Good morning, welcome to the Precision BioSciences Investor Update. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Precision BioSciences website following the conclusion of the event. I would now like to turn the call over to Naresh Tanna, Chief of Staff and Head of Investor Relations at Precision BioSciences. Please go ahead, Naresh. Thanks, Tara. Good morning. Welcome to the Precision BioSciences EASL 2026 Investor Update. Today, we will be sharing new and late-breaking updates from our PBGENE-HBV program and ELIMINATE-B trial. During our call today, we may make forward-looking statements. You can review the Risk Factors section in our financial disclosures, including in our latest 10-Q, for the factors that could cause our actual results to differ materially from any forward-looking statements we make today. Without further ado, I would like to introduce Michael Amoroso, President and CEO of Precision BioSciences. Thank you, Naresh, and welcome team. Welcome to our investor community. We're very excited to be here with you. We've got half the team across the pond at EASL on-site. There's a palpable excitement. Again, it's my pleasure, maybe the most proud day I've had so far of a series of proud days at my time at Precision, so thanks for being with us this morning. First, I am accompanied by a world-renowned team here. MF Yuen is really our principal investigator. He's got the most clinical experience. We thought it's super important to come to you credibly with the people doing the work. Right? MF really needs no introduction, and it would probably take me a half hour to do all of your titles, MF. He is the Division Head of Gastroenterology and Hepatology at the Li Shu Fan Medical Foundation out of Hong Kong, and we're really blessed and excited to have MF with us. Dr. Sulkowski, who probably fields more phone calls than he'd like from me on a regular basis, but again, needs no introduction, but our Division Head of Infectious Disease at Johns Hopkins, Special Advisor to myself, to team at Precision, who's really made incredible impact of overseeing clinical development and making sure we're making the right steps for patients. Cassie Gorsuch joins us in voice and video and in spirit. Really excited to first share data today of Cassie has added to the family. Right. Cassie is now out on maternity. She is really the lifeblood behind the program, the gene editing, the first dream of gene editing a viral genome and eliminating a virus really is Cassie, and she's with us not only on video and voice today. She'll be presenting the data, which she taped before she went out, but she's added a beautiful baby boy to the family. We're happy to have this team with us, and we'll open this team up for a full panel to answer Q&A and answer all the sell-side questions at the conclusion of the presentation. Today's title, Are We at the Turning Point? We believe we are. We believe we're at the precipice. We're excited about that. A lifetime of viral suppression, living on therapy, continuing to question what is the percentage we're knocking down late-stage outcome issues like liver disease, cirrhosis, and hepatocellular carcinoma, to biomarker-guided viral cure. We've known some real key quotes here, some even interesting sell-side analyst reports as the data and posters have been out since about 2:30 in the morning on the Eastern Standard Time in the U.S. Dr. DiCicco, amazing partner also on our Safety Committee. From 2023, "True cure for HBV requires eradication, degradation of cccDNA." The FDA guidance talks about HBV DNA viral destruction and the confusion of viral biomarkers like S and how good a predictor they are for a cure. We've seen some palpable excitement today. First clinical evidence of reservoir elimination emerges in HBV. Again, we're excited to be with you this morning and share the data. First, and no fault to our wonderful physicians, but 50 years plus of drug development in chronic Hepatitis B, we've never been able to target the direct viral source. cccDNA is the factory that produces infectious virus, HBV DNA. All drug development to date has really had the ability to target downstream from the viral source. Frankly, that's led to a functional cure rate of about three percent and just not good enough for patients. As discussed, cccDNA has really evaded us to date, evaded us as an industry. We have not been able to have direct targeting and elimination of the viral replication source. For this presentation, it's vital for all of our sell-side analysts to understand cccDNA, the factory, the only source that makes infectious replicating virus HBV DNA. PBGENE-HBV is the only program designed to permanently eliminate, target, and eradicate cccDNA at the viral source. In fact, the FDA guidance from 2022 has been very clear on what the gold standard is for curing hepatitis B. You see multiple endpoint pathways, but at the center of all, the gold standard is destruction, eradication, and loss of HBV DNA, the common therapeutic goal necessary for viral cure. Now let's revisit quickly here for our teams out there. Exactly the design behind PBGENE-HBV. What was it designed to do? Before I turn it over to the team to tell you what PBGENE-HBV is doing in patients and for patients. First and foremost, PBGENE-HBV is an LNP drug-developed packaging mRNA that's encoded to deliver ARCUS directly to target cccDNA. Our binding site is conserved across 96% of hepatitis genotypes to make sure we're leaving no patients behind. This visual here at the bottom, which we call the math equation a bit, if we eradicate and eliminate cccDNA, we therefore will eliminate pgRNA, the only source precursor necessary for making replicating virus HBV DNA. We'll revisit the math equation, as we call it, several times throughout the presentation, but the primary design of PBGENE-HBV was to directly target and eliminate cccDNA. In addition, you know that obviously Hepatitis B targets and makes viral integrations into the host genome. Obviously, these are non-replication competent. These are fragments of virus. We also designed PBGENE-HBV at inception to target the transcript level, the RNA level downstream from S-antigen and disrupt the ability to express S. You might say, "Michael, why? If we know the only replication source, if you tell me cccDNA is the most important path to cure, why were we also targeting the integrated disease?" For years, we've talked about any expression of S really suppressing the patient's immune system to try to turn that immune system on against the virus. Of course, anything that's knocking down viral transcripts is a good thing. I will remind everybody, we have done a great job in clinical development of knocking down, masking, and suppressing S without getting the viral core and source of HBV DNA. To date, that has not led to an immune system eradicating this virus. Please keep that in mind as the team takes you through the data today and the proof sources. With no further ado, some highlights of what my team is going to take you through. First, late-breaking data. We now know not in pre-clinical animal models, but in human beings. PBGENE-HBV directly targets and eliminates cccDNA, potentially the path to viral cure. This is our primary antiviral mechanism, now proven in human beings through biopsies. We've been able to show a potent cccDNA effect, targeting cccDNA, knocking down and eliminating cccDNA 10-fold. One log reduction from baseline. We've also been able to show, the team will take you through, the cumulative edits. Number of administrations of PBGENE-HBV have been additive in continuing to inactivate and eliminate cccDNA. This is the spoiler alert for today's data. Mechanistic human proof in biopsies that we are eradicating and eliminating cccDNA. Obviously, eradication of HBV DNA aligns with eradication of cccDNA aligns with eradication of HBV DNA, which aligns with the 2022 FDA guidance. The approvable endpoint, we'll talk about a lot of biomarkers today and the specificity for the source of cccDNA, the linkage, the endpoint for FDA approval for patients is destruction of HBV DNA. We need a good biomarker. We cannot get biopsies in every single patient. It's difficult for clinical utility. What is the biomarker for PBGENE-HBV? Today, we have that answer for you. pgRNA is the appropriate blood biomarker, directly comes from cccDNA, and is the necessary precursor for the packaging and production of HBV DNA replication. Frankly stated, you cannot make HBV DNA without the precursor of pgRNA, and pgRNA only comes from the viral source, the factory as we call it, cccDNA. In today's data, you'll see 100% of our patients who had detectable pgRNA at baseline are undetectable post-treatment with PBGENE-HBV. In fact, we have liver biopsies that will support the eradication of pgRNA at the liver in tissue, as well as in blood biomarkers. Again, we must have the appropriate biomarker for clinical utility that links to our mechanism. Elimination and inactivation of cccDNA is synonymous with pgRNA eradication in the blood. I've been told a picture is worth a thousand words. Today, I'm really excited to show you one of the highlights from our presentation. Six out of our 15 patients, about 40%, had pgRNA detectable at baseline. Remember, these are E-negative patients, about 80% of all patients at any given time with chronic Hepatitis B. This is very similar with what you see in the community. About 40% of patients will be detectable at baseline. Every patient that had a pgRNA in the blood at baseline has had eradication of their blood biomarker post-treatment with PBGENE-HBV. You'll see here depicted in the picture the diamonds, which show number of administrations, and this is something we're still working through and watching the durability, durable responses. Once they've gone undetectable, all of these patients have stayed undetectable. We'll talk to you more about that throughout the data. You'll see across different number of dose administrations when the patients move from detectable in the gray to undetectable in the green. We take a step back and we say, are we at the precipice of the foundation of treatment going forward? Direct targeting of cccDNA, viral cure, not functional cure. I know Sovaldi and hepatitis C is a different virus. It doesn't integrate into the host genome. It's at the RNA level versus the DNA level. I think it was an important parallel to show to say directly targeting the virus is the only path to sterilizing and complete cure, the best chance of lack of relapse. Today, we now have evidence that PBGENE-HBV is directly targeting the virus at the DNA level. Finally, before the team takes you through the data, I want to walk you through the standards of what we hold ourselves and PBGENE-HBV to. The product was designed to directly target and destroy cccDNA. We think we're going to show you some pretty magnificent proof of that today. It must have permanence. The mechanism for patients must be a finite treatment, and what we eliminate stays gone. Not masking, not suppressing, eliminating. This virus can never come back. Eliminating and inactivating, knocking out the POL function, and the team will walk you through that. The MOA ideally would have a viral precursor in the blood because we cannot get biopsies longitudinally in every patient. The viral biomarker in the blood must be specific to the sole source of cccDNA. That biomarker is pgRNA, and the team's going to continue to take you through that data today. We must have a well-characterized, understood, and predictable, manageable safety profile. Remember, this is the first time prospectively in liver disease anybody has taken representative doses, packaging mRNA, and repeat dosed for cumulative editing effects. The great news is we really feel like our translational team has understood them, and we've been able to learn through phase I and put them in effect for the benefit of patients. Last, we leave no patient behind. We talked about the conservation of our target site. The idea here is this is regardless of viral load. This is regardless of protein load. 15%-50% of hepatocytes are infected with a contagious variant, cccDNA. We've got great evidence of full biodistribution across the perfused liver, and we're able to cut out all the virus we see as we accumulate administrations. That being said, I'm now going to turn it over to Cassie, who has pre-recorded her presentation, and I think you'll enjoy it. Thank you. Thank you, Michael, thank you all for joining us today. It's really my pleasure to be able to share some really exciting data coming out of our ELIMINATE-B study, really demonstrating for the first time ever the ability to eliminate cccDNA through treatment with PBGENE-HBV. Before we get into the data, I'd like to take a couple moments just to review some of the basic disease biology underlying chronic hepatitis B. When hepatitis B infects the liver, it really establishes two viral DNA sources, cccDNA and integrated HBV DNA. cccDNA is the full viral genome, full-length viral genome. It is the only source of new infectious particles, and we call those infectious particles HBV DNA. It does this by producing a precursor to HBV DNA that we call pgRNA. CccDNA is really the only source of these new infectious particles, and the persistence of cccDNA is what drives chronic hepatitis B infection. We've known for a long time as a field that targeting cccDNA is really the ideal therapeutic strategy to cure hepatitis B. Integrated DNA is also present in infected hepatocytes. Integrated DNA is not full length, so it's fragments of the viral genome, but not full-length viral genome. Integrated DNA does not produce new infectious particles. It can't produce HBV DNA. It does produce S antigen. S antigen can come from both cccDNA and integrated DNA, which really makes it a challenging tool for understanding or characterizing the cccDNA pool in the liver. In fact, in the vast majority of chronic hepatitis B patients, those who are e antigen negative patients, which account for about 80% of the population, S-antigen is primarily produced from integrated DNA, which really limits its ability in the context of PBGENE-HBV of characterizing the mechanism of effect on cccDNA. What this really means, if we summarize all of this, it is because we have lacked the tools, the field has lacked the tools to directly target cccDNA therapeutically. We have been focused as a field on really the role of S-antigen as a therapeutic target as well as a biomarker. S-antigen comes from integrated DNA and cccDNA, but only cccDNA can create new infectious particles. In our view, we have really gotten things kind of mixed up, and it is time to go back to the basics. What do we know? Hepatitis B is a viral infection in the liver. The reason people persist long-term with chronic HBV infection is because of cccDNA. The ideal therapeutic goal would be cccDNA targeting and elimination of cccDNA. Again, because we haven't had a tool that could actually do that, we've been focused on other strategies like S-antigen targeting to try to cure Hepatitis B. It hasn't worked. I think it's time to refocus on what we know for a long time has been the real problem behind Hepatitis B, and that's cccDNA. I'm really excited to share some data with you today demonstrating that now we have a tool, we have a therapeutic approach that directly targets and eliminates cccDNA. Let's talk about PBGENE-HBV and how it does this. How does it actually work on cccDNA? PBGENE-HBV is a lipid nanoparticle that encodes an ARCUS nuclease. It contains an mRNA that encodes an ARCUS nuclease. This ARCUS nuclease was designed to directly target cccDNA. What we have found is that the predominant outcome of targeting cccDNA is actually elimination of that viral genome. We demonstrated that preclinically through a lot of data we've previously shared. Today I'm going to share with you clinical data, the first evidence in humans of cccDNA elimination. When you eliminate the cccDNA viral genome, you also eliminate the production of pgRNA. We'll talk through that today as well. PgRNA is the precursor to HBV DNA. As Michael indicated in his section, HBV DNA eradication is really the goal of FDA-approved endpoints. Loss of HBV DNA is necessary for a finite treatment cure for Hepatitis B. PBGENE-HBV, what we have found is that this primary mechanism of eliminating cccDNA can drive undetectable pgRNA in all patients who are detectable at baseline. I'll show you literature support that pgRNA is a positive predictive indicator for sustained loss of HBV DNA and viral cure. By eliminating cccDNA, because it can produce S-antigen, we also expect to see corresponding reductions in S-antigen as a result of viral DNA targeting elimination of cccDNA. Michael mentioned earlier that there are really two mechanisms by which PBGENE-HBV can act. When you think about the effect on cccDNA, the primary mechanism and the predominant outcome that we've observed both preclinically and now clinically through biopsy data is elimination. This means that after cutting cccDNA, the cccDNA viral genome is eliminated from the cell. The secondary mechanism for PBGENE-HBV is through inactivating indels. This means that after an ARCUS nuclease cuts the cccDNA, there is an indel that forms in the DNA sequence. In both of these editing outcomes, both elimination and inactivating edits, both of them results in replication incompetence. cccDNA can no longer create new infectious particles. Now really the question becomes how do you demonstrate the effect of PBGENE-HBV on cccDNA in the liver utilizing available clinical markers? Of course, as a scientist, I would love to have liver biopsies on all patients in our study, but that may not be the most clinically feasible approach. We talked earlier about S-antigen, the role of S-antigen, and while it is a useful marker for characterizing the effect on cccDNA directionally, it's not specific to cccDNA, as much of S-antigen actually comes from integrated HBV DNA. While we use S-antigen directionally to support activity and effect on cccDNA, it's not the most specific marker. pgRNA, however, is a specific marker as it is only produced from cccDNA. pgRNA sits directly between cccDNA. It only comes from cccDNA, and it is the only precursor to HBV DNA. However, patients who are on NUCs are undetectable on HBV DNA. You can't utilize that as a marker for evaluating the effect of PBGENE-HBV. Therefore, really for a direct targeting cccDNA mechanism that PBGENE-HBV has, pgRNA is the specific blood biomarker for measuring the effect on cccDNA in the liver after treatment with PBGENE-HBV. pgRNA has actually been pretty well established as a positive predictive indicator of successful NUC withdrawal. You can see here in patients who have detectable pgRNA when they stop therapy, only three percent of those patients go on to achieve cure. pgRNA presence is associated with unsuccessful stoppage of NUCs. In patients who have undetectable pgRNA when they stop therapy, that probability of cure increases about tenfold, up to 30%. Because pgRNA is a specific indicator of the amount of cccDNA in the liver or the viral load in the liver, it is a very strong indicator of the potential success when stopping NUCs. This is true across numerous studies, as you can see indicated here on this slide, thousands of patients. In fact, pgRNA actually outperforms other biomarkers like S-antigen in predicting both safe and effective NUC withdrawal. We will utilize pgRNA because it makes sense for the mechanism of action for PBGENE-HBV and because it's been strongly demonstrated to support a positive potential cure outcome when stopping NUCs, as indicated in the literature. Now let's get into the ELIMINATE-B study and some of the data coming out. First, just to highlight where are we from a dosing perspective. As you can see, we have enrolled patients into five different cohorts one through five indicated here, evaluating both the effect of different dose levels of PBGENE-HBV from zero point two milligrams per kilogram up to zero point eight milligrams per kilogram, as well as the dosing interval, looking at the effect of both every eight-week dosing and every four-week dosing. To date, we have dosed 38 administrations across 16 different patients in these five cohorts. This is the data update that we'll share today from these 38 doses across 16 different patients. I'd like to start with the efficacy data. This is, as I mentioned before, really exciting, just a really important moment for PBGENE-HBV, and in our view, the Hepatitis B field, as this is the data that demonstrates the ability for the first time ever to target cccDNA specifically. We've collected multiple orthogonal data sets to support the ability of PBGENE-HBV to directly target cccDNA. These include liver biopsies from multiple patients, confirming the ability for cccDNA elimination after treatment with PBGENE-HBV. We'll also utilize pgRNA as a blood biomarker to characterize the potent effect on cccDNA in the liver. S-antigen, while it's not specific to cccDNA, continues to be a useful marker for characterizing the activity, as you'd expect cccDNA elimination to result in directional declines in S-antigen. In the liver biopsy data, we've demonstrated a 10-fold reduction or one log reduction in cccDNA transcripts in patients evaluating pretreatment to post-treatment, really supporting that elimination of cccDNA mechanism. On pgRNA, we have had 100% of patients who had detectable pgRNA at baseline go to undetectable after treatment with PBGENE-HBV, demonstrating that potent effect on cccDNA. Finally, looking at the S-antigen data, I'll show you that in 100% of patients that we've treated, we see substantial S-antigen declines, and this is highly supportive of the ability to target and eliminate cccDNA. Let's start with the liver biopsy data. We have had two patients, both in cohort two, dosed at zero point four milligrams per kilogram on the every-eight-week schedule, who have consented to liver biopsies. In the part one of the study we are in right now, liver biopsies are optional, and so we were very excited to have both of these patients consent to biopsies. In patient five, we have a pretreatment biopsy collected prior to any administrations of PBG ENE- HBV, as well as a post-treatment biopsy that was collected after dose two. In patient six, we have a post-treatment only, so no pretreatment biopsy for this patient, but we had a post-treatment biopsy, and this one was collected after three doses. As a reminder, both of these patients had the same dose level, same dosing schedule, having one patient after two doses and another patient after three doses can allow us to look at the effect of cumulative repeat administrations. The analysis that I'm going to talk through today is a transcript sequencing method. This is a long-read transcript sequencing method. We utilized this approach because it allows us to identify if the transcripts are derived from cccDNA or integrated DNA, which is obviously important as you think about the goal of targeting cccDNA. It allows us to compare, as I mentioned, the effect after two doses versus three doses in these patients. Looking first at data from patient five, this is our patient who had a pretreatment and post-treatment. That post-treatment was after their second PBGENE-HBV administration. When we look at the abundance of cccDNA transcripts, comparing their pretreatment to their post-treatment, what we can see is a 10-fold or one log reduction in the amount of cccDNA transcripts. This demonstrates the ability of PBGENE-HBV to potently eliminate cccDNA, resulting in loss of viral transcripts. In this post-treatment biopsy sample, we see less than one percent of transcripts are derived from cccDNA. When we look a little bit closer at this remaining cccDNA transcripts, what we can look for is that secondary mechanism I mentioned earlier, the inactivating indels. What we find is that in the remaining cccDNA transcripts, 23% of those transcripts have been inactivated through edits of PBGENE-HBV at the target site. When we compare this inactivation, this secondary mechanism through indels from patient five, who received their post-treatment biopsy after two doses, to patient six, who received that post-treatment biopsy after three administrations, we see this increases to 80%. This is really supportive of the ability to accumulate edits through repeat administrations and really supports potentially considering administrations even beyond three and the potential ability to continue to increase the inactivation of cccDNA through subsequent administrations of PBGENE-HBV. Looking a little bit closer at this secondary mechanism, I want to spend a couple of minutes here because this is a really exciting data set that came out of our biopsy analyses. When we selected the ARCUS target site for PBGENE-HBV, we did so very intentionally in a region of the cccDNA that is highly conserved across all genotypes, and that sits in a part of the viral genome in the polymerase gene, as you can see here in green, that is essential for polymerase function. Why we did that is that if we had this secondary mechanism of indels, of editing the viral DNA versus eliminating the viral DNA, we predicted that this could inactivate the polymerase protein. What we have found now is that through this secondary mechanism, the cccDNA-inactivating indels, is that the types of indels that we create at our ARCUS target site in cccDNA, all of them inactivate the function of polymerase. Polymerase is absolutely essential for viral replication. It is also essential for packaging pgRNA. When you look at the schematic in the bottom, what we see is that when we inactivate cccDNA through indels and we turn off the polymerase protein function, that that will shut down the ability to package pgRNA, and will also shut down then the ability of pgRNA to create new HBV DNA. What we know now is that both our primary mechanism of eliminating cccDNA and our secondary mechanism of inactivating cccDNA through indels in our clinical data demonstrates complete viral inactivation and no ability of viral replication for any remaining cccDNA that's been edited through indels or through elimination. Now let's talk about the effect on pgRNA. I mentioned pgRNA is a specific marker for cccDNA, and is really indicative of the amount of cccDNA in the liver. When we look at our patients who were detectable in pgRNA at baseline, you can see those patients are listed here. Not all e-antigen negative patients are positive for pgRNA. We have six patients who had detectable pgRNA at baseline. You can see after treatment with PBGENE-HBV, all of these patients have now achieved undetectable pgRNA through their course of treatment. What's really interesting here is you can see this occurred across four different cohorts, which indicates there are multiple paths using PBGENE-HBV dosing, multiple different regimens, that allow us to take a patient from detectable pgRNA to undetectable. Those occurred at dose levels between zero point four milligrams per kilogram up to zero point eight milligrams per kilogram on different dosing schedules. Different patients achieved undetectable pgRNA at different time points during their dosing, whether that was after a single administration or repeat administrations. This was really exciting to see because it offers us different types of flexibility as we think about how to optimally dose PBGENE-HBV to drive undetectable pgRNA, resulting in hopefully sustained loss of HBV DNA once we stop NUCs in patients. One really interesting point in these pgRNA patients is that patient six was one of our patients who was detectable at baseline in blood pgRNA and was also one of our biopsy patients. As you can see here, the gray and green bar indicate their blood pgRNA levels. They were detectable at baseline, went to undetectable during their course of treatment. Their post-treatment biopsy was actually taken there at about 20 weeks after their first administration. This was a time when they became pgRNA undetectable in the blood. When we look at the transcript sequencing data from the liver biopsy, we actually found undetectable pgRNA in this patient in the liver as well. This was a really nice correlation of undetectable pgRNA in the liver, as well as undetectable pgRNA in the blood, which really further supports the ability of using blood pgRNA as an indicator of the effect of PBGENE-HBV in the liver. Now I'd like to turn to talking about S-antigen and the effect of S-antigen after treatment with PBGENE-HBV. As I mentioned earlier, with S-antigen, while it's not specific to cccDNA, we would expect to see durable reductions in S-antigen after treatment with PBGENE-HBV as an effect of elimination of cccDNA. When we look across all of our evaluable patients on study from cohort one through cohort five, you can see every patient we've treated to date demonstrates a substantial S-antigen decline during their course of treatment. This is really exciting because it indicates that PBGENE-HBV can be effective across a really diverse patient population. These patients have different baseline S-antigen levels. They come from different geographies around the world. They're likely different genotypes. We designed PBGENE-HBV to be active across genotypes, across S-antigen levels, across geographies, and that's demonstrated here that that's effective because of the substantial decline in S-antigen that we see across all of these patients. When we think about how do we utilize S-antigen in the context of an overall marker strategy for characterizing the effect of PBGENE-HBV, we can layer that into using pgRNA as well as S-antigen. As I mentioned, pgRNA is specific to cccDNA. S-antigen is less specific, but you would still expect directional declines in S-antigen to correlate with reductions or loss in pgRNA. In fact, that is what we see. In pgRNA, our six patients who were detectable at baseline, 100% of them have gone to now undetectable pgRNA. The duration of this response ranges based on when these patients were treated, from one to greater than now six months of ongoing data. On the S-antigen side, as I mentioned and just showed you, all patients that we've treated so far on study have demonstrated a substantial decline in S-antigen, indicative of broad activity of PBGENE-HBV. The duration of this response in S-antigen ranges from about one and a half months to greater than one year based on when patients were enrolled and dosed on the study. Really all of these biomarkers, each of these biomarkers support the ability of PBGENE-HBV to target cccDNA through two mechanisms. One, elimination, and two, inactivating indels. As we think about the permanence of gene editing, this is really the promise of a gene editing approach, is that once you target cccDNA, that the effect can be permanent, long-lasting. If we go back to patient one, first patient on study that was dosed, what you can see is this patient we've been monitoring for more than one year now, and we see this sustained substantial S-antigen decline continue out past one year now in this patient. This is expected, exciting to see, but expected because the effect of gene editing should be permanent removal or permanent elimination of cccDNA in the liver, resulting in long-term suppression, long-term reductions in S-antigen and other markers. This continues to support the potential for PBGENE-HBV to really provide this long-lasting effect going directly at the root source of the viral genome. Just to summarize the efficacy data, I mentioned I'm really excited about where this program is today, demonstrating for the first time ever the ability to target for elimination cccDNA. This is the first clinical evidence that a therapy can target and eliminate cccDNA as a direct-acting antiviral. We've demonstrated in patient five that one log reduction in cccDNA transcripts, and that was after only two administrations of PBGENE-HBV at zero point four milligrams per kilogram. Of the less than one percent of cccDNA transcripts that remain in that patient, we can also see evidence of that secondary mechanism, the inactivating indels. We've demonstrated through analysis of our biopsy data that the inactivation through indels, it shuts down the function of POL, preventing any sort of potential for viral replication. Finally, through that biopsy data in patient five and patient six, we see cumulative editing is possible. Repeat administrations of PBGENE-HBV continue to increase the antiviral effect observed in the liver. We've identified pgRNA as the appropriate biomarker for the PBGENE-HBV mechanism of action. pgRNA is specific to cccDNA, and it is the only precursor to HBV DNA. We've demonstrated in all patients, 100% of patients who had detectable pgRNA at baseline, they are all now undetectable in blood pgRNA, demonstrating a potent effect of PBGENE-HBV on cccDNA. We've found through the literature sources that the association of pgRNA, the undetectable pgRNA in the blood is associated with potential success in stopping NUCs. It increases the success rate about tenfold. That loss of pgRNA in the blood in patient six was also correlated with loss of pgRNA in the liver through biopsies. Finally, S-antigen. 100% of our patients that have been dosed on study have demonstrated a substantial S-antigen decline. This really supports the goal of PBGENE-HBV, which was to be broadly applicable across this giant patient population, across geographies, across genotypes, across baseline S-antigen levels. We are seeing that across our patients that have been dosed so far. The sustained S-antigen decline in patient one, first patient on study, continues to support the permanence of PBGENE-HBV mechanism of editing viral DNA results in long-term viral suppression. Together, it's really these multiple orthogonal data sets that continue to support the development of PBGENE-HBV and continue to demonstrate the ability of PBGENE-HBV to go directly at the viral source, resulting in long-term outcomes for patients. Now I'd like to turn to the safety evaluation from our ELIMINATE-B study. Starting first with really just a summary of what we've observed so far on the study. I mentioned earlier we have administered 38 doses across 16 patients in five cohorts. Really since our last update in November of last year, we've really deepened our clinical trial experience and our experience dosing PBGENE-HBV across patients. We've seen no dose-limiting toxicities on this study thus far. The most common adverse events that we've observed have been infusion-related reactions that are consistent with known LNP effects. The onset and resolution of these infusion-related reactions is typically within 24 hours of the infusion. While we've observed transient and reversible ALT and AST lab abnormalities, they were asymptomatic, They were not associated with any changes in bilirubin, Therefore, no Hy's Law in any patient at any dose level has been observed thus far. We have seen grade three hypotension, We've mentioned this in November. We've seen this as we've dose escalated with PBGENE-HBV. In one patient in our highest dose cohort, which was the point eight milligram per kilogram dose level, that patient experienced two serious adverse events after their second LNP administration. We'll talk in more detail about these SAEs in just a moment. One of them was mechanistically linked with hypotension. Through deep characterization of our clinical data, we have now characterized the etiology of the hypotension, and we've implemented some fairly straightforward mitigation parameters that have helped ameliorate the clinically significant decrease in blood pressure. I'll show you the effect of those new mitigations in just a couple of moments. Really, our experience continues to deepen as we've continued to dose PBGENE- HBV, and we've learned a lot. We've implemented some new things that we're really excited about. Looking a little bit deeper now at the safety profile of PBGENE- HBV. Here, you're looking at grade three or greater adverse events that were observed across these different cohorts. As I mentioned, we've seen no dose-limiting toxicities and no liver-related serious adverse events. We have seen grade four ALT and AST lab abnormalities. These were transient and asymptomatic, as I mentioned. They were not considered clinically significant and were not associated with changes in bilirubin. No Hy's Law criteria have been met in any patient at any dose level. We do have a flare committee that reviews these ALT/AST lab abnormalities as they arise. These are hepatology experts, and they've viewed all of these ALT/AST data and determined that none of them were considered dose-limiting. The LNP-related ALT/AST elevations have been transient and occurred within the expected time frame after the LNP infusion. Typically occurring within about a week of the LNP infusion and quickly back down into baseline levels. Grade three hypotension that has been observed as we've dose escalated did not require any sort of vasopressors and generally resolved with saline infusion, either prophylactically or reactively to the hypotension. The one patient in cohort three, as I mentioned before, did experience two serious adverse events after their second LNP administration. One was a grade two myocardial ischemia that was characterized by a mild troponin elevation and an EKG finding on the day of the infusion. This event was deemed mechanistically linked to the acute hypotension that was also observed in this patient and was considered treatment-related. This patient was discharged 48 hours after the infusion following a normal CT angiogram. A follow-up echocardiogram demonstrated that there was no heart structural damage and normal function within the heart. No persistent damage within this patient. This patient also experienced an intracerebral hemorrhage that occurred 30 days after dosing. The timing of this is notable because the expected LNP exposure window is really about within the first two weeks, all of the components have largely been cleared. This was well beyond the expected exposure of LNP. This patient, importantly, is ambulatory, is home and is stable, is doing well. There was no clear pathophysiologic mechanism that's been attributable to PBGENE-HBV with this event. This patient did have a history of atherosclerosis and had initiated aspirin therapy four weeks prior to the intracerebral hemorrhage. This event occurred in the context of this clinical study, it is considered possibly related to PBGENE-HBV. I mentioned that hypotension was really one of the more common adverse events that we've observed on study and was mechanistically linked to one of the SAEs. We as a team at Precision really wanted to understand what is the underlying effect driving the persistent or the characterization of the hypotension, the cause of the hypotension. What we found through deep translational work was that this was really an LNP-mediated inflammatory response. What we observed was in the very acute time frame after LNP infusion, we saw rapid onset activation of complement cascade and cytokine elevations. These typically resolved within about 24 hours, very acute increase in cytokine elevations right after LNP dosing. We have implemented a number of prophylactic measures and slower infusion rates since characterizing this LNP inflammatory response. You can see our initial prophylaxis and infusion rate in blue, and then the current prophylaxis. These were fairly straightforward mitigation strategies, but really mechanistically driven by our understanding of what was driving the hypotension. Largely what changed here is an increase in the amount of steroids. We're already giving a dose of steroids on the day before and the day of the infusion, and we increase the overall dose of those steroids. We also slowed the LNP infusion rate from two hours in our initial infusion rate to now five hours in our current dosing strategy. This has been a very successful implementation of these mitigation strategies, as you can see here. Now we are looking at the tolerability or safety of PBGENE-HBV in doses that have been given since the new safety mitigations were implemented. This is data across five patients and seven administrations. About 20% of overall doses in the ELIMINATE-B study have now been given. All of the future doses will occur under these new mitigations. What you can see is we've had no occurrence of grade three hypotension since implementing these new strategies. Interestingly, we do have one ALT, AST lab abnormality in cohort four that occurred. What's really notable about this is that this is a delayed AST elevation. This didn't occur in the same acute timeframe of LNP-related ALT, AST elevations that we had seen previously. This one actually occurred a couple of weeks after the infusion. What was really interesting is that this ALT elevation was also associated with a delayed reduction in S-antigen in this patient. We're seeing as ALT, AST elevations go up, we see this decline in S-antigen, and we're hypothesizing that this may be indicative of a efficacy-related immune ALT flare. These types of effects have been observed in the context of other HBV therapies, where reductions in S-antigen can lead to an immune-related ALT, AST elevation. The team is continuing to generate data to more thoroughly characterize this effect, but it appears it could be potentially related to an immune or antiviral effect. Now I'd like to summarize both the efficacy data and the safety data that we've observed from our ELIMINATE-B study thus far. As I mentioned, we now have, for the first time ever, demonstrated the ability of a therapeutic agent to directly target cccDNA for elimination. This really set up the primary mechanism for PBGENE-HBV of targeting cccDNA and eliminating cccDNA. This has been supported by multiple orthogonal data sets, including liver biopsies, blood pgRNA marker, and S-antigen data. The liver biopsy data demonstrated a 1-log reduction in cccDNA transcripts, and that was after only two doses of PBGENE-HBV at point four milligrams per kilogram. In all patients that were detectable for pgRNA, blood pgRNA at baseline, all of them have gone to undetectable after treatment with PBG-HBV. We know that pgRNA presence is associated with lower cure rates, so getting rid of pgRNA is also associated with better cure rates. We're really excited about identifying that pgRNA is really the best marker for indicating the effect of PBG-HBV mechanism in the liver. S-antigen declines, while not specific to cccDNA, are supportive of that same mechanism. Durable S-antigen declines have been observed in all of our pgRNA loss patients. We've seen S-antigen declines consistently across all of our patients who've been dosed on study indicating broad activity of PBG-HBV. We've also really dug in on the safety of PBGENE-HBV, have really deepened our clinical trial experience through now 38 doses administered. We're able to really build a mechanistic understanding of the mechanism impacting repeat LNP administrations. We've implemented these targeted and simple mitigations in order to resolve the occurrence of hypotension-related adverse events. Today, about 20% of doses on study have been given under these new mitigations, demonstrating really an improved tolerability of PBGENE-HBV using this new mitigation approach. We'll continue to dose patients under that new and improved mitigation strategy. No grade three or grade four LNP-related adverse events have been observed since we've implemented those mitigations. Finally, I think really excited based on the biopsy data, the pgRNA data, the S-antigen data, it appears that multiple dose levels or dosing schedules are options as we think about moving this study into the expansion phase of the trial under these new safety mitigations. We're seeing loss of pgRNA across multiple different dosing paradigms, which really gives us a lot of flexibility as we think about next steps for clinical development. With that, I am happy to hand it over to both Dr. Sulkowski and Michael to talk about next steps for the ELIMINATE-B study. Well, great. Thank you, Cassie, for that unbelievably clear presentation of some really interesting translational science. Really what I want to talk about is how that translational science leads us to the next steps for PBGENE- HBV. What we're doing here, I think Cassie has demonstrated that as she's shared the liver biopsy data, is really transforming the natural history of chronic hepatitis B by targeting cccDNA. Where does that take us? Well, certainly you've seen the data for the current cohorts of cohort four, point four milligram per kilogram, and cohort five, zero point six five. Certainly continuing to dose patients with these regimens to expand upon the clinical experience while enrolling patients at new sites in Europe, in France and Romania, is critically important to the program. In addition, the goal is to increase the size and strength of the translational science. We discussed how the liver biopsy data, as we looked at cccDNA, really informed the role of pgRNA as a biomarker, and we want to build on that with additional biopsies to support this and really to establish the foundation of PBGENE-HBV as a potential cure. The logical step is really to stop the NUCs. Recall that this is a e antigen negative cohort of individuals fully suppressed on nucleoside/nucleotide analogue therapy. Therefore, the DNA in the blood is undetectable. The goal to test whether viral cure has been achieved is to stop NUCs. We are developing a framework around how we will stop NUCs, working with really some of the most knowledgeable and skilled Hepatitis B clinicians around the world. Our initial thinking, as Cassie outlined, is that the loss of pgRNA for greater than six months is an excellent marker for when we've eliminated ccc. We also, of course, want to see normal liver enzymes and sustained reductions in hepatitis B surface antigen. Keep in mind that the reduction we're seeing, that Cassie outlined, is due to the elimination of cccDNA not integrated. The goal is to evaluate current patients who have achieved loss. We talked about the six individuals who entered with pgRNA in the blood, have been edited by PB GENE, and now have no evidence of PB GENE in the blood. These are the initial candidates for stop NUC. We'll then learn from that data and take these into the other individuals who were negative at entry into the PB GENE editing process, and we'll test in that group. This is an important next step for the program that we're currently laying the foundations and discussing the framework. The next logical step is really to expand. The goal, as you recall, of the phase I was really to determine the optimal dosing schedule. There's been tremendous progress towards that goal to move to phase II. More work to do as outlined as we continue to dose patients at point four and point six five. In addition, I'm quite excited about the idea of understanding how PBGENE-HBV will work in different patient populations. A real critical one is e antigen positive patients. These patients are at a different stage of the natural history of chronic Hepatitis B. They're earlier. They generally have more cccDNA in the blood, I'm sorry, in the liver. pgRNA is generally positive. We'll learn more as we move into this cohort and continue to assess how PBGENE-HBV could serve as a potential viral cure, as a monotherapy, or perhaps in combination with other regimens for HBV. With that, I'll turn over to Michael to walk us through the next steps from program and where we go from here. Thank you, Mark. For our investors, our current investors, our future investors, our sell side, what have we talked about today? The evidence from lifelong suppression toward what we hope believe is a huge first step in biomarker-guided viral cure. The data today, number one, elimination of cccDNA confirmed in human model, obviously aligned with the eradication of HBV DNA and FDA guidance. Destruction in our secondary. Remember, elimination is about 90% of the editing outcome when PBGENE-HBV targets cccDNA. In the secondary mechanism, when we make an indel, we now know for sure from our biopsy data that we have inactivated polymerase function. Any mutated religated virus cannot make HBV DNA. Simply stated, when PBGENE-HBV targets and connects with cccDNA, we eradicate and virally destruct its capability. pgRNA, a practical and appropriate biomarker in the blood. Remember, these patients are controlled on NUCs. HBV DNA, while it would be a good blood biomarker, that's already suppressed. That will ultimately be the FDA endpoint. We need something upstream from the nucleoside analog that directly measures PBGENE-HBV's mechanism on cccDNA. That is pgRNA in the blood. The e-negative patients, as Mark alluded to, it's about 40% of the population. Does that mean we don't work in the 60? Of course not. That's where you look at secondary biomarker like S-antigen reductions, and we have just as good reductions in those patients. It's just not only specific to cccDNA. Of course, the pgRNA enrich is an obvious place to start when we're tracking and making this new, if you will, pioneer guidance for how you stop NUCs with a gene editor like PBGENE-HBV that eliminates and directly targets cccDNA. The pgRNA loss is very reassuring when we see it in 100% of patients, and it stays gone, which it should. PBGENE-HBV is a viral elimination mechanism. What we cut stays gone, and we've seen that with all viral biomarkers in the blood to date, pgRNA and longer S-antigen. What we cut stays gone. Finally, a clear therapeutic window. We see four different dose levels, four different dose levels that are the optionality for going forward. What are we watching in those dose levels? We're watching differences in the frequencies, differences in the new safety protocol mitigations that we've learned, I think are great, of how to avoid LNP complement cascade and some early cytokine elevations. Also, is there difference in durability of these viral markers? That's why we haven't stopped the NUCs tomorrow and just we're excited to do so. We want to see, is there any differences? You can obviously look at the higher dose level, where you seem to have some of your grade three events that we clearly understand and have been able to mitigate around and think about, do you not even need that dose level? Remember, those dose levels are before we understood the cascade and the cytokine levels. Today, we're not revisiting point eight at the moment, but we of course, could in the future. Right now, there's a greater focus on the point four and the point six five because we think we have the therapeutic window we need. That being said, for our investors, next step catalysts for you to think about with Precision as I open it up to the Q&A for today's ELIMINATE-B data. Obviously today, I would argue our watershed moment so far to date, where we've now shown you 38 doses delivered across 16 patients in five cohorts. Proven viral elimination, proven viral blood marker, and important understanding and characterization of the safety profile and how to proceed forward. This year, we will come back to you with additional data we continue to accrue in the current cohorts and the framework for stopping NUCs toward the end of the year. Equally as exciting, of course, I didn't talk about it today in the context of our new data, that wouldn't be appropriate. We're on the precipice of starting in the clinic for FUNCTION-DMD, PBGENE-DMD, a novel approach of editing the exon 45-55 mutation, the hotspot region in children with DMD. Really excited about the preclinical models and what we've shown there, and excited to go into the clinic and start and show that data in humans, as we've done today with ELIMINATE-B with PBGENE-HBV. That being said, I'm going to open us up for Q&A, I'm first going to say, MF, no one's had this in their hands more than you. You've treated more patients than anyone else. What do you think of your experience, today's data? Please give us some of your thoughts to kick us off to the Q&A today. Thank you. Okay. Thank you very much. I'm truly honored to be here today and to share in the excitement surrounding these highly promising agents. In fact, for more than 30 years, I have worked in the field of hepatitis B. Throughout that time, one truth has remained clear. If we are serious about curing the disease, we must confront the cccDNA. Today, for the first time, we are seeing real evidence that this may be possible. PBGENE-HBV molecules represent a historical advance. The first therapy to directly target the HBV genome and demonstrate reduction in cccDNA. We have signals that this effect can accumulate and endure over time. This is not simply progress. This is a breakthrough to me. It gives us a clear glimpse of what once seemed out of touch, the possibility of eliminating cccDNA and fundamentally changing the future of hepatitis B treatment. I'm profoundly encouraged by these results and deeply confident that the continued development of this HBV gene targeting program could bring us closer than ever to the ultimate goal, total elimination of cccDNA. Thank you. Thank you, MF. Appreciate your perspective. With that, I'll look forward to hearing all the thoughts and sell-side analyst questions, our investor questions coming in. Please, let's open it up, Tara, to the phone lines. Great. Thank you, Michael. Yes. Please hold for a brief moment while we poll for questions. Our first question comes from Debjit Chattopadhyay at Guggenheim. Please go ahead, Debjit. Hey, good morning and congrats on the, maybe I could use the word groundbreaking data. Thank you. A question for the panelist here. I know, Mark, you talked about sort of a six-month follow-up before we can sort of either start tapering NUCs or stopping NUCs. What would be the follow-up you think would be required to start using the word a functional cure? Yeah, happy to. Thank you for that question. It's really about, you're really focused on the notion of stopping NUCs and then following biomarkers to determine cure. I'll do a couple things. First of all, I would frame it as a viral cure. The virus is cccDNA, and that's what we're eliminating. The six months that I alluded to really stems from FDA guidance in which they talk about 24 weeks off of a NUC to determine that what you've seen is an effect of the intervention, in this case, PBGENE. By following pgRNA in the blood for 24 weeks, we'll have determined that that is a durable effect meeting the criteria. By stopping NUCs, we can then assess the ultimate marker, HBV DNA, in that time point. I would conclude, if that remains not detected in the blood, that we have achieved a viral cure. Happy to expand on that and happy for MF's perspective as well. MF, anything you want to add? Thank you. In 24 weeks, it's actually an arbitrarily defined observation period, where we are more confident in saying that this therapy actually maintained after stopping. This is a very standard and expected duration, where we will just observe for 24 weeks and then we stop. That will be associated with a high confidence that this therapy actually can at least functional cure the disease. Now we are hoping not only functional cure, we really want to eradicate the root of the infection, the cccDNA. Debjit, if I could just add a comment. As you might imagine, I've thought a bit about this, but what MF and Mark forgot about infectious disease, I haven't learned yet. I think it's fair to say right now, team, the pgRNA, because you're controlled on the NUC, as Mark said, I want to make sure we don't miss this. The pgRNA is really your proxy upstream for HBV DNA being gone. I think that's where the six-month durability before we stop being very ethical, careful for these patients is in our minds. Remember here, team, once you withdraw the NUC, our mechanism is not suppression. We've got proof of permanence and elimination. Once you withdraw the NUC on any therapy, if you didn't complete the job and the lid's off the pot, you see HBV DNA tick back very quickly, Debjit, within a month, within a couple of weeks, two, three, four weeks. I think when you know this mechanism and we stop the NUC with pgRNA as the obvious blood marker because we don't have longitudinal biopsies in everybody. Of course, those are important in our dialogues with the FDA, taking them through the thought process of what our path forward will be. Think of pgRNA, if you will, in the past as kind of the S antigen marker of being willing to stop. By a month after, if HBV DNA doesn't come back, I think it makes a lot of sense with our mechanism. Sure, I'm sure regulators who we haven't talked to yet will want to see an HBV DNA sustained period of six months. Again, pgRNA is really meant to be that proxy upstream from the nucleoside analog. Great question. These are the things we're being really thoughtful as we reshape the framework on a new technology with a new target. If I could follow up with another one. With respect to the inactivating indel, you went from roughly 23% to 80% from dose two to dose three. Yep. When you think about the hepatocyte turnover, roughly 200-300 days, how are you thinking about the timing of the fourth dose, or if you need a subsequent dose beyond the fourth dose? Yeah, Debjit, excellent question. I'm going to make a comment, and then I'll ask MF and Mark to chime in from the gene editing side. Remember, team, what we showed here, 90% of our edits from our biopsies confirmed. It was about similar in the NHP models, but 90% was an elimination mechanism. Debjit, now you had less than one percent of the cccDNA transcripts left. What you showed is if you cut again, of what was left, the less than one percent, you were able to get additive benefit of elimination. Remember, you wouldn't show the elimination in the pie chart, it's gone. Then the secondary mechanism, the 10% of the time was the 23%. You're showing you're getting really closer to zero-zero, and you say, "Look, if you leave anything in the liver, could that be problematic?" Billion-dollar question. I'll remind everybody here that patients today who are in functional cures or even beyond a long functional cure timeframe, the minority, these folks will have cccDNA transcripts in their liver if you biopsy them at a very, very low level, even though they're not expressing HBV DNA. Really, really important here to understand that 90% is the elimination mechanism. We know when we inactivate, that POL function is lost and gone, and we can continue to cut, Debjit. We now know this. This was really important from the safety standpoint. Remember, no one's trying to give subsequent LNP representative doses before. Getting that cytokine cascade under control and understanding it was huge for what you just brought up, Debjit, to say, "Do I need to give a fourth cut or not?" That's kind of what we're assessing right now. Remember, last point here. When I show you the six for six pgRNA chevron, if you will, where people go to undetectable green, different patients got there at different dose administrations. One of the things we're trying to understand right now, Debjit, there's no heterogeneity when it comes to full S-antigen reductions, sustained reductions, pgRNA loss. Some people got there sooner than others. Is that based on how many hepatocytes are infected? Debjit, these are some of the things we're trying to find out and figure out now in our go-forward path. I think what I want you to hear, at least today, why we decided to come out and talk to you today with this data is it's not if, it's when. Appreciate that, and I'll hop back in the queue. I have a few more, but I'll come back later. Thank you, bro. Thanks, Debjit. Our next question comes from Maury Raycroft at Jefferies. Please go ahead, Maury. Hi. Good morning. Congrats on the great data. Thanks for taking my questions. Maybe to start off, for the next data update by year-end, it sounds like you'll have the framework in place for stopping NUCs. Do you expect to have a few patient examples for these pgRNA patients who've stopped NUCs? I'm also wondering, have you already stopped or will you stop NUCs on some of these six patients to help validate your NUC-stopping framework? Yeah. Maury, I'll answer the first part, and I'll open it up to any other comments from our panel. We have not stopped the NUCs yet. We're at that period of observation that we've shown you. Remember, we've got four dose levels optionality. Yes, the higher dose level had some more of the AEs, but remember, that was not under the current safety protocol. Whether we have to go there or not, as we've said, point four and point six five look really good. Right now, we're not revisiting point eight at this moment, but I'll remind everybody, nobody had problems with point eight on the first administration, Maury. there's really four dose levels that are open here. Remember, biopsy data, gold standard. Primary biomarker, pgRNA. We're looking and showing you that different durability. We've got some people coming up on six months right now, but the longer, the earlier treated. Some were a little earlier in that journey. We're also managing S-antigen reduction and seeing that that stays durable, because that's a really important secondary biomarker because cccDNA is one of the two sources that express S. Frankly, it's the more important source, because I would argue that S coming from integrated disease, the damage is already done. The insertions occur, the chances of cancer, and those numbers have happened. That's where Mark talked about are we going to bring this earlier in the spectrum of disease to even e positives so we don't allow the integrations to happen. I won't promise you, Maury Raycroft, exactly where we'll be on how many patients have stopped NUCs by the end of the year, because we don't want to rush this. We want to get this framework being new right. We want to make sure there's no difference in durability of the different doses and schedules, and that we have a really clear picture before we stop. Mark, M.F., anything you guys would want to add or subtract from that, please? Go ahead, M.F. Oh, yeah. I think this is very reasonable. When we look at others, our undetectability, and then we may think about whether it's a time to stop the NUCs for our patients. It has been shown that even some patients who are RNA negative, then we may see some relapse. The fact is, most of these patients, in our experience, where we can stop NUCs with our RNA being very low or undetectable, they actually stay at the same status. I'm very positive where when we have a persistent RNA negative, pg RNA negative in the patients after being treated with this molecule, then they will have a high chance of getting a remission after stopping NUCs. It's a matter of time. I understand we are all under regulation or the design of the study. I remain very hopeful to see we will have success in stopping patients who have pgRNA undetectable in the future. Thanks, M.F. Mark, anything you want to add here? I just wanted to add to that. I wanted M.F. to comment because these are patients that he's treated at his center in Hong Kong. There is a human being, a research participant at the other end of this. I think as Michael outlined and as Cassie outlined, the translational science informing next steps is critically important. Making sure that we've dotted our i's, crossed our t's as we take this critical step to test for viral cure I think is critically important. Got it. Great point. Go ahead, Maury. All helpful. I guess, is there any precedent or information that provides a roadmap for running a pivotal study in an enriched population of pgRNA e-antigen positive patients? Is this your plan? What could timelines look like to make this decision? Yeah. Maury, I think the plan right now, look, you're always thinking steps ahead. I get it. I want to be clear here. Do we think we have a better effect on the pgRNA detectable at baseline? No. We just have a clear blood biomarker to start. I'll remind you, the S reductions coming from cccDNA elimination is 15 for 15 was in the evaluable. The other nine patients don't look any less effective on S. It's just that S alone comes from integrated in C, so it can't be a perfect biomarker in the blood for cccDNA elimination. Maury, sure, the pgRNA-enriched is obviously a smart place where you'd feel comfortable. You have the most data of where you're going to stop. What a pivotal would look like, I won't speculate here, but I will go back to something Debjit said. The endpoint for us, again, we're not creating a new endpoint. It's HBV DNA. That's what the FDA's asked for since day one. With all due respect, the field had moved S-antigen up as a predictive marker of that because cccDNA eradication, therefore HBV DNA eradication, has evaded us. Okay? The reality here is functional cure exists because we don't have something better. We're not looking to stop for six months and a day. If this mechanism continues to hold true, this is permanence. You're seeing cccDNA in humans at less than one percent and going down with accumulative edits. Maury, I won't speculate, but you're always very smart and thoughtful. A pgRNA-enriched population is definitely an obvious place to stop the NUCs to begin. What does the BLA path look like? We'll talk about, there's a reason we're collecting these biopsies in combination with these biomarkers. Make no mistake about it, we don't need to pave a new endpoint with the FDA. In fact, we're giving the FDA what they've been asking for forever, HBV DNA destruction. Yeah. Okay, that's helpful. Last quick question, then I'll hop back in the queue. For the S-antigen reductions, you're showing the max levels of reductions, can you say if all of those patients are showing that they continue to decrease S-antigen over time, or are you seeing any patients rebound? Yeah, I think if I was to sum up the 15, and I'll ask MF and Mark to comment on this, I think you're seeing a durable, stable reduction. We've had a couple of patients that are outliers that continue to erode, and you go, "Huh. Is the immune system doing something since you're pushing the CC, not the S, the cccDNA level down, therefore the S?" Maybe, but I think stability is how I would call those 15. They're not popping back up. They're not drastically popping back down. They're staying stable. Mark MF, is that a fair depiction of the data? Yeah, I'll jump in because I've spent a lot of time thinking about that in the context of what we've talked about and what we're seeing in the liver biopsy specimens. It's important to remember that S-antigen in the blood is a messy biomarker, and it's because there are multiple sources integrated as well as cccDNA. The way I've thought about it is we're eliminating cccDNA and seeing a proportional decrease in the blood based on the amount that was produced by cccDNA. What happens to that produced by integrated, I do expect it to decline over time, but I think that's not a direct effect of PBGENE-HBV. That's a great point. To Deb's point before about liver turnover, obviously PBGENE-HBV also targets integrated and upsets the regulatory component to express S. Frankly, it's not vital to our mission. We like reducing the S. To Mark's point, the body will do that over time. We need to make sure no more integrations happen. That's the purpose of our drug. We're going to stick around and answer everybody's questions. This is a big, monumental dataset for us. Please feel free. I'm not going to evade your question here. We're going to get to you. Okay, Tara? Maury, thank you. Thank you. Yes, thanks for the questions, Maury. Our next question comes from Patrick Trucchio at H.C. Wainwright. Please go ahead, Patrick. Thanks. Good morning, and congrats on the data. My first question is, I'm wondering what level of formal alignment you have with the FDA on pgRNA as the upstream blood biomarker for cccDNA elimination, and what specific data set would be required for pgRNA loss to support dose selection in Phase II development? Yeah. Patrick, let me hit that directly on. First of all, Patrick, let me give you your flowers because you were one of the first believers of eliminating cccDNA. I do want to state that publicly, and I pulled your sell side quote in today. Congratulations to you. Hopefully, we're making you look pretty smart today. From there, please, I'm so glad you asked the question. The FDA alignment exists. The endpoint for the treatment of chronic hepatitis B is HBV DNA. Remember, I showed you the slides of, I think it was slide two or three in the presentation. That's the commonality and the gold standard to the FDA. To date, people have targeted S to decide in their trial designs when to stop nucleoside analog to measure the endpoint agreed upon by the FDA, HBV DNA. Our biomarker is direct to our mechanism. No, we haven't talked to the FDA yet. Patrick, the obvious answer is clinical data. The biopsy data we have of direct targeting of cccDNA. The fact that only, and I use the word only, pgRNA is specific to our mechanism. Remember, when you eliminate cccDNA, things that are unique. MF had asked this question and brought this up early on, and he taught me about it. Things that are unique, viral transcripts that are unique to cccDNA, pgRNA, Core antigen. Those are all gone when you eliminate, Patrick. In the minority of the time when we inactivate and make it replication incompetent, it's mutated, and it could express S, it could express Core, but it can never express the precursor for making HBV DNA, pgRNA. Of course, our biopsy and our clinical results of efficacy markers in the blood and safety will be the package that we talk to the FDA about our go forward on. Patrick, I want to make sure we're clear here. We're not paving a path forward for FDA endpoints. That's clear. It's HBV DNA and viral destruction. In fact, there's multiple pathways in the guidance, regardless of S levels, because the FDA gets it. It's just a unique biomarker for your product. Patrick, the answer is you bring them the mechanism and the proof, and we'll have that conversation with the FDA as we move forward to phase II. Yeah. That's helpful. Can you just clarify the biopsy methodology when you describe that tenfold or one log reduction in cccDNA-derived transcripts, and then also less than one percent of transcripts remain. What exactly was being measured and normalized? Separately, how are you now prioritizing the go-forward regimen across point four milligram kilogram, point six five mg per kg, and potentially point eight mg per kg, and what specific efficacy and safety criteria will determine the regimen for expansion? Patrick, I'll take the second part of the question first, and I'm going to open it up to the panel after I answer the gene editing portion of the question. First and foremost, we really like our safety profile after the 20% of trial doses that have been given, seven of 38 right now. We weren't having a problem with first dose. We were having problems with subsequent doses that had a complement cascade activated C3, C4, C5 proteins, Patrick, in the first couple of minutes after LNP is introduced to the blood. Frankly, cytokines, IL-6, IL-1 beta. We needed to make sure. We were also a program that was a bit aggressive in a two-hour window we were dosing. Most programs were delivering LNPs at much lower doses and not subsequent. Have never done an infusion rate in that time. We elongated the infusion rate, and there's less time per minute. In fact, we brought some real experts on LNPs into the Safety Committee who helped us with that. We took the steroid from 10 to 20. What Cassie showed you in the post-mitigation AE table, we don't want to see grade three hypertension or higher. We don't want to see it. Lab abnormalities about LFTs. Frankly, guys, we're cutting hepatocytes. Debjit and I spent a lot of time talking about this in the early days. There's no magic number for me. Remember, this is the DAIDS criteria, very different than some of the other companies used. Grade three is five-X, grade 4 is 10X. The bottom line is it's a transient. Mark's talked to me about this forever. It's a transient, about a week, elevation in an ALT, AST. It has had zero implications of bilirubin. That's what we watch like hawks. No Hy's Law, no even suggestion of synthetic liver problems. We put the best ALT flare committee in the world together analyzing this. There's really been no trepidation there. I think you want to see a safety profile that persists of what we've showed you post-mitigation. I will ask the panel to speak to that here. Let me open it up to MF and Mark to comment on that. I'll go back to the gene editing question. I think the safety profile is actually quite okay and after we actually amend some infusion protocol because obviously what I observed right now by dosing many patients in our center is actually a reactive phenomenon to the LNP, where we actually can correct quite successfully by using medications and also dehydration. This is totally, I would say, controllable for patients receiving this kind of therapy. You know what? Emily. I'm going to cue Emily right now. Even though you've taught me well, Emily, our head of translational, I'm not going to take your flowers here to talk about the incredible biopsy work you've done. Em, why don't you address the first part of Patrick's question, please? You're on mute at the moment. Thank you. I'm using the room audio here, so I hope you can hear me. We can hear you great. Yeah. When we were thinking about the correct methodology to examine our biopsies, we wanted the most information-dense methodology we could to allow us to look at both transcript level to reflect our primary mechanism and the edits that we see in both cccDNA and integrated HBV DNA. We used a long-read RNA sequencing that is able to differentiate the viral transcripts and whether they originate from the cccDNA and have a viral poly sequence, or whether they originate from the integrated HBV DNA and have a human poly sequence. This is really one of the very few methodologies that can differentiate S antigen from integrants versus cccDNA, and it can also tell us whether we've edited those transcripts from these different sources. This is how we're able to pull out the cccDNA transcripts that have the viral poly and see that those were decreased by one log, and how we were able to understand that in those cccDNA transcripts, the fraction that was edited was up to 80%. Thank you, Emily. I want to give Emily some incredible credit in a fast time. Mark used the word complete before. Emily and team did incredible fast, I call it fast feedback loop work translationally to understand the complement cascade, the cytokines, to help us figure out exactly how we were going to go at subsequent administrations as we increase dose. Emily, congratulations to you and your team. You play a huge role in today's data. Thank you. Honored to be here. Tara, back to the questions. Great. Yes. Our next question comes from Catherine Novack at JonesTrading. Please go ahead, Catherine. Hi. Good morning. Thanks for taking my question. I wanted to ask why some patients have undetectable pgRNA at baseline and is spontaneous reduction pgRNA something that is observed in HBV patients? Yeah. I'm going to put this one over to Mark here in a moment. I will tell you, the e-negative patients, if you remember Cassie's early slide, she talks about everybody goes through the continuum here, team. You start off as an e-positive, right? Where most of your transcripts and virus are coming from that cccDNA and starting to get integrated. You want to stop that integration period so that you don't have higher risk of cancer. Okay. The reality here is when you settle in, and everybody unfortunately does settle into this disease until we have a cure, you have most of your expression coming like S-antigen from your integrated disease. PgRNA is lesser of a load of the viral mix versus integrated at that point. The thought process is that pgRNA in the blood, we know they all have it in the liver. Remember, patient five in the biopsy had no detectable pgRNA in the baseline blood, but we did show the eradication in the biopsy. It's just the detectability of how much there is. The thought is the 40% that are detectable in the blood have a little bit more prominence of cccDNA. I'm going to go to my teacher here, Mark, to add or correct me. Well, I'm happy to add that, but I think, Michael, you've been learning. That is a nice explanation of the natural history of chronic hepatitis B. I do want to put in the context of the natural history. When you look at hepatitis B and follow people over their lifespan, we are seeing people at different stages, HBsAg positive, HBsAg negative, and I think that pgRNA in the blood is a measure of that progression along the natural history. Of course, MF has done much of the seminal work in defining that natural history in patients with chronic hepatitis B. I'm going to turn it over to him for comments on what we're seeing. Thank you, Mark. In fact, we have done a lot of study on looking into the pgRNA, the role of pgRNA in assessing a patient's chronic hepatitis B status. In fact, we understand, the e antigen negative patients, they have a higher negativity rate in terms of the pgRNA. When we look at the biopsy, they actually, you can see that it's a matter of a detection limit where we can measure. Obviously, we will measure at a high positive rate in the D positive patients. Some patients, somehow the circulating pgRNA is not detectable. I can guarantee to you where even these patients with undetectable pgRNA in the blood, we can measure it in the liver, and this is for sure. Okay. Thank you. I guess with the updated safety regimen, looking forward, do you think it would be possible to study PB and HBV in subpopulations of interest to the FDA, such as those with cirrhosis or decompensated liver disease or pediatrics? Yeah, Catherine, I think all things have to be on the table. We're going to be very deliberate and evidence-based in how we follow this. Of course, right now, I think you're starting in trying not to let the liver get more sick, if you will. Right? I think, at some point in time, once we have our first path forward and our second, you're talking about things that make a lot of sense in the life cycle management plan. I don't think, and I'll ask MF and Mark to talk about this, remember, we have acute hypertensive events we had to deal with really early on. I don't think we've seen, and knock on wood, we haven't seen any liver AEs. I think that only increases our confidence in possibly testing in the future in somebody who maybe has a little bit more of a decompensated liver. MF, Mark, don't let me go too off script here. I'm speculating, but I think we've kind of like the liver profile so far. Please. I think, studying in the broader population is obviously indicated. The good thing for studying this drug, particularly in pediatrics or young adult, is of most important to me because they are at the relatively early stage of the disease that this drug actually can have a higher chance of success. For sure, I highly recommend to think about it. For compensated liver disease, I don't know. Decompensated liver disease, I don't know. Whether we can alter the natural history of these patients as far as Hepatitis B is concerned, we really need to understand better, not until we have a good data for adults or even pediatrics before we should move on studying compensated liver disease patients. Completely agree. I think what you're hearing MF say is, let's stop the damage from being done. Great. Thank you very much. Great. Thank you, Catherine. We're going to go back to Debjit at Guggenheim for his follow-up question. Please go ahead, Debjit. You know what? I'll follow up with the company directly. Appreciate the call back. You got it, Debjit. Thank you, bud. Tara, please proceed. Great. Yes. Thank you, Michael. I'll now turn it over to Naresh, who will read some of the questions that we received over the webcast. Sure. Thank you, Tara. One question for the team here. Following the mitigation strategies that were implemented, did the IRRs get reduced or go down? Yeah, sure. MF, happy to have you speak to that. I will just quickly say, in scouring the data, the answer is yes. You've seen some lesser fevers. You've seen some lesser achiness. The idea of lessening that complement cascade, it really carries, and the cytokines, really carries across the board. MF, anything you noticed about the 20% of patients who have been treated with the new mitigations, the longer infusion period, and the increased steroid that you would talk about on the day of infusion? That is definite. When you increase the duration, I think from two hours to four hours or to five hours, then it decrease all the reaction quite a bit. Some patients do have low-grade fever. They don't have these bad hypotension that we observe so far. This is definitely helping in terms of changing the protocol associated with a lesser, let's put it, adverse event during the infusion. I want to emphasize it is likely due to the LNP rather than the drug itself. People know this is universal. The LNP is associated with all this, but we did a lot of amendment in terms of the infusion protocol, and then it's now shown to be successful in mitigating the side effects or the clinical profile of a patient, particularly on the day when they receive the infusion. Great. Thank you, M.F. All right. Next question, if we go back to pgRNA. Michael, you did mention that the six patients who were detectable at pgRNA baseline. Do you have a rough estimate on approximately what the levels are for these patients who are pgRNA detectable when controlled on nucs? Yeah. I think it's important, no one may be the analytics guru of the world, but we do use the Roche assay. I think that detectability on the sensitivity side is really excellent. You can detect a level of sensitivity less than 10, and there's no upper limit. It's across the gamut, depending on the cccDNA load. What I want you to take about the undetectable to detectable is we've got an incredibly sensitive tool that knows if the patient has pgRNA expressing in the blood at baseline and will track longitudinally post-treatment when they stop expressing and stay durably non-expressed, if you will. Just to double-click on that point, for those patients who had pgRNA loss, what was the average time or duration to induce the loss? Yeah. Mark and MF, you guys can comment too, but if you look at the bar graph slide, and I'm looking at it right now as I turn my head, I think you see some patients get there as early as first administration, some as second, and some up to the third. We're talking about six for six here, but this is some of the things I think we're studying in the durability of the different dose levels. Does anything change? Not that we would think it would. Again, the mechanism is permanence when you're eliminating. It's been across the board in the six. MF, Mark, any other way you guys would interpret the six-for-six results? Some people got detectable, undetectable rather, sooner than later. I think it supports cumulative editing. Mark, MF, let me know if you want to share anything there. I don't have any additional information, I mean, comments, but I think please be reminded that they are receiving different doses, right? It matters in a way that some patients may have the loss of pgRNA earlier than the others. Even they are receiving the same doses. Sometimes, hepatitis B, we don't understand fully, and some patients respond very quickly, some patients doesn't. The thing is, we have shown definitely that using this regimen, the pgRNA can be reduced to undetectable level, at least in the blood. That is the effect we see. Obviously, bigger study, we need to look at the time of undetectability of pgRNA, whether it will affect, for example, the long term, rate of remission, and that is another story. Yes, I'll remind our sell side group and our investors today, patient six with pgRNA detectable in the blood and a post-treatment biopsy both showed non-detectability of blood and non-detectability of molecular tissue after treatment with PBGENE-HBV. That's very reassuring. Mark, is there anything you would add there? The only thing I think I would add, I think it's a very interesting comment, is time to pgRNA negativity is certainly one of the variables that we'll look at. I mentioned earlier that the goal of phase I is to determine the optimal dose and dose interval, number of doses, et cetera, to get to phase II, and I think that's an interesting comment because that's one of the things we can look at among many other factors that we'll be evaluating. Great question. All right, Mark, I think that's a perfect place. I see the questions are drying up. Hopefully, the data continues to speak for itself. I want to thank MF for his leadership, Mark for his leadership, and most importantly, all of our investigators and our patients who have boldly really embarked upon this journey of viral cure with us. I want to thank our investors, our sell side analysts for their time, the very thoughtful questions today. I know we'll have some one-on-one follow-ups, but hope you're as excited as we are. Thanks again, and thank you, Tara, for moderating.