Hello, everyone, and welcome to the First Annual HCW Virtual Genetic Medicines Conference. My name is Patrick Trucchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. Together with my colleagues at HCW, we are pleased to be hosting some of the most innovative biotechnology companies in the world, alongside leading key opinion leaders in areas of gene -editing, RNA medicines, and gene therapy. We're excited to feature a broad mix of established and emerging players to highlight the next generation of approaches advancing genetic medicine. And with that, it's my pleasure to introduce our next speakers, Precision BioSciences Co-founder and Chief Research Officer Jeff Smith, and Chief Science Officer Cassie Gorsuch. Precision is a clinical -stage biotechnology company using its proprietary ARCUS gene -editing platform to pioneer development of Precision medicines.
While Precision's lead program, PBGENE-HBV, is advancing in a phase I trial for treatment of chronic HBV infection, today's discussion will focus on PBGENE-DMD, a differentiated program designed to restore near full-length dystrophin or Duchenne muscular dystrophy, or DMD. So maybe just if we could to start, let's begin with Precision's ARCUS gene-editing platform. This is a unique platform that you're using to develop in vivo gene-editing therapies to target the root cause of rare genetic disease, as well as prevalent infectious disease. What makes it distinct from other gene-editing approaches?
Sure. Thank you, Patrick, for that question. So really, it boils down to the difference in origin. My entire career, nearly 30 years, has really been in the field of gene-editing and developing gene-editing tools. And I was fortunate enough to be involved in some of the first gene-editing tool development. And I learned from that experience basically some characteristics that would be involved in an ideal gene editor. And after pursuing trying to build our own gene-editing platform, we ended up with ARCUS. And I mentioned as far as difference in origin, ARCUS is unique from all the other gene editors in that it is derived from a class of enzymes called homing endonucleases and not based off of CRISPR, which is sort of the basis for many of the other gene editors in the field.
And really, this difference in origin helps bring some key differentiating advantages, the first being that ARCUS generates this staggered cut, which actually we've just published a paper, a Nucleic Acids Research that highlights the importance of that cut in being able to drive efficient cutting and as well as certain types of repair, and then a second advantage has been size. ARCUS is by far the smallest gene editor, and that helps in particular with delivery, and then the third is what we call simplicity, but basically, ARCUS is a single component gene editor. You don't have to deliver multiple components, and this really helps with both efficacy as well as delivery.
Can you tell us how does ARCUS's compact size and single protein structure enable delivery of two nucleases and one AAV? And why is this important?
Sure. So as I said, ARCUS is the smallest gene editor. And this is key because in order to be able to do a gene edit, you really have to be able to deliver your gene editor to where you need it to be. If you can't get it there, you can't edit. And so that's really the first challenge you have to overcome. And because of ARCUS's small size, we're able to put it into a delivery vector called adeno-associated virus, which allows you to deliver a gene editor beyond the liver. And in particular, in the case today where we're talking about DMD or Duchenne muscular dystrophy, being able to deliver it to muscle. And what has been really key for the success of this particular program for us is that we were able to build two different ARCUS nucleases and pair their kinetics.
So basically, we are excising a piece of DNA out of the dystrophin gene to reestablish functional dystrophin. And in order to do that, basically, we need to be able to cut in two different spots within the dystrophin gene and release those spots at the same time. And so pairing the kinetics was key. And then the other piece of that is that we're generating two compatible sticky ends with that unique cut that I mentioned. And being able to bring those two sticky ends back together helps to drive up efficacy in terms of getting a very specific repair. And basically, in some of the other gene editors, if they are not able to package all of that in, then that's a key limiter for them that we're able to overcome because of that small size of ARCUS.
Right. Now, moving on to PBGENE-DMD, what led you to prioritize DMD as one of the first genetic disease applications for ARCUS?
Yeah, I can take that question. At Precision, when we think about our pipeline, there's really two important considerations. One is the unmet need in the space. And I think this is a real obvious answer for Duchenne muscular dystrophy. We prioritize going into indications where we think we can really provide a transformative approach that could really change the treatment landscape for these patients. I think that's especially true when you think about DMD today. We heard recently from a KOL interaction that, unfortunately, we have over 100 years not really changed the prognosis, the outcomes for Duchenne patients. And I think we're really hoping to be able to provide some benefit for these patients that perhaps could be that in this indication. So first, it starts with unmet need. And then it goes to what Jeff was just talking about.
Is there a unique advantage of our technology, of our ARCUS technology, that we can leverage to be a best-in-class in that indication? I think, again, very true for DMD, where we can take advantage of the small size of ARCUS, the simplicity, and actually the cut. All of those come into play when you think about what we're doing with PBGENE-DMD. So it's unmet need, and does our technology have a competitive advantage to provide meaningful benefit for patients? And so that's really what led us to prioritize PBGENE-DMD.
Can you provide an overview of PBGENE-DMD and how it is designed to address the exon 45-55 hotspot?
Sure. I can take that, so as high as 60% of DMD patients have a mutation or deletion, the portions of DMD between the exons 45 and 55. That's what we mean by hotspot for the cause of the disease. We designed two different ARCUS nucleases to recognize a site that sits in the intron before the exon 45 and after the exon 55, with the idea that those two nucleases would cut and liberate that intervening piece of DNA, and then, as I mentioned before, generate compatible overhanging ends so that the two pieces of the genomic DNA could be religated to restore the function of a slightly truncated piece of dystrophin, and so removing that section restores the normal function of the gene and gives you a nearly full-length dystrophin protein.
Got it. And how does your approach compare to other gene-editing programs emerging in DMD?
Yeah. So we've seen a couple of other gene-editing approaches come out for DMD. The big difference is that these other approaches target a single exon. And so they're CRISPR-based approaches. Some of them use two or even more in theory, AAVs. And so in order to deliver all of the components necessary to execute the edit, they need multiple AAV vectors, which we see as a real challenge for getting the material needed to make the edit. And at that point, now you're starting to talk about very high-dose AAV to get enough of those materials to the target tissues in order to affect the edit. And so we are an all-in-one AAV. It's one AAV that contains all of the necessary components for our PBGENE-DMD edit that Jeff just mentioned.
The other big difference is because they're targeting a single exon, the patient applicability is quite limited, and so it would be more like an exon skipping approach than really a broader gene-editing approach, and so our approach, because we're removing this hotspot region between exons 45 and 55, is applicable in up to 63% of Duchenne patients, patients that have mutations in that region, versus a single exon approach is typically in the single-digit percentages in terms of the overall patient population.
Right. That's helpful. I think that partially answers the next one, but I'll ask it just to make sure there's further perspective. What are the advantages of restoring near full-length dystrophin compared to the truncated microdystrophin or the exon skipping strategies?
Yeah, yeah. I see those actually as two good questions and a little bit different. So the first one that we just talked about is really our editing approach versus some other editing approaches. Now we're talking about our editing approach versus microdystrophins. And when you think about a microdystrophin, that's really a gene therapy approach. And what I mean by that is the AAV vector itself contains the therapeutic gene, so in this case, the microdystrophin. And dystrophin is the largest gene in our body. It's a huge protein. The coding sequence is much too large to contain the full sequence in an AAV. And so what microdystrophin approaches have done is severely truncate that dystrophin gene down to a size that can fit into an AAV.
And in that approach, then you deliver the AAV, the therapeutic effect is linked to the persistence of the AAV vector because that AAV vector contains the dystrophin expression cassette. And so what you get is a requirement for long-term AAV persistence and a much shorter microdystrophin protein. We know from literature that shorter microdystrophins are not nearly as functional as longer, fuller-length dystrophin proteins. So for our approach, while it also uses an AAV for delivery, the AAV is not necessary long-term in order to elicit a therapeutic effect because the AAV in our case contains the ARCUS nucleases, which edit the gene at the endogenous locus and allow for natively expressed near full-length dystrophin. So there's a number of differences between our approach and a microdystrophin approach.
Even though they both use AAV, that AAV is used very differently in those two therapeutic approaches, and the resulting protein is quite different. In terms of an exon skipper, I would say the resulting protein from an exon skipper is more similar to the type of protein that we make a near full-length dystrophin protein. However, exon skippers have to be continuously readministered. It's not a one-and-done therapy like a gene therapy or a gene-editing approach. And they're applicable to small numbers of patients because they're single exon-specific approaches. And so I think our approach really takes advantage of the benefits of those two approaches into a single approach that has broader applicability, one-time treatment, near full-length dystrophin.
Right. Just some questions around the preclinical data. I'm wondering if you can summarize the key findings from ASGCT 2025 data as well as the July preclinical update.
Yeah, it's been a really exciting and productive year for our preclinical DMD team here at Precision. And so the data that we shared at ASGCT was really an update on a long-term mouse durability study. And we wanted to conduct this study because really the promise of gene-editing is durability. If you can fix the gene at the native locus, and you could do that in satellite cells, which we also demonstrated in that mouse study, you could really think about long-term benefit beyond even microdystrophin approaches because you don't require that AAV long-term. And so the data at ASGCT showed improved muscle function out to nine months in a DMD mouse model. And that was really backed by increases in dystrophin protein expression within both skeletal tissues and within cardiac tissues.
And then in the July update, we provided a further piece of data from that study that took a little longer, wasn't quite available for ASGCT, but that data was actually three -and nine-month data comparing the % positive dystrophin cells within that mouse study. And again, what we saw was actually an increase in the amount of % positive dystrophin cells over time. And so what this is really showing us is that there's good durability with a gene-editing approach, that there's good functionality from the protein that gets made, and that that improvement seems to actually increase over time. And so we were very excited about those results. And I think that dystrophin -protein positive cells really suggest that satellite cells are being edited and are helping to replenish the tissue long-term, yielding improved function over time.
Right. And how do you interpret the threefold increase in dystrophin-positive cells between three and nine months? And what does this say about durability?
Yeah. So in all of the tissues that we looked at, including skeletal tissues, diaphragm, and heart, we saw an increase in dystrophin -positive cells. Some tissues showed up to a threefold increase. I think the gastroc achieved up to 85% dystrophin -positive cells in that mouse model at nine months. And so what I think is going on here is that you're actually seeing at these later time points that muscle fibers that now express dystrophin are healthier, and so they're sticking around longer. And that is consistent with the disease progression in DMD, where the absence of dystrophin protein leads to muscle degeneration, muscle wasting. And then secondary, you have satellite cells in these skeletal muscles that we know we can edit. We've demonstrated that consistently across mouse studies. Those satellite cells are the stem cells within the skeletal muscle tissues that give rise to new myocytes.
And so if you've edited a satellite cell and it then differentiates into a new myocyte, it carries that edit with it. And now that myocyte is capable of making dystrophin protein. And so I think that increase in dystrophin -positive cells over time is really probably driven by satellite cell editing, giving rise to new myocytes, giving rise to new myofibers that are now dystrophin expressing.
Right. What level of dystrophin restoration do you believe is needed to translate into functional benefit in patients?
Yeah, it's a good question. So when you look across the natural history data that's available in all muscular dystrophy patients, and so this would be Duchenne patients and Becker patients. And Becker patients typically follow the in-frame rule, which means that they have mutations in the dystrophin gene that allow for an in-frame mutation and production of some dystrophin protein versus Duchenne patients that have out-of-frame mutations that really don't make much dystrophin protein at all. What you can look at across this large data set is that there's a threshold around 5%. If you have at least 5% dystrophin protein, the length of ambulation is longer in those patients, so they're able to walk around a lot longer. They're less likely to be wheelchair-bound younger, like most Duchenne patients. And there's an overall survival advantage in those patients.
And so I think minimally at least 5% seems like a good benchmark based on natural history data that's available.
Right. What have you seen across different muscle groups, including cardiac and respiratory muscles? And why is that important clinically?
Yeah, it's a good question. And I'm going to start with the second part of the question. It's important clinically that we're able to target both skeletal muscles, respiratory muscles, and cardiac muscles, particularly respiratory and cardiac, because that's what these kids die from. They die from pulmonary and respiratory, sorry, respiratory and cardiac deficiencies. And so being able to target those muscle groups is really important to really think about improving not just muscle function, but longevity for these kids. And so what we've seen in mice is that we are able to achieve greater than that 5% threshold in the heart. The diaphragm is a tissue, of course, involved in breathing function. While the overall amount of dystrophin protein in the diaphragm in our mouse studies is on the lower end, we do see that increase over time.
And I think it's also important that the intercostal muscles are actually very well hit by PBGENE-DMD. Those perform more like many of our skeletal muscles. And so I think it's going to be really interesting to see how this translates into humans. We know from really natural history data from Duchenne patients that even a little bit of dystrophin protein in the diaphragm can be really meaningful. And so I'm encouraged that our mouse data demonstrates the ability to get to both of these tissues, particularly the heart, which is a tissue that others have really struggled with. And I think it'll be interesting to see how that all translates, but it's important to get to those tissues because that's why these kids die.
Right. Can you walk us through how PBGENE-DMD editing of satellite muscle cells may contribute to long-term durability?
Yeah, of course. And we've touched on this a little bit. So I mentioned before, satellite cells are a population of stem cells in skeletal muscles. And what they do is they actually replenish new myocytes within the tissue. And so particularly important in Duchenne patients where muscle fibers are undergoing degeneration and regeneration, those satellite cells are trying to keep up with that degeneration. And they're actively dividing, trying to repopulate new healthy muscle fibers. But without dystrophin in the fiber, the muscles continue to waste over time, unfortunately.
And so at Precision, when we were considering various vector components like the capsid and the promoter, we really prioritized the ability to get to satellite cells and edit within satellite cells because we knew if we could get to those cells, because those are the stem cell population, you could actually increase the amount of edited cells within the tissue over time. And so we're excited to say across numerous mouse studies, we consistently observe the ability to edit satellite cells. And I think that long-term durability data that we talked about earlier, particularly the increase in percent positive dystrophin cells, is probably a result of satellite cells replenishing the myofibers with new myocytes that have been edited, and that's leading to an increase in the dystrophin -positive cells within the tissue.
I think they're absolutely essential for thinking about long-term durability, long-term functional benefit for Duchenne patients, particularly in the context of a gene-editing therapy.
Right. Great. So maybe just a few on the development path and regulatory considerations. The first is just what's the status of your IND enabling work and what are the next steps for your planned IND or CTA filing by year-end 2025?
Yeah. So I mentioned earlier, it's been a very busy year for Precision on the DMD team. A lot of people working a lot of hours to keep this thing moving forward. I'm happy to share we're on track for that end-of-year filing this year. Our toxicology studies, the in-life on those is actually complete. So we are now finishing all of the analysis, writing reports, lots and lots of writing, lots of documents. The specificity analyses, which are extensive for a gene-editing approach, have been completed and really working on final touches on regulatory with the plans to file that CTA or IND by the end of the year and be dosing patients early next year.
Perfect. And so then what are regulators most focused on for first-in-human gene-editing trials in DMD?
Yeah. You know, I think a couple of things that are maybe more unique to PBGENE-DMD being a gene-editing approach. I mentioned specificity analyses, and so Jeff actually and his team, he really oversees the team that creates the nucleases and characterizes the activity and specificity of those nucleases, and so that's an extensive amount of effort to generate the nucleases, and then once you have the clinical candidates to demonstrate good specificity of those nucleases, and so that's been a big piece of work that we had really aligned at our pre-IND meeting with FDA on exactly what that work package needed to look like, so we're feeling good about that work package going into IND or CTA filing just based on regulatory feedback we've received, and that's actually U.S. and ex-U.S.
The other pieces, you know, I think are really just long-term durability, which is where that ASGCT data really comes into play. And then, of course, all of the toxicology work, the manufacturing work, all of the assays for characterizing your GMP product. So all of that's underway. All of that will be included in our submission. And again, I think the team did a really great job earlier this year, actually, with the pre-IND of aligning those various work packages with expectations with IND. And again, we have also received ex-US regulatory feedback on that.
Right. And so what will success look like in early clinical studies? Well, you know, measures of biomarker thresholds, functional measures, or a combination of both?
Yeah, I think it'll be a combination of both. Of course, you know, the path has been really pretty well established on the microdystrophin trials that biomarker data is valuable here, and you can really leverage biomarker data in the context of accelerated approval. At Precision, we think it's really important to link that biomarker data with functional benefit. But obviously, the functional benefit may take a little bit longer in terms of collecting that data, depending on the age of the kids that you enroll within your trial. We haven't disclosed all of our trial design considerations just yet, but the functional data is a little bit more complicated just based on the age of kids that we may be considering enrolling. Therefore, I think the first pieces of data that we'll have coming out of this study will, of course, be safety. It's an AAV-based therapy.
Safety is going to be top of mind for everyone, and then secondary would be the dystrophin biomarker data from biopsies.
Right. Do you anticipate corticosteroid regimen or other immunomodulation will be necessary alongside PBGENE-DMD?
Yeah. I mean, I think it's a global trend that we're seeing in all AAV-based therapies is to err on the side of safety. I think that's the right thing to do by patients. And so I imagine we will also be including a steroid or immunosuppression regimen as part of our treatment paradigm. It's too early to say exactly what that immunosuppression regimen may look like. But I think, yes, I would expect to see that as part of our clinical trial, really prioritizing safety of AAV administration.
Just maybe a few on manufacturing and commercialization. I'm wondering, you know, can you talk us through sort of the manufacturing process for delivering two ARCUS nucleases and one AAV? How scalable is this approach? And, you know, ultimately, what proportion of DMD patient population could be eligible?
Sure. I can take that one. So, you know, as you mentioned, in terms of the AAV, it's important to understand upfront that AAV really has two parts. It has the cargo, which is our editor, as well as the shell or the capsid or protein around it. And one of the first major considerations is really the ability to make sure that as much of the capsid is full of the cargo. And we have actually optimized our process that we know that we are amongst the best in class for the full-to-empty ratio with as high as in the 80% range of full versus empty of the AAV. And this is critical for ensuring that we are maximally efficacious for the dose that we are delivering.
In terms of the number of eligible patients, as we mentioned upfront, the hotspot that we're addressing could be as high as 60% of the patient population could be addressed with this AAV gene-editing product.
Right. And how do you see PBGENE-DMD fitting into this evolving treatment landscape, especially now with multiple gene therapy approaches and development?
Yeah. I think when you think about the DMD population right now, I would say the, you know, obviously we have an approved microdystrophin in Elevidys. Once a patient has been treated with an AAV-based therapy like that one, even though it's a different capsid than what we're using, it's likely they will develop neutralizing antibodies that will prevent treatment with a different AAV-based therapy approach. And so for us, I think we're really focused on the incident population, which is still a huge number for DMD patients. And so as I think about how does this fit into the landscape, I think we're thinking about kids that haven't yet received a gene therapy approach. And I think with clinical success, you could really think about really owning that incident population and really then taking over in terms of kids who've received PBGENE-DMD versus a microdystrophin approach.
But I think that's how we think about it today. And I think with clinical success, it could continue to grow.
Right. Terrific. So then as we look ahead, what are the most important milestones investors should track over the next 12 to 18 months as PBGENE-DMD advances towards the clinic?
Yeah. So we said earlier our goal this year is really to file an IND or CTA by end of year, and we're on track for that goal. We then intend to very quickly be up and running in the clinic in early 2026, and we expect to have initial clinical data in 2026, second half, probably later in the year in 2026. But you know, based on how AAV gene therapies are typically administered, hopefully we'll have first patient dosed early in 2026. There will be a stagger period where we collect safety data on that initial patient dose before we dose a second or third patient.
And so I think next year we'll have, you know, a small number of patients, but meaningful when you think about what the path has looked like for microdystrophin approaches to start to collect that biomarker data and start to think about what a pivotal study could look like. And so really it's regulatory filing this year, clinic next year, data next year, and hopefully with positive clinical data, start to think about what a pivotal study could look like. I think PBGENE-DMD has the potential to move really, really fast.
Right. Terrific. Maybe just as a final question, I'm wondering how you envision ARCUS building a broader neuromuscular franchise over time beyond PBG and DMD?
Sure. So we have a few options to build the broader neuromuscular franchise. We announced at the beginning of the year our switch from another neuromuscular indication in mitochondrial myopathy to DMD for reasons Cassie covered. The program was in IND enabling studies, and much of what we will learn in DMD is directly transferable to the mitochondrial myopathy programs. Success in the DMD program positions the company well for rapid development of this mitochondrial program. Furthermore, we have a portfolio of mitochondrial indications that could follow on the first program's success. Alternatively, we have been approached by families interested in excising other segments of the dystrophin gene, which could let us expand into the remaining 40% of the patient population not addressed with our current DMD therapy.
Right. Terrific. Well, thank you so much. That does bring us to the end of our session. Really appreciate Precision BioSciences attending the conference, and thanks so much to Jeff and Cassie for providing these intriguing answers to these questions. Really appreciate it. Very exciting time for Precision. We can't, you know, we're looking very much forward to the next clinical updates on the programs. Thank you again to everyone. Have a great rest of your day and conference.
Thank you, Patrick.