inactivated the iDNA, the integrated that cannot replicate, you'll also show as a result no S antigen. I hope that helps clear up. These are very much real-world patients. Over 70% around the world walk in the door of the clinic, less than 1,000, and more than 90% are less than 3,000. Mark, is there anything you would add or subtract there? Please feel free to correct me if I'm off. Yeah, thanks, Michael. No, I think you described it quite well. In the clinical practice, certainly in the United States where I'm based, this does represent a large share of the patients we see that are negative controlled on nukes with relatively low hepatitis B surface antigen levels. I do anticipate that this is something that will be applicable to the majority of people that we see. The other point to make is that when I talk to patients and I talk to every person I see with chronic hepatitis B, we talk about curative treatments. This is really something that is exciting on their radar. Looking forward to getting into clinic this week, coming back from the liver meeting to further discuss. This is incredibly helpful. Thank you. One quick follow-up. Could you please speak to the 5X ALT AST level you have, which is higher for these patient populations compared to the trigger highest level? Any enrollment change or monitoring you're thinking of seeing safety concern from your peers, like restricting on the baseline bilirubin level, liver pathology, liver obstruction, anything that you want to be more careful about? Yeah, Soumit, I'm going to have Mark comment on that in one moment. I will say this. When you deliver an LNP, and if you compare LNPs, and all of you guys do, and I understand that, from the preclinical work where you had healthy monkeys to patients with different baseline diseases, of course, we have patients of liver disease. The liver, LFTs, are an obsession of ours to make sure our patients are safe. I think you'll see our transaminases compare very favorably, of course, any LNP. As long as transient, really your top hepatologists, we have a liver flare committee. I'll ask Mark to talk about it. We're not greatly concerned. In fact, I would sign up for it to keep the same safety profile we have going forward. I'm going to ask Mark to maybe define a little more layman Hy's law and the transient nature. Maybe Mark, you can speak about the baseline of our patients that are not cirrhotic in their FibroScan scores, for example. Thanks, Mark. I will turn it to you. Sure. Thanks, Michael. I think it is important to note that the patient population did not have cirrhosis using very conventional staging modalities like FibroScan. The other point to make is that in clinical practice, as well as in any kind of treatment with medications, including drug development, one of the real key things that we look at is ALT and AST elevations. We think of those as measures of hepatocellular injury. This is clearly an important thing to monitor. The critical element is what is happening with liver function. Here we are talking about things like total bilirubin and PT- INR. Hy's law refers to an observation made by a very famous hepatologist, Hyman Zimmerman, who said that the combination of hepatocellular injury with AST, ALT elevation, and an increase in bilirubin is something that should raise concern both in clinical practice as well as in the development of a therapeutic. The critical point here is that when the ALT flare committee and the investigators reviewed this particular research participant, they did not see any evidence of a change in bilirubin. This did not meet the Hy's law definition and did not raise concern that might lead to not dosing further. I'm happy to, I'll stop there and happy to take any clarifying questions. No, Soumit, just to round out the last piece of your question, I think we've learned a lot about the manageable around the globe. You're talking about a therapy that has a low-dose steroid the day before and the day of, an antihistamine. We're using Tylenol around the globe, things that are really accessible to people. We're learning more about making sure they're hydrated at baseline. We're doing some orthostatic blood pressures. Right now, from a liver intervention standpoint, we feel really good, as you said, that there's nothing cumulative going on. We know we're going to see a transient uptake in LNP delivery. We know you'll see a transient small nadir in our platelets. We haven't dropped below the 100,000 level there, so nothing clinically significant. We think that's the reality of managing LNPs. Think about how Alnylam has been delivering it for years. Right now, yes, we have learned a lot about the management as we've gone through, and we're implementing those things like orthostatic blood pressures and hydration at baseline. Right now, nothing different for the liver. We feel really good about where the totality of liver health has been. Thank you again. Congratulations on a very clean data. Thank you, Soumit. Thanks, Soumit. Soumit. Next question, please. Next question is from the line of Maury Roth Raycraft with Jefferies. Please go ahead. Hi, this is Farzin Haque from Maury. Congrats on the progress, and thank you for taking our question. Nice to see the evidence of biopsy confirmed on target editing, but are you also assessing any off-target editing? Bigger picture, what fraction and distribution of the cccDNA and integrated DNA editing are required for seeing the sustained off-target control? Okay. Farzin, I appreciate the question. I'm going to turn it over to Cassie. I love that you asked the off-target question because we're really proud at Precision that we do an incredible amount in our pre-IND work of what I call integrating genomic integrity. Maybe Cassie can walk you through that. Cassie, I love Farzin's question of what's the perfect amount of gene editing in the patient to get us to zero. I'm going to turn those to you, Cassie. Thanks, Farzin, for the question. Yeah, thanks, Farzin. We are also really excited about this first proof of mechanism of editing viral DNA in the liver. I think it may represent first gene editing biopsy data across studies, across any clinical studies. I think it's really notable. We're excited to have our investigators working with us towards that goal. Your first question about the clinical biopsy data and how much editing do you need? The data that we have today demonstrates the indel fraction, which we expect to be the minority outcome. We're working on quantitating the elimination fraction from that biopsy sample as well. We'll need both pieces of that in order to understand the totality of editing observed with two administrations of 0.4 mg per kg. I think it's premature at this point to say how much total editing has been observed. To your question of how much editing do you need to achieve, it's the billion-dollar question, I think. Because this is a novel modality, I think we will be the people that get to answer that question clinically. How much viral DNA editing do you need to achieve cure? Our goal is 100%. Preclinically, we achieved 99% with two administrations in primates. That data set was really influential for the design of our clinical study, allowing for three dose administrations. I think we're optimistic that our LNP has great biodistribution within the liver as we've increased the dose. We've obviously shown the ability to edit more viral DNA, resulting in persistent declines in S antigen. I think we'll continue to gather the data to definitively answer the question of how much editing do you need to achieve cure. We're optimistic we can get there. The question about off-target— yeah, go ahead, Cassie, please. The question about off-target editing, we do an extensive evaluation of this preclinically. We use genome-wide, unbiased orthogonal assays really to evaluate the specificity of the nuclease. The specificity of the nuclease used in PBGENE-HBV is very good. At therapeutically relevant doses, we can detect no off-target editing, no increases in translocations or integrations as a result of editing viral DNA, and no interruption of normal gene expression of the human genome. We feel very good about the specificity of this nucleus going into this clinical study. Thank you so much. Cassie. Thank you. Farzin, I think the one thing I want to point you to in cohort three, and we're hoping that's the cohort. When you think of that stop-nuke data, Mark has said this well, 10 years ago, cutting and eliminating virus with gene editing was a fantasy. When you think of the stop-nuke data, which came out way before the modality of gene editing, the idea of getting under 100, which is not the goal for all those out there, is to get undetectable. That makes it easy to know we've got it all gone. I think the point is a lot of those patients had eliminated their cccDNA. When you stopped, you knew that some low levels of S that was being expressed steady and stable over time was from integrants. Remember, the really important point here, integrated S cannot hurt the patient going forward. It cannot make replicating virus. cccDNA is the culprit that does that. Farzin, I suspect there'll be a different level of editing based on that 15% to 50% of hepatocytes infected needed. That'll be a heterogeneity question for the individual. I'll remind you to Cassie's point, in the non-human primate work that she did with the surrogate virus that was brilliant, with two doses, we were able to cut 99% of all hepatocytes. Cassie over-infected those hepatocytes with about 100 virions of virus versus the 5 to 10 you see in chronic hepatitis B patients. I just share those final points. Again, that's never a perfect model because primates don't achieve. That is the billion-dollar question and answer we're hoping to provide here, Farzin. Thank you so much. Thank you very much, Farzin. Next question, please. Our next question comes from the line of Patrick Trucchio with H.C. Wainwright. Please go ahead. Thanks. Good morning and congrats on this data. I just wanted to ask about the paired biopsy findings and see if you could elaborate a bit more on how these findings validate Arcus's mechanism of action and what additional molecular analyses, for example, pgRNA, cccDNA quantification are underway to strengthen that evidence. Can you elaborate a bit more on the viral DNA editing pattern observed, specifically this relative contribution of DNA elimination versus inactivation through indels? How does that correlate with HB surface antigen decline? Yeah. Patrick, I'm going to turn this over to Cassie here in a moment. The answer is yes on some of the biomarkers we're using because that is how you delineate S coming from pgRNA, for example, you spoke about is going to be very important to us as that's something that is really clearly associated with the regulatory path that Cassie showed you on HBV DNA, which equals cccDNA. It can only come from cccDNA. Therefore, pgRNA is only specific to that pathway. But Cassie, let me turn it over to you of where we're at right now and maybe qualifying the biopsy data you showed so far, hot off the press, as you said, and maybe what's to come and why we want to delineate some of those things to understand where transcript is coming from. Yeah. Thank you, Patrick, for the question and good to hear from you. I think if we revisit slide 24, which is the biopsy data, what we are observing here, this is our first cut of data from the biopsy, and we expect there's more to come, to your point. What we see in the biopsy data is it's a paired biopsy. We took one prior to dosing, and we took one after the second administration at 0.4 milligrams per kilogram. In that first sample, prior to treatment, we see no evidence of mutations within the target region of the Arcus nuclease in the viral DNA. What we see after the two doses of PBGENE-HBV is 28% mutations now introduced by Arcus. They are consistent with what you expect to see after Arcus double-strand breaks and mutations in that DNA sequence. We are still working, as you mentioned, on the elimination fraction of editing. Consistently across preclinical data, we see that is the majority editing outcome. I expect that the 28% editing that we have observed so far is in the remaining viral DNA. You cannot sequence DNA, obviously, that is not there. In that DNA sequence that has been eliminated, I expect that to add to the total amount of viral DNA editing. At that biopsy time point, we saw a 44% reduction in S antigen. Preclinically, those have trended pretty well of mutations or inactivation, total editing, and S antigen decline. I expect we're going to see with the elimination data when it's available, an increase in the overall amount of editing in that biopsy sample. We are also looking at some more sophisticated methods in the biopsy sample to come that will help us identify the source of S antigen as either cccDNA or integrated DNA, which to Michael's point, we think will be really valuable as we think about that alternative path forward with the FDA guidance suggesting that if there is detectable S antigen, it's being produced from integrants only. More to come on biopsy data, but this really demonstrates proof of mechanism that PBGENE-HBV is doing exactly what we expected it to do and that it is through inactivating and potentially eliminating virus that we are seeing these S antigen declines for the first time ever. Yeah, it is really interesting. It is the first-ever clinical biopsy evidence of gene editing in HBV. It is very interesting. Patrick, we think it might be the first clinical biopsy evidence of gene editing in the liver. You can correct me if I am wrong about that. I know you will. Patrick, the other thing is I just want to make sure I state for all your peers. I know you are very close to this story. When Cassie mentions the word mutation, that is an inactivation of replicating virus. A mutation or an elimination still results in deeming that virus inactive or eliminated that it can no longer replicate and harm the patient going forward. That's helpful. I did want to ask about just the dose escalation and safety and the compounds now have been administered safely across doses up to 0.8 milligrams per kilogram. I'm wondering what this tells you about the emerging therapeutic window and the ceiling for safe exposure. Yeah, I'm going to open this up to Mark and Cassie in a moment. The first thing I want to say is we've been saying since the preclinical data that all LNPs aren't the same, and the quality of mRNA is really important. You'll remember, Cassie spent almost two years optimizing. I joke because I used to say, "Is it ready yet?" She would tell me the quality and the length really matters, Michael. I am very proud of the team for that because this matters for the therapeutic index, specifically safety in patients. If you cannot give this drug repeatedly, you cannot get to viral elimination and cure. The most important piece of data we are showing you, this AASLD, I hope everyone understands, we all jump to the antiviral curves. It is the ability to repeat dose without cumulative tox. If you cannot give the drug, you cannot win and cure the virus. From there, I will ask Mark or Cassie if they have any other thoughts on your question, Patrick. Mark, do you want to start? Sure. I don't know if there's too much to add to Michael's comments, but I think the real key is simply to follow the data that we've seen regarding safety and tolerability in making these decisions. Thus far, both the DMC and the ALT Flair Committee have been quite satisfied. Thanks, Mark. Cassie, is there anything? Yeah, go ahead, Cassie. Maybe I'll just add. I think I'm really excited about the data we're seeing in cohort three. I think that this 0.8 milligram per kilogram dose with the repeat administration still to come represents a path forward for PBG and HBV in potentially stopping nukes and achieving cure. I'm very interested in continuing to follow that data. I think we had an investigators meeting over the weekend at the Liver Meeting, and I think there was palpable excitement in the room over the data and where this program is headed. I think there is, as Mark said, we need to continue following the data. He spoke to the safety data, and I think I will speak to the efficacy data that I think it is always going to be a balance of what you are observing on the efficacy side as well as the safety side in the decision to continue dose escalating. I think we are seeing very good antiviral activity. Right. Great. Congrats again. Thank you, Patrick. Next question, please. Our final question comes from the line of Ry Forseth with Guggenheim. Please go ahead. Morning, everyone. Congratulations on the development progress, and thank you for organizing this discussion. Two questions from us. Number one, could you tell us more about the rationale for potentially exploring the four-week dosing interval? Is this mainly to leverage kinetics to drive down S antigen and/or develop a drug that has a more convenient profile for the patients? Yeah. I'll start with that one, and then I'll open it up to my smarter and more talented colleagues in Mark and Cassie. First and foremost, I think it's very important to look at what we've seen from cohort one, two, and three. Cohort one, a dose that was very low, less than we put in primates, 0.2. The thing that jumped out the most for us in that cohort is the permanence of mechanism when you cut and eliminate, right? You'll see, you'll remember two of the three patients, everyone had a response, an antiviral response, but two of the three kind of rebounded in that 14-28 day interval. When you dig into the why, remember what you're doing with more dose and gene editing. This is not an AUC of a small molecule. You're biodistributing to more of the 15% or 50% of hepatocytes that are infected with more dose. You're putting, if you will, I give this visual, more Arcus scissors within a sick infected cell cutting during your PK window. The PK window for an LNP is about three days, and Arcus is about a half-life of about a day, day and a half. The work is done in that first four or five days. As you looked at cohort two, right, you see that you started to now blunt the rebound, the upregulation of the virus that was still there. In cohort three, patient seven, and why it just qualifies Cassie's comment from it is so exciting. The first time between the two-week nadir and day 56, remember, there are eight weeks between, that you do not see upregulation of virus because you have eliminated and cut out enough virus at that dose. That is why we are excited about that dose and why we are approaching that 100 level. While, again, the goal is undetectable, we know what 100 means in this disease. A lot of times, we are getting to an eradication of cccDNA. Now, the reason for the frequency of our dosing interval, Mark says it is great. There is dose. There is frequency, time in between. We started at eight weeks in between administrations before we had ever had human data to make sure we had the safest profile. What that was based on, just so you all know, two weeks is kind of the period when LNPs settle in. You get those transient spikes. There had been some data with other mechanisms, not gene editing, from our hepatologist saying you could have a late efficacy flare up to six weeks. We do not see that with this modality. We wanted to be really safe before first human data, right, and make sure we had about eight weeks in between. That was a bit of empiricism. Now, when you look at the 22 doses, we really understand the profile. We are not seeing those late liver flares. Let's go back to cohort two for a minute. Every patient there was a responder, but everyone was a durable responder at 0.4. They're sitting somewhere after three administrations of 50-70% of their baseline S is eliminated. Now, that's not all the way home. You can't stop your nuke yet. You now know with no late liver flare what happens if you cut those remaining reservoirs four weeks apart. What if you cut a fourth and fifth time? Could that be a dose at half the dose that takes you to stop nukes? That is the idea of the levers we're still playing with. 0.8 in cohort three is our go-forward right now because it's safe. There's no cumulative tox. Of course, we're getting really close in those IUs per mL on S. We are still looking in parallel. We can go to expansion with 0.8 and still look in parallel with part one of the study. What happens if we take a little bit of a lower dose and shorten it to four weeks apart now that we know from our safety profile we can? I hope that makes sense, right? It does. Maybe for our second question, for part two site expansion, is there any geographic preference for onboarding sites? Also, looking forward to pulling nukes, when we think about discontinuation of nucleotide or nucleosides, just to be clear, what is your definition for S antigen approaching undetectable levels on a sustained basis? Yeah, good question. I'm going to turn it over here to my colleagues in a moment. As far as globally, we want to be globally. We want to recruit. We look at a phase II. An expansion is going to go up to 45 patients, right? Then we're going to just roll right into the phase II as long as we're at a therapeutic index where we can stop nukes, we find the right dose and schedule. Think about a phase II of 100-150 patients. We really, since day one, were committed to a global approach. This is a global disease. We started in sites that did not have low regulatory hurdles. We started in sites that had large amounts of chronic hepatitis B and where the infectious disease experts have lived in drug development around the world. People like M. F. Yuen, people like Ed Gane, right? We wanted to be in those sites. We're still opening more sites here in the U.S. We've got a site ready to go in the U.K. and regulatory approvals. We're looking at France and other countries because we really want to be able to run once we're out of the dose phasing, if you will. I'll open it up to Mark or Cassie for the second half of the question if there's any other thoughts, please. Yeah, I think one—go ahead, Cassie. Go ahead. One thing I wanted to add in terms of the global nature of this study is that when we selected the target site for the Arcus nuclease that's used in PBGENE-HBV, it was selected with geography in mind and genotype in mind. The target site is well conserved across genotypes, which is important in order to be relevant across geographies, across Asian populations, European populations. Really, I think as we think about site expansion and we think about the data already coming out of this Eliminate B study, you can really start to appreciate that PBGENE-HBV is designed to be globally applicable. On the point about stopping nukes, I would say on slide 26, there is a little bit of an outline of how we are thinking about this. You would want to see two measurements in S antigen at least four weeks apart to have confidence that the level of S antigen that this individual is at is sustained. There are other markers that will not always be present, actually most often will not be present in antigen negative patients. Those are HBV RNA and correlated antigen. Those are markers that are directly relevant for cccDNA. They indicate cccDNA transcriptional activity. If those are undetectable in a patient that had them detectable at baseline, then you have a lot of confidence that even if there is some detectable S antigen, that it is being produced by integrants and not cccDNA. I think there are a couple of different pieces of data that can be used to inform the stop nuke decision. It is going to be a requirement that they have a sustained low level or undetectable level of S antigen in order to stop that nuke. Maybe I will turn it to Mark to see if he has any additional clinical perspective to share on the decision for stopping nukes. Yeah, Mark, maybe you can hit the washout period of the nuke too because we talk so much about paired biopsies, and that is all part of the expansion. There is also a more practical way to do things that you described so well. Could you maybe talk and educate about the washout period of the nuke too, please? Yeah, great. And thanks, Cassie. You described the literature quite well on this. There is an extensive research into this stopping nuke criteria. What Cassie outlined, less than 100 IU per mL for S antigen, negative RNA, negative correlated antigen, is a strong predictor of success in stopping nukes. This was actually discussed in a number of the HBV-related sessions at the recent liver meeting. The other point that Michael makes is that when we see people stop nukes, if cccDNA is present and replication competent, it will start to produce transcriptional activity, and DNA can be found in the blood really within four to eight weeks. The definition of cure is at six months. Patients will be monitored very closely when stopping nukes because the DNA can emerge much more quickly. Thank you, team. Any other questions on the line? We have no further questions at this time. I would like to take a moment to thank our investment community for joining us today, our current partners and new partners who have joined us on the Precision mission, the team who has been working tirelessly, and most important, our investigators and patients who are making it happen at our site. Thank you to all. We are really excited about this progress, and we are going to continue our pursuit of eradicating chronic hepatitis B and really changing the paradigm and the quality of life for patients with Duchenne muscular dystrophy. I look forward to speaking to you all soon at the next quarterly. Please, everybody have a wonderful day. Thank you. This concludes today's conference call. You may now disconnect.