Thank you for joining Guggenheim's 2026 Emerging Outlook Biotech Summit. I am Debjit, one of the therapeutic analysts, and my privilege to welcome our next presenting company, Precision BioSciences. From Precision, we have Cassie Gorsuch, company's CSO, and Alex Kelly, company CFO. Thank you. Alex, if I could ask you to do a very brief intro for, of Precision? Sure. Sure. Thanks very much, Debjit. Always appreciate the opportunity to be here at the Guggenheim conference. So Precision BioSciences is. I'll just, I'll be brief, is a very focused in vivo gene editing company. The company was founded 20 years ago. We just celebrated our 20th birthday. The founders invented a technology called ARCUS, and then they spun that off from Duke in 2006, and over the course of those years, we've really refined this technology. We've become experts in protein engineering, and we can deploy ARCUS for a broad variety of in vivo gene edits, and right now, our company's very focused on two specific programs in vivo gene editing. The first of those is chronic hepatitis B, a disease which affects 300 million people around the world, so probably the biggest possible opportunity for gene editing is in that space. We have our programs in a phase I/II clinical trial. We've already generated data for that, which Cassie will walk through in a moment. And the next program, we just got IND clearance from FDA to begin the activating clinical trial sites for the PBGENE-DMD program, and that's our gene editing approach for Duchenne muscular dystrophy. Cassie can talk to you about the differentiating features of ARCUS that allow us to do gene editing in places where other technologies cannot. So that's a perfect start with Cassie, then. You got the IND clear, 20th anniversary. Congrats, and, you know, I think, help the audience understand, the differences between an edited, almost full-length- Mm-hmm ... Dystrophin versus a gene replacement with a truncated Dystrophin, which could be 30%-40% the size of the actual Dystrophin gene. Yeah. Thanks, Debjit. It's exciting times at Precision right now, and exciting to have the IND cleared for DMD. So our approach for Duchenne muscular dystrophy really takes advantage of a couple of the key differentiators of our platform. As Alex mentioned, this is a first-in-class approach utilizing our ARCUS technology to actually correct the dystrophin gene at the DNA level, which is something that's really never been done before. Today, the treatment options for Duchenne muscular dystrophy can be categorized into micro dystrophin gene therapy approaches or exon skippers. And in our view, you know, if you think about those two approaches, both of them have some limitations that we sought to overcome with PBGENE-DMD. On the micro- dystrophin side, it's a one-time treatment using an AAV approach, but it delivers a severely truncated version of the dystrophin protein. The dystrophin gene is the largest gene in your body. It makes a very large protein, and what it does in muscles is it helps prevent muscle degradation over time, kind of as a shock absorber. And so along this very large protein, it interacts with a bunch of other proteins throughout the entirety of the protein. And so when you take a miniature version of that and deliver it by an AAV and a micro- dystrophin, it's about 30% of the natural dystrophin, and we know that the function of those micro- dystrophins is compromised compared to a full-length or even a near full-length dystrophin protein. On the exon skipper side, you can make a larger protein with these types of approaches, but the patient populations that are eligible for exon skippers are much more limited, and so it's more of a, it's more of a patient population-specific approach, typically around 10% or fewer of population, depending on which exon you're skipping. So PBGENE-DMD is a one-time treatment using an AAV, and it contains two ARCUS nucleases that cut and excise exons 45-55 of the dystrophin gene. And we selected this region for a couple of reasons. One, about 60% of patients with Duchenne muscular dystrophy have disease-causing mutations in this region, and so it overcomes the limitation of the exon skippers in that it is broadly applicable within the patient population. The other reason we selected to excise this region of the dystrophin gene is that the resulting protein that's made retains 80% of the full-length dystrophin protein, and we know it's functional in humans because this same protein occurs in a subset of Becker muscular dystrophy patients. Those patients with Becker muscular dystrophy that have the same genotype and create the same protein have very good long-term prognoses, so they live into their 60s or 70s. Many of them are ambulatory their entire lives. From an overall quality of life perspective, it's a huge improvement over kids living with Duchenne muscular dystrophy. And so that really overcomes the challenges of the micro- dystrophins, where you've got this compromised, very small micro- dystrophin protein. With PBGENE - DMD, you get a much larger protein that has known function in humans because of the Becker patient. We like to think of it as we already have the animal model. It's the best animal model. It's humans who have this protein and walk around every day, and so we know it can work in humans. So it brings up an interesting point with the micro- dystrophin, mini- dystrophin constructs. We've seen expressions in the 30%-100%- Mm-hmm ... kind of range, depending on the age group. You mentioned a subset of Becker's patients who have relatively normal- Mm-hmm ... lives.... What, how much Dystrophin do you need to mimic that? Yeah. So in the case studies that have been published for the Becker patients who have this delta 45-55 genotype, the amount of dystrophin expression in those patients varies quite broadly. When we look at across all muscular dystrophy patients, Duchenne and Becker patients, and you look at large natural history studies, you can start to appreciate that there's a threshold of about 5% that really differentiates severely compromised muscle function from much better muscle function in terms of, how long these people live, how long they're ambulatory, how long they have good respiratory capacity. So right around 5%, we think, is a differentiator for near full length or full length dystrophin. And it's important that you recognize when we talk about near full length dystrophin, the amount of dystrophin that's needed is gonna be less because the protein just works better than a micro- dystrophin approach, where we're seeing companies achieve 30%-100% of normal dystrophin protein expression, but it's not translating into the functional benefits that we want to see. I think that that's really because that smaller micro- dystrophin or mini- dystrophin is just compromised in its ability to function within muscles. And so our therapeutic target is somewhere in the range of 5% or greater in order to achieve therapeutic benefit for these Duchenne patients. Got it. So that lends itself to the obvious question: if you're not shooting for 30%, 50%, 100%, can you operate at lower doses? Mm. Does that make the product, at least on liver, where we have seen most of the issues, make that safer? Yeah, good question. So because the micro- dystrophin approaches and our approach both utilize AAV, there's often a desire to compare, you know, what are those approaches gonna be like? I think you have to take a step back and think about what is the AAV being used for in these two different therapeutic approaches. In the context of a micro- dystrophin, this is actually for everyone, AAV today can be dosed one time. Patients today don't have the option to be re-administered if the therapeutic effect wanes over time. For AAV gene therapies, the therapeutic benefit is dependent on the presence of the AAV, and so you get one shot to get as much AAV into those tissues, into those muscles as you can. And so I think what we're seeing is that companies are pushing the dose for micro- dystrophins because they know they have one opportunity to give this child as much AAV as can be there. We know that AAV is gonna turn over time because this is a progressive muscle degeneration disease, where myofibers, myocytes are dying over time. They have to be replenished, and as that cell division and new muscle fibers are forming, the AAV is getting lost in that process. And so when you think about that, that's, I think, really helps understand why we're pushing doses on micro- dystrophin. Now, for a gene editing approach, we don't need the AAV to be present long term. We need to get to the tissue, and so there's gonna be a minimum dose necessary to get the biodistribution you need within tissues. But we just need to get there, create the edit, and then the AAV genomes can go away. So we're not gonna be affected by cell dilution in the same way that a gene therapy will. And so I think it really, if you think of it from the mechanism perspective, it's really different on what you're relying on that AAV for. I think you can expect us to see different dosing levels than what you've seen in the micro- dystrophins. So the question then in my mind is, we have seen 30% expression in the older patients and 100% plus in the younger patients. Mm-hmm. What's your target audience if you want to keep the AAV dose low and handle fibrosis, et cetera, on the other side of the spectrum? Yeah. So, we shared in our press release this morning announcing the IND, that we will be having a company event to share some more details on the clinical protocol here soon, but we are planning to dose ambulatory patients in this first part of the study. And that's really to start to establish safety. It's a phase I study. Safety is the primary endpoint. I think consistent across gene therapy programs, we've seen the safety in younger patients tends to be more tolerable than safety events in older patients. And so we will be starting in an ambulatory population, and I think a lot of what you're seeing in the younger patients versus the older patients in terms of efficacy is driven by biodistribution. We think that there's probably a little bit of a benefit in biodistribution in younger patients compared to older patients. You mentioned you get one shot. How are you thinking about manufacturing, especially empty-to-full capsid ratios? Because that's been another challenge for the field where- Mm ... you've, you know, we can clearly see the effect of, you know, better purity given better outcomes. Yeah, absolutely. So yes, AAV, a couple of things I think that you have to keep in mind. You get one administration per kid that you dose, and so you want that dose that you select to be both safe and efficacious because you're not gonna get a chance for them to be redosed at a higher dose level. So our clinical trial design will be a single dose level. We're not dose escalating. The dose that we're selecting based on our preclinical and non-clinical data will be expected to be both safe and tolerable.... I'm sorry, safe and, and efficacious. Those are the same thing, safe and tolerable. And so from that perspective, you know, manufacturing does play a big, a big role, as you said. We've put a lot of effort into optimizing our AAV manufacturing process at Precision. I'm really proud of the work that our CMC and analytical teams have done to really build a very robust process. I think as it relates to tolerability, AAVs are dosed on how many viral genomes are present within your batch, but you will also have viral capsids that don't have a genome in them. Those are the empty capsids. Those come along for the ride whenever you dose on viral genomes, and so the higher your full capsid ratio is, the fewer empty capsids will come along for the ride, which will control your total capsid dose. And capsid, we think, is what drives a lot of the toxicities associated with AAV. And so our full capsid ratio is typically in the 85 to higher% range of what we've seen so far, in our engineering runs and into our CTM. I think we have a lot of confidence that our product is as good as it gets in terms of AAV manufacturing today, and that will lend itself well to the overall tolerability of the drug. Got it. So the two ARCUS nucleases are attached to the AAV9 vector. Mm-hmm. AAV9 historically has had a bad rep. Mm-hmm. You're going in a pediatric indication. Mm-hmm. How are you thinking about immunosuppression, so you maximize benefit without any SAEs? Yeah, I think this is something that we're definitely paying attention to in the context of gene therapies. We've seen different trials employ different immunosuppression regimens to help support the tolerability of the drug during the initial phases after dosing, and so I think this is something the field has learned a lot over the last couple of years in terms of the steroid regimen, potential drugs that can help with some of the liver toxicity you mentioned earlier, complement inhibitors. All of those things are starting to be employed in various micro- dystrophin trials. I think, again, we plan to share a lot of the details on exactly what our protocol will look like here in the near future, but we are going to take an aggressive approach in terms of managing the safety of this, because these kids only have one shot, and you want it to be safe and efficacious. In the preclinical data, I'm not sure what the cardiac transduction looks like for AAV9... Mm-hmm. because that, unfortunately, these kids eventually die of cardiopulmonary issues. Mm-hmm. So how are you thinking about both the diaphragm and the, you know, cardiac muscles? Yeah. So our preclinical data, we selected our capsid and our promoter based on the ability to target all of the relevant cell types necessary, so skeletal muscle, cardiac muscle, and diaphragm, and intercostal muscles, respiratory muscles. And so in our preclinical data, we can see in our mouse model, we have a humanized mouse model that we can actually measure editing, we can measure dystrophin protein expression, and we can measure functional outcomes in those mice. And we saw a really nice broad transduction across all of the affected tissues, up to, I think it was about 10%-15% dystrophin protein in the heart, so well above that 5% threshold we talked about earlier, and up to about 25% dystrophin protein in the skeletal muscle and in the intercostal muscles. A little bit lower in the diaphragm, but we think based on some clinical data from other studies, potentially in the range of diaphragm protein expression, that may still provide therapeutic benefit. And so I think we are hitting all of the affected tissues, at least in our preclinical data, and it'll be really exciting to see how that starts to translate into the human study. Going back to the immunosuppression, I mean, there are literally two spectrums that is in the clinic right now. Mm-hmm. Are you going towards the more complex 90-day sirolimus, you know, et cetera, along with corticosteroids or somewhere in the middle? I think we'll take a pretty aggressive approach on this. I think you only get one chance to provide a safe AAV dose, and you don't want it to go wrong. Nobody wants it to go wrong. And so I think from our perspective, we would rather err on the side of a more comprehensive supportive care package along with the AAV dosing to ensure that we're making this as safe as possible for patients. Got it. Now, I get it, the IND was cleared today, but we are in February. Do you think we'll get any data this year from DMD? Yeah, so that's still the plan. We are planning to... So now that we have the IND clearance in hand, we're working with our clinical sites to go through the IRB process. So that's really the next stage, is start to get sites activated. And we're able to do some of that work in parallel to regulatory review. So our clinical operations team has been hard at work anticipating the IND clearance that we've now received, working with our clinical sites to get as much of the work done up front as we can. Now we'll continue into the rest of the IRB process that's contingent upon regulatory clearance. And so that's really the next step that the team is focused on. We're still aiming to treat three to five patients this year and be able to share data. Initially, it'll be safety data, looking at various safety parameters that we can collect from blood draws, but also looking for Dystrophin protein expression from biopsies, and hope to have data available to share from those initial patients this year. That'll be the three-month-ish kind of endpoint, because that's also roughly the duration of immunosuppression. You get a safety plus the Dystrophin data? ... That's right. So the goal is to. Our protocol is designed with an early biopsy and then a later biopsy, and we hope to be able to have that early biopsy dystrophin data from at least those first couple patients by the end of the year. And I think we're looking, you know, as we talk about the timelines here, towards the end of the year for that. There will be a staggering of dosing between patient one and two, and two and three, to really establish safety as we move through those early patients, you know, in the four to eight week time frame for those initial patients in terms of the staggering, and then we'll be able to progress a little bit more rapidly with some safety established initially. Got it. Hey, Debjit, if I could just add, I mean, I think one of the things that we've seen on the hepatitis B front is that our team has been very good at execution operationally, getting patients lined up to be in the trial, ready to go. And in 20-- you know, we've dosed 12 patients in the hepatitis B program in a year, got that done ahead of schedule, and then as you look at the DMD program, we got the IND filed in a very timely way on our timelines, and we're already working with the sites so that we can run fast towards the IRB process and get those sites activated and treat the patients that are available there. The manufacturing, how much control do you have over it, or are you working externally with a CDMO? Yeah. So we have a process development team at Precision within our CMC group that helped develop the process by which we make our AAV, and then we transferred that process, and many of the analytics into CDMOs and CROs to support the manufacturing process for the clinical trial material. So we don't have internal manufacturing capabilities for GMP AAV, but we utilize a CDMO for that. Our team is on site with them. So we are routinely traveling to get to the site and make sure we're there for all the key steps in the manufacturing process. We like to have a lot of oversight because the team has been very involved, as Cassie said, in developing the approach. Does your CDMO start with a C? No. No? Okay. Very happy with that. For obvious reasons. Yes. All right. Let's move to the HBV program you had. Sure. November last year, you had some interesting exciting data at AASLD. Could you just remind us where that program is right now? Yeah, of course. Our ELIMINATE-B study is a phase I study where we are testing PBGENE-HBV. Mm. So PBGENE-HBV is a lipid nanoparticle that encodes an ARCUS nuclease that is designed to cut and eliminate cccDNA, and cut and inactivate integrated HBV DNA with the goal of providing cures for patients. This study started about just over a year ago, and we submitted a late-breaker abstract to the liver meeting hosted by AASLD in November. Per their own website, phase I studies aren't considered for oral presentations, but they gave us an oral presentation. I think that really speaks to the excitement in the field for a new approach for hepatitis B, and this is the first clinical modality ever aimed at cccDNA elimination. We were really honored to be able to be represented by Man-Fung Yuen, a really prolific HBV investigator out of Hong Kong. He gave the presentation at AASLD. And so since then, we shared data at that meeting for our first nine patients dosed on the study through cohorts one through three. And then we shared in January, through a press release, that we have dosed an additional three patients in cohorts four and five, and we can talk about exactly what those cohorts are aimed at. But that's really where we are today, is really great data presentation at AASLD and continued operational execution into this first quarter of this year. So, there were clear differences in baseline S antigen levels between the cohort that were shared versus the- Mm-hmm ... the original cohorts. You think the elimination is that a factor of the baseline, or you don't think that matters? Yeah. So one of the things I think that's unique about our trial is that we're enrolling e antigen-negative patients who are on NUCs, but no restrictions on S antigen levels, on baseline S antigen levels. And so we've had patients up to almost 12,000 IU per ml baseline S antigen come into our study. Many of them are in the thousands, down to about a couple of hundred, 400 or so, I think, was about our lowest. And so we have a nice range of baseline S antigen levels coming into the study, and we've had activity in every single patient dosed so far. And so what that tells you... And good activity. Mm. It doesn't appear to correlate with baseline S antigen, and so I think there, today there seems to be no effect of the treatment efficacy based on baseline S antigen, which is great when you start to think about eligible populations. How is the cccDNA evolving in these patients? Because I don't believe I've seen that data. Yeah. So what we are monitoring as a primary efficacy endpoint today is S antigen, and that's really because that's a serum biomarker that's easy to follow, and it should trend well with editing of viral DNA in the liver. So I mentioned our goal is cccDNA elimination and inactivation of integrated HBV DNA. By eliminating the viral infection at the root source, you should shut down production of downstream viral antigens like S antigen. And so we've seen nice S antigen reductions in all patients. As we've increased the dose, the durability of those responses has, has improved, out to our cohort three, where we were seeing really nice initial data at the AASLD presentation. We do have biopsy data from one patient that we've presented at the AASLD meeting. Biopsies are optional in part one of this study. They will be required as we move into later phases of this study to be able to answer this question of what's happening in the liver for cccDNA. What we know so far from the biopsy data is we have evidence of the mechanism of PBGENE-HBV cutting and editing viral DNA. We're working on the analytics to be able to quantitate the cccDNA elimination fraction, but we can see edits in viral DNA in the liver. And again, this is the first time of any gene-editing company that I'm aware of sharing proof of mechanism in humans. Given that we are running the clock here, the cohorts that are currently underway, you're trying to explore both a shortened dosing window. What are you trying to achieve with that, and at what dose? Yeah. So cohorts one through three were really dose escalation cohorts, moving from 0.2 to 0.4 to 0.8 mg/kg. Cohorts four and five, which we recently opened, are looking at dose intensification, and so cohort four is 0.4 mg/kg every four weeks, versus every eight weeks, where we were prior in the earlier cohorts. And then cohort five is 0.65 mg/kg- Mm ... on a four-week schedule as well. And so those are actually proceeding in parallel to finishing out cohort three. So three, four, and five, we're collecting data on right now. The goal of those shorter dosing intervals is to evaluate the effect of a more intense dosing regimen to drive towards that undetectable S antigen and stop nukes. Well, we have run the clock. Looking forward to all the data this year. Congrats on the progress, and thank you for making time for us. Thank you, Debjit. Thanks, Debjit. Nice to be here.