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Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'd like to welcome the Precision Biosciences team. Maybe if you guys want to give an intro and a brief intro to the company as well. A lot going on with the company, so I'll let you take over. Thanks for joining us today. Sure. Why don't you guys introduce yourself first, and then I'll go last. I'm Adam Mishler, Translational and Research Lead of our Duchenne Muscular Dystrophy Program. Emily Harrison, lead of the HBV Translational Program. Laurie, thanks for having us. Michael Amoroso, President and CEO of Precision. Precision is a gene editing company, in vivo gene editing only. We are applying our proprietary Arcus technology, which has some very unique properties to it. We talk about the cut, very unique cut type, the size and the simplicity. have some advantages with the types of programs, how you can deliver the gene editor, the type of repair mechanism for different functions like excising or adding function insertion. So we apply that in our clinical programs where, you know, where it makes the most sense. Precision is out of Durham, North Carolina, been public since 2019, have about 100 employees, and right now we are focusing on HBV, chronic hepatitis B. We just showed at the Easel Conference some really groundbreaking data of what PBG and HPV, our Arcus gene editor wrapped in an LNP, can do in chronic hepatitis B directly eliminating CCC DNA. And we'll start in the clinic in the second half here in Duchenne muscular dystrophy very soon. We've got an IND approved. We have our onboarding sites. And next step is clinical initiation. Got it. Yeah, it's a great intro. And you mentioned the updated easel recently. There you had the first demonstration that CCC DNA can be eliminated from the liver of a patient with chronic HPV. What's been the feedback from KOLs and investors since that update? Yeah, so Emily was on the ground in Barcelona, and maybe I'll let you start with some of the buzz and excitement we heard in Barcelona and I'll kind of cap us. Yeah, I think this is something the field has been waiting for for decades to try to find a technology that can directly target and eliminate the ccc dna so there was a huge positive reception at the at the data showing that we can actually uh cut and eliminate ccc dna to drive importantly the loss of a key biomarker for cccdna pgr so there is a very positive reception yeah and i would say more obviously we spent a lot of time together in the last week or so i'd say the understanding that you could dream about a complete viral cure Right? I'll remind everybody. CCC DNA is the only source in this chronic hepatitis B that makes infectious virions that can make replicating virus. It's during that stage of replication where some virus gets integrated in the host genome fragments, but those can never replicate. Those are not replication active. That's when cancer happens in patients. So you really need to cure the source. To date, in drug development in HPV, we have tried anything we could do with the tools we had targeting downstream viral transcripts and markers to try to turn the immune system on to attack the CCC DNA. But we've never been successful as an industry. This is the first time we have proof of direct targeting and elimination, biopsy proof, blood marker proof with pgRNA of elimination of the replicating viral source. Got it. That all makes sense. And you mentioned the pg RNA, which is a key part of the update. How established in the field is the use of pgRNA as a direct biomarker versus traditional S-antigen that can be assessed via blood draw? Yeah, I'll start and then ask the team, Emily, to weigh in. I think pgRA is obviously a very understood and a collected biomarker, but it comes down to the biomarkers for your mechanism. Remember, it was important to us that we needed a sole biomarkER, not a sole source biomarkR, for CCC DNA elimination. These patients are controlled on nukes. The FDA endpoint is very clear. It's HBV DNA eradication virus, replicating virus, once you're off nucleoside analogs and off treatment. So all PGRNA is for our mechanism, it is upstream of where the nuke works, and it is only produced from CCC DNA. Every molecule of PGRN is the precursor to package and make one molecule of infectious virus HPV DNA. So PGRRNA is well understood, hasn't been used as a lead biomarker, Maury, because as I said before, no one's ever directly targeted CCCDNA. So the FDA endpoint? Crystal clear HPV DNA. PGRNA is our biomarker to eradicate, eliminate, and know when we can start to stop our nukes, when we have the right dose and schedule. I would say it's very similar to how S-antigen is used on other mechanisms of action. Other mechanisms can't target CCDNA. They try to shut down the S. And what we've seen, again, is that's never turned into a true viral cure eradicating CCDN. In fact, what is a functional cure? The endpoint that almost everybody uses today in HPV. It means you have viral suppression, not elimination, of your HPV DNA and your S antigen off of treatment. However, it's not been a good predictive marker. We've used S because that's the tools we have, but we only have a 3% functional cure rate in 50 years. The BEPI data just came out. That's great. That is a step forward for patients. But again, it is still not a viral elimination and eradication of the source that makes virions infectious particles. So we're really excited, and I heard some of you guys wrote last week about the next generation of what HPV could look like, having a foundation of therapy directly targeting ccDNA like pBG and HPV. Emily, anything you'd like to add there about pGRNA? I think the one point I'd like to add on to that, Michael, is that there are a number of studies that have been done to understand what biomarkers are predictive of safe nuke withdrawal and effective nuke withdrawal in patients that have been on nukes for a period of time. And S-antigen has been used, but there is a growing number of studies supporting that PGRNA may even be a better marker of safe nuke withdrawal than S-anogen. So I think we are evolving with the field to appreciate the importance of both CCC DNA and the biomarkers that track CCCDNA as an important marker of viral cure and sustained new withdrawal. And one last, great point, Emily, one last point on this. S-antigen is still a very important secondary marker of PBDHBV. Think about it, it comes from two sources. CCCDNA, the most important source, because that allows viral replication. And it comes through those integrins I talked about before, after the fact, those fragments that cannot replicate. So of course, if we're eliminating the viral source, S- antigen's going to come down. We had a homogeneous effect in our data on 15 patients, somewhere between 35 to 70% substantial reductions in S-antigen. It's just not the sole biomarker for PBG and HPV because it's not specific to CCC DNA. Got it. And so based on your comments and the other studies that Emily referenced, so with the PG RNA, if you're seeing patients that have that eliminated, that should give you more confidence to stopping nukes rather than seeing the S- antigen decrease. We agree. Yes. It is the precursor for HPV DNA. Right. And maybe jumping into the data a little bit more. So you talked about cumulative editing after three doses. Do you have a sense of the kinetics of the CCC DNA elimination? And do you expect a dose response? And what is the theoretical ceiling? Emily, why don't you start? In terms of the genetics, the editing happens fairly quickly with the Arcus nucleus expression peaking one to two days after we think of you know one to weeks complete editing has occurred so that's sort of the kinetics we're looking at so we can see fairly rapid declines in biomarkers like pgRNA whereas other modalities like nukes that erosion takes decades so that the kinetic for a dose response right now when we're looking at pgRNA in this patient population we're seeing pg RNA loss across all the dose levels and schedules that we had PGRNA-positive patients. So right now, we're thinking there's a good flexibility to find that right therapeutic window, considering both safety and efficacy. And we're collecting more data from patients in our 0.4 mg per kg and 0.65 mg per g towards to really nail down what the correct dose level would be for this drug. Yeah, that's a great point. And I think you also saw from our biopsy data, subsequent edits, subsequent administrations of LNP were very important here, very important to extinguishing the totality of the viral source. So I'll remind you, we had more than 99% eliminated and or inactivated CCCDNA in our biopzy evidence of the pre- and post-treatment with PBG and HPV. Remember, PBGN-HPV eliminates CCC DNA directly at the source more than 90% of the time. that's the outcome of our edit. There is an edit where the CCC DNA can come back together about 10% of the time, Maury, but it's mutated. And we proved in those biopsies also that we have knocked out pole. And without pole, that mutated CCCDNA cannot virally replicate. The most important thing for cure, viral cure, and to reduce the outcomes of HCC, right, hepatocellular carcinoma, must turn off viral replication capability. Got it. And so for picking a go-forward dose for expansion, what are some of the key things that you need to learn in the ongoing study? Yeah, so I'll remind the group, in a phase one, part one, completely dose finding of a nascent technology, we had the 0.4 mg per kg, the 0,65, the 0.,8. And in fact, we had two different cohorts of 0.04 because remember I said there's multiple administrations in this part of the study up to three. And we have 1.4 group that's four weeks in between administrations and one that's eight weeks. All of these four options for the therapeutic window have shown really great results in eradicating and getting once detectable baseline PGRNA undetectable. So now, Maury, I think what you want to see, if PGRN, as I said at the beginning, is a one-for-one marker, a precursor molecule that must be generated by the ccDNA to make infectious virus, HPV DNA. You want to see sustained eradication and elimination of PGRNA. So right now, we're looking at those first six patients. Those were the ones that had the blood marker at baseline. And we want to get to about a six-month window. And then we'll consider that. That's an obvious group. We haven't been so clear yet. And there's some reasons on that, right? We want to hold some things close to our vest. But that is the obvious group where we would start to remove the nuke first. A six-month durability period there matters. Remember I said S-antigen is also a very important secondary mechanism, a biomarker, to illustrate our mechanism of PBG and HPV. Those patients with reduced, significantly reduced S- antigen, we have over a year on the early treated where it shows the permanence of a gene editing mechanism. So we also look at the threshold where those people sit today and make sure there's no changes, they're stable, they have that durable response. And I think that's a group where, you know, we're going to start in the PGRNA at baseline in the blood who have the sustained S antigen reductions. That's a group when we would look to withdraw the nukes next. In addition, I think Emily said this, we want to be even more robust than six. We're continuing to accrue relatively quickly here in H2, the 0.4, 0.65 dose level right now to see is there any differences on that therapeutic window. safety of course first efficacy so what we're we're pushing up our numbers here so we can make a very evidence-based decision on stopping nukes got it okay um and then you'll be able to pick the dose after you stop the nukES and get an understanding of that i think so and we don't have to pick one dose we could pick maybe two arms if they're like right now what we'RE doing in this wait period maury is really trying to differentiate is there a difference between these four different doses and schedules, the great news is so far we don't see one. So multiple options is always a good thing. Right. Okay. And for the data you showed, the S antigen declined across all the patients you treated. But can you give us a sense of the kinetics and the source of the S-antigen declines, the S anagen and the declines? And if you're eliminating CCC DNA and S anogen is only coming from integrated DNA, will the S a anagen eventually just go away completely? Yeah. So I'll start and then Emily can clean up if anything I get wrong. Okay. How's that sound? So S-antigen again comes from the most important source, CCC DNA, the replication factory of virus. But most S in E negative patients, remember this study has started, I'm sorry, let me take one step back. This is an 80% of all chronic hepatitis B where everybody ultimately graduates to. They're E negative. That means they're controlled on nukes. Their viral markers of S are coming mostly from the fragments of their integrations into the host genome. Very important point. While S has been used as a marker based, again, on the tools we've had prior to now, S that comes from the integrated disease cannot replicate more virus, and very thin data to say it's anything more than frankly inert. We feel good seeing the blood marker go down, but the most important thing is we know we have a preferential impact on ccc dna elimination of s we also target the integrated we have an indirect targeting there where we hit the rna transcript level we we disrupt regulation for the expression of s i think the thing we're saying is always want to see s going down with a treatment for hpv but there's not a magic number for us in order to potentially stop the nuke except refocus pgrna undetectability okay biopsy sits above all but we can't get it in everybody and then pgrn a sits above very close to biopzy they're hand in hand we kind of showed the data that the biopisy was very predictive of the blood marker pgr na s antigen sits a little bit below that quite a bit below when it comes to the mechanism of pbg and hpv emily anything you'd want to add maybe just to reiterate that the primary mechanism for our product is elimination And that, of course, will reduce, that will get rid of all S antigen that is coming from the CCC DNA that has been eliminated. So we do expect drops. But in these patients, that contribution of S antogen from CCCDNA is very small. So that part of the drop might not be very big, say 20%. And we also have our secondary mechanism, which creates edits and down-regulates expression from integrants. And so that's where the remainder of that drop could come from. So we think that these two mechanisms together contribute to the durable drops that we're seeing in S-antigen that help represent the durability of the mechanism of action and in combination with PGRNA loss can help us predict a sustained response off of NAPES based on the current literature. Yeah, Maury, I guess the only thing I would just add to that is we've talked about other therapies in the space that target downstream about different viral loads, and maybe some therapies look better there. I want to be careful here. S-antigen doesn't depict viral load. S- antigen, if we knew only from the source of CCC DNA, that absolutely depicts viral load, S- Antigen coming from integrins that cannot reproduce does not depict viral load. So one of the things I want tell you is what we showed in our data, 15 for 15 substantial S antigen reductions. Not everybody had been cut three times, maybe 35% all the way up to high 70%, so substantial. But the most important thing we showed was, to Emily's point, if our mechanism is permanent elimination, then what we cut should stay gone. And it did, 15 for 15. We've got patients over a year out, whatever we cut stays gone. Durable and permanence of mechanism, super important to get viral not functional cure yeah makes sense okay um and wanted to talk about the gsk uh data the bepi data where they showed 19 overall functional cure 26 functional cure in the patients with the s antigen less than a thousand um mechanisms different uh that does not eliminate the ccc dna um one could argue that the bepidate is good but they're still limitations around the approach. How should investors weigh and value the GSK approach versus what you guys are doing? Yeah, I think the key word for me more is and, A-N-D, right? So Bepi, and congrats to the GSk team. Luke Miles is a good friend of mine. So BEPI took a big step forward. Functional cure rates after 50 years, guys, have been substandard, 3%. If we're now taking people to the early 20%, and Maury, remember, it's a suppression mechanism, right, destroys someone at the RNA level. But the reality here is, if you look at the phase two data versus the phase three, we have to see where people net out at 18 months, two years, three years. But even if a 20-ish percent functional cure pulls back a little bit to the 10, 12, 14, 15 percent, still a big step from 3 percent. So that's great for patients. Now, what we have to ask ourselves in the next question is, is functional cure good enough? And the answer is No. Because CCC DNA is still there. Cancer risk is still there. Viral replication still happens. We call it leakage at the liver level, even controlled on nukes. So there is some risk. So the reality is Bepi really takes a nice step forward for patients. I think you have to think about, and it's very synergistic. We don't have any plan to do it right now, but for me, I'm biased, but if you just look at the science, the foundation of the house is you now have the biggest culprit that we've always known for 50 years is the viral reservoir ccc dna now you've got 99 plus elimination and eradication of the virus plus whatever's left you could possibly target with a bepi that could be very synergistic so i think it's a good day i think the last week at easel was a nice day for patients with chronic hepatitis b i think we're moving in the right direction yeah um and for the gsk phase through design and the data? What are some of your key learnings from that that you could leverage to fast-track your program? Yeah, look, I think, I don't know if there's anything super groundbreaking. I think they did a wonderful job with the study. I feel like, you know, that you need to have the correct biomarker for your mechanism. Remember, HBVDNA, we talk all about it. HBDNA is still the principal foundation of FDA approvals as per the 22 guidelines. The guidance for infectious disease and chronic hepatitis B. S-antigen is the biomarker for them to know when to stop nukes because that's what their modality does. Similarly for us, HPV DNA is the gold standard. And we can only measure our complete elimination of that once we stop the nuke. So therefore, PGRNA tells us when to top it. So I think the biggest thing that comes out of it for me is use the right biomarkers of your therapy to be predictive of your outcome of, in the case of Bepi, functional cure. And in our case, I sure hope complete viral cure. Yeah. Okay. And you've provided some tidbits on just how you're thinking about stopping nukes in patients, but maybe just kind of go through the key next steps and framework for how you are going to do this. Yeah. Continue to collect data in the current cohorts that are having wonderful results. Continueto collect both all things that matter for therapeutic window to compare the four different dose levels, safety, and durability and permanence of our eradication of PGRNA and CCDNA. When we can collect biopsies, of course, we'll continue to do that. Super informative and very important. Big step forward for patients. I think those biopsys were on the presentation May 27th. And I think right now there's a path to stopping nukes that's most evident in the PGRN detectable at baseline. That's about 40% in the E negative population where we've started. But remember, that doesn't mean we don't work wonderfully in the other 60%. Once we have the results, all of the patients, remember Maury, I said all 15 had similar and the same results on the secondary biomarker, great permanent reductions from eliminating ccDNA of their S antigen. We will stop nukes in that group second when they didn't have pGRNA at baseline. But the obvious is to focus on the first six, add more patients who are pgrna enriched and continue to maybe take them off their nukes in groups here and really try to see if we see any differences over time in the different dose levels it's the most i can kind of give you right now exactly what that looks like and we'll give an update later in the year later inthe year uh for like how many patients you've taken off of nuked later in there okay okay and um uh how much data in terms of number of patients and duration of follow-up can we expect by year end? And is there a set number of patients or internal benchmarks that you want to achieve to clarify the development path and accelerate investment? Yeah. I don't want to be misleading or obtuse, but just we'll see how many patients stay in durable six-month PGRNA elimination. We'll see How many we stop. And obviously we'll always come out at the major liver conferences make sense. So we'll give some more updates as we know what that looks like. Got it. Okay. And And have you guys done, which I'm sure you've done, internal projections on just the relationship between the degree of CCC DNA elimination, PGRNA loss, and durability of functional cure? Kind of how do you see those three different metrics working together? Yeah, I'm going to ask Emily to chime in in a minute here. First and foremost, we need to tweak the question more. And I get it. It don't mean to embarrass anybody. But yes, PDRNA, direct correlation to CCCDNA elimination. No unfunctional cure. Got to change the verbiage, guys. This is a viral cure, a complete cure. Functional cure means I suppress S-antigen and HPV DNA for six months in a day. So again, we believe that PGRNA as a blood marker is a wonderful biomarker. It's the only sole source biomarkers specific to ccDNA. and one for one, you must have that precursor molecule to make HPV DNA, which will be the ultimate endpoint. Emily, anything you'd add here? I think if we're moving away from functional cure here for a second, talking about viral cure and the ability to come off nukes and have HPV DNA suppressed, these nukestop studies are the thread that connects loss of PGRNA, the sustained HPV DNA expression. In a PGRNA positive patient, one of the key landmark papers had a 3% chance of that patient coming off of nukes safely. But with PGRN loss, that brings them to a 30% chance of sustained safe withdrawal of nuches. And when we're thinking about the BEPI data and where that's landing the field in a subset of patients less than 30%, I think we're in the right direction here with pgrna as a biomarker for viral cure awesome thanks got it um yeah all makes sense and uh and getting at the the root cause of the disease with targeting ccc dna if i guess what kind of feedback are you getting from doctors and even from some of the uh doctors at easel on their level of confidence in stopping nukes and patients who are on your approach versus an approach like the BEPI approach. Yeah, look, I think a palpable excitement, right? I mean, this is, you saw DeShako's quote that has been in New England Journal for a while. We've all known we got to get to the source of ccDNA. You saw on the May 27th presentation, Mark Zolkowski, MFUN. I mean top godfathers, if you will, of infectious disease, hepatitis B. We've got all the top thought leaders in the world respective to their country, Ed Gein, the French affiliates, the UK. So we've, you know, sites onboarded, sites on boarded for phase one dose finding in the U.S. We didn't see that with Sovaldi. So there's a palpable excitement. And again, I don't think anybody thinks it's an arms race of or who's going to be better. It's real excitement about what possibilities could be for and. We took a step forward in functional cure with Vepi. And wow, now we might be able to dream about a true complete viral cure with PBG and HPV. Yeah. Okay. And on safety, you implemented mitigation protocols with slower infusion plus higher steroid doses. Will this risk mitigation steps, will they have any effect on editing efficiency or subsequent doses? Yeah. So Emily did a wonderful job of characterizing cytokines and some complement proteins that were present when you pushed dose level in subsequent doses. And we know you need cumulative administrations to eliminate 100% of the virus. amazing work that happened in her shop. So I'll let her tell you kind of those findings and reinsure you about the gene editing from two to five hours, please. Yeah, I think the team did an amazing job. And what we learned is that the concentration in the blood is really what's driving some of the adverse events like the hypotension. The complement cascade leading to cytokine elevations can be reduced through these mitigations. When we think about actual activity of the gene editor, we're thinking about a different compartment of the body, right? This is the liver, where we're trying to get this sink of LNPs to the right concentration to do the gene editing work. And we are not concerned that this longer infusion time by a few hours is going to affect the maximum concentration in the liver and impact the ability of the nuclease to do its job to eliminate CCCVNA. So this is a good safety mitigation step that we have not seen impacting our efficacy. And Maury, I just remind everybody that a simple mitigation, thank God for patients, right? It can't be arduous. From a two-hour infusion to a five-hour, remember that first day is when you have your LNP infusion reaction. So they stay in the hospital one overnight anyway. So that doesn't really change their course of action. And we just took a 10 milligram steroid dose to 20. And that seemed to really blunt the complement proteins and the cytokines. So we've had 20% of total doses in the study given under the new protocol. And the IRRs, the fevers, the hypotensions, these things have really ameliorated. So, we're really excited about that. Got it. That makes sense. And I want to shift gears to DMD. You've got a DMD program where we could see data by the end of this year from that program. It's an innovative approach using dual Arcus nuclease in a single AV to excise exons 45 to 55. You can restore near full-length dystrophin, which could be relevant for about 60% of the DMD patients. Talk about the patient's age range and functional measures that you plan to collect for this update by the end of this year. Yeah, we're super excited about a novel and unique approach in DMD. We've needed one. What we're doing there is just not enough. And Adam, in a short time period. This has kind of been your birthright here. So please tell us why we should be excited about the DMD function, DMD trial. Sure. So we're creating one of the most functional dystrophin proteins that hasn't been seen with the gene therapies today. We've shown preclinically that we're able to produce up to 35% dystorphin and up to 85% of the cells overall and those levels increase over time and so we've shown durability functionally as well and then from the data that i presented at asgct i've shown that when we treat even early younger mice that we see even higher efficacy and so when we're treating the patients the age range is about two to seven uh age range uh in the clinic we're hopeful that we will see strong efficacy based on our preclinical results. And Adam, maybe in our last couple of seconds here, can you just tell me the basic conventional gene therapy approaches about sending an AAV and looking for episomal expression for like a synthetic dystrophin approach versus gene editing? Can you give me one or two complete differences, why it's unique? Yeah, so we're editing the source of the disease. And so once we edit at that DNA level, that's permanent. And so with cell proliferation, all daughter cells will contain that edit and produce that functional dystrophin. With the gene therapy, with cell-proliferation, you're losing that therapy over time, and it waxes and wanes, especially when we're seeing the movement move to a younger patient population where that cell proliferation is even more exacerbated to it than an older population. Thank you, Evan. Yeah. Makes sense. One of the key differences between gene therapy and editing, which sometimes people get confused on. Yeah. I think durability is key for these kids. And we've shown that pre-clinically, and I'm confident that we can show that clinically as well. Makes sense, and we're pretty much out of time. So maybe in closing, if you want to highlight your cash position and runway and key catalysts over the next six months, investors should be focused on. Yep. We reported our cash runway at the end of Q1, $125.8 million. That takes us through. We're very, very operationally savvy. That takes US through 2028. Key milestones, which is that could take us through the Eliminate B trial, through its expansion, and well into phase two, maybe completely through phase two for PBG and HPV. And now we feel like these studies will continue to ramp up and go forward based on the latest data that we just showed you at EASL. and that money cashed one way takes us through our phase one the design that adam and team put together it's a phase one two three you know once you treat the first patient you're already collecting bla ready type of endpoints so this takes us though um all the way into pivotal and potentially through pivotal our cash one way here for pbg and dmd that's our function dmg study endpoint uh inflection points for the rest of this year updates the second half of the year on pbg and hpv at uh at you know probably at the major liver conferences but i know all eyes will be looking at those six patients who are pgrna negative did they stay undetectable did they stop the nukes we'll continue to add to the robustness of that data and initiation and commencement of first patient dosed in the pb gene dmd function dmg trial right and some data by the end of the year early data definitely safety from a couple of patients and maybe some early efficacy or or early efficacy, maybe into Q1 of 27. Got it. That's where we're at. Michael, Kelly, Adam, thanks so much for joining us today. Thank you.