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Sam Chang: Hi, everyone. My name is Sam Chang. I'm a urologist at Vanderbilt University, and we are quite fortunate to have really a rising star in urologic oncology, Dr. Vikram Narayan, who is at Emory University Medical Center. Dr. Narayan has been very, very active in multiple clinical trials looking at therapeutic interventions for different types of urothelial carcinoma. And today, he's going to talk about a presentation that was given at ASCO GU 2025 looking actually at a newer entity that was actually a non-viral, actually, impactor of therapeutic advances for urothelial carcinoma.

So, Vik, I'm going to turn it over to you. And thanks so much for spending some time with us.

Vikram Narayan: Yeah, great to see you, Sam. Thanks so much for highlighting this work. I'm happy to do it. So what I'm going to be presenting is data from our project that was the EG-70 study. So this is the enGene trial. So thanks again, Sam, for inviting me to do this. It's great to see you. And I really appreciate the opportunity to present our work.

So what I presented on behalf of our group of investigators is information from the detalimogene voraplasmid translational work, going into the background of how this agent works and making some important comparisons to, for instance, some of the other viral therapeutics that we have heard about and seen in the last few years.

So detalimogene—this is being manufactured by a company called enGene, which is a biotech startup that has focused their interests on bladder cancer. The previous name for it was EG-70. So in the interest of being simplified, I may refer to it as EG-70 or detalimogene as we go through this. But what's really unique about this drug is the fact that it actually uses a proprietary delivery mechanism to deliver DNA plasmid into the bladder lumen.

And EG-70 specifically has a dual synergistic approach to activating the immune system. So it uses double-stranded RNA agonists of RIG-1 to essentially take over or activate the RIG-1 receptor and activate the innate immune system. And then it also has an adaptive immune system component and activates IL-12—secretes IL-12 to activate the adaptive immune system. So this is local stimulation of T cells. And together, what happens here is essentially that anti-tumor immune activity for bladder cancer that we're all familiar with and expect.

Now, the preclinical studies that have looked at this have been very interesting. So this is what we presented at ASCO GU. There have been murine studies that have looked at essentially taking EG-70 in a mouse version of that in MB49-treated mice. And what you can see is that, in fact, there is T cell recruitment and there is remodeling of the tumor microenvironment to promote this adaptive immune cell response.

And in terms of actual anti-tumor activity, you definitely see profound anti-tumor activity when you're treating the MB49 cells with this EG-70 product. And one of the things that I think is really interesting is in some of the mice that had a complete response, when those mice were actually rechallenged with a subcutaneous injection of tumor, you actually saw the rechallenged mice actually not have any growth of that tumor, which suggests that there may even be a broader anti-tumor effect systemically.Now, the mechanism of this is not fully elucidated yet. And obviously, this requires additional validation and work. But it potentially opens the possibility of looking at using this either in conjunction with other treatments for more advanced disease than NMIBC. But it's obviously very exciting and tells you that in fact, this is an agent that seems to have activity.

Now, some of the things that are interesting about EG-70 that are different from, let's say, nadofaragene or cretostimogene or even BCG is the fact that there's actually no cold chain storage required. So this is a lyophilized drug that can sit on the countertop. It's very simple to prepare. You mix it, and then you give it into the bladder. And it can be done on an open table or benchtop.

And of course, because it's not a viral product, that has additional things that make it attractive too, because it's really quite stable and doesn't require all of the special handling that we know about and that can add wrenches in the typical clinic workflows.

The other thing is, the company doesn't necessarily recommend any post-treatment urine bleaching for the same fact that it’s not a virus. It’s not a bacteria. And so, I don’t know. I think there’s a lot of variability in how our nursing staff instruct patients on what to do after a patient gets BCG or what to do after a patient gets adstiladrin. But nevertheless, none of that is required for EG-70.

In terms of how the trial was actually put together, and in terms of what we've seen in our early results—so there’s been a phase I study on this that has shown one, it’s safe. And then this was presented at AUA last year, that in the 24 patients that got this EG-70 dose in patients who were BCG unresponsive, the response was actually relatively good, although we don’t have a lot of durability.So this is just early data that shows—any time 73% complete response rate. I always like to see the durability number longer term as being the more significant thing that we care about, obviously, because the patient is—as you know, Sam, we want to know what’s the likelihood that I need to get something else? And that, I think, is the biggest open question right now.

One other thing that I’ll share in terms of how this product works is, this is the construct of EG-70. So it’s this proprietary, dually derivatized Oligochitosan, as they call it, or DDX. And essentially what this is, is it’s a short-chain poly-D-glucosamine chitosan. And that essentially can pick up the plasmid that you’re trying to deliver.

So one of the unique things about this that I think is very exciting is obviously, the EG-70 we know about. The RIG-1 activation, the IL-12 secretion. But we’re also interested, I think, in using this platform potentially to deliver other things that may be of interest for us when we’re trying to target pathways in bladder cancer pathology.

So the actual manufacturing process is—I’m not going to say simple, but comparatively straightforward. As you can imagine, a lot of the adenoviral or viral vector projects require fairly specialized workflows and handling and procedures and so forth. But essentially, it’s a matter of mixing plasmid DNA of a drug substance of your choice. In this case, obviously, it’s the immune stimulating factors that we talked about. Mixing it with the DDX along—with PEG, and then you have this nanoparticle that then can be reconstituted with sterile water in less than a minute and then put into the bladder.

And in our experience at Emory, where we’ve been one of the larger sites that has enrolled patients in the LEGEND study as well as the phase I study, what we’ve found is that patients tolerate this quite well. So, as you know with adstiladrin, with cretostimogene, and BCG as well, there is a lot of irritative symptoms that patients have, which we can treat through, obviously with anticholinergics and so forth.

But some of that, I think, comes from the fact that in some of these cases, they’re bacteria. They’re viruses. They have detergent, for example, that’s intended to break down the GAG layer. So I think the fact that this doesn’t have that is very interesting. And universally—and I’m just sharing my own experience as an investigator. And Shreyas Joshi, actually, my partner, is the PI of the EG-70 study that’s currently ongoing at Emory. What we have found is that patients really, really tolerate this well. And that’s been obviously a huge boon for us because a lot of times, patients are kind of like, gosh, what are the side effects? What am I going to deal with?

So like I said, it’s early days, but it was exciting to be able to present some of this pre-clinical work, going into how this drug works and how it’s fared in the lab setting. So happy to take any questions. And thanks again for highlighting it.

Sam Chang: Vik, thanks so much. It was a wonderful presentation that highlights the unique mechanism of action. Kind of a combo treatment here of the innate and the adaptive. IL-12, I think, people have heard of. I don’t know if people have heard much about the retinoic acid inducible genes. The RIG-1. Do you have a little bit of historical and contextual background regarding that mechanism?

Vikram Narayan: Yeah. So it has been looked at as, as I said, part of the innate immune system. And essentially, the biggest thing that we can talk about with that is that it seems to be associated with bladder cancer signaling and progression. I don’t have the citations offhand to get into more details on that. But my understanding is that’s where the origins of looking at that as being the pathway to target for bladder cancer came from when that was picked.

So as you know, the reality of these immune pathways is that they’re very complex and they’re very variable in patients. So we like to look at things as a puzzle piece. There’s a puzzle that’s missing a piece. And let’s click something in, and it solves it. But in real life, I think as you and I know, our patients come to us, and what they have is sort of a very heterogeneous picture. And some of that has to do with even how we crudely categorize our patients.

We say they have CIS. We say they have high grade disease. But in fact, not every CIS is the same. So do we know, for instance, is RIG-1 something that’s being, for example—how much of that immune system is being promoted in each individual? It’s hard to say, and I think that’s why it’s going to be really, really important for us to look closely and continue to do some of this translational work in the real patients that are getting treated so we understand more about what actually is happening in human patients that are being [INAUDIBLE]. So that’s all part of it as well. And we don’t have that [INAUDIBLE].

Sam Chang: I think really important points. And I think unique about this, obviously, were the things you outlined towards the end of your presentation looking at the non-biologic nature, the fact it doesn’t need cold storage at all, but also the unique application of the DDX platform that could be utilized, just as you said, with other plasmids. And then being able to then present that in different ways beyond bladder cancer, et cetera, I think, which makes it really, really exciting.

As we look at the data, and you may not be as familiar with this, we’re asked now because there’s so many trials going on now with—and I know you’re an investigator. I’m an investigator. A number of different exciting agents. Obviously efficacy is important, and we’ll learn more of that as phase II data starts getting accumulated within this trial.

But also, people look at dosing and side effects, et cetera. You mentioned a little bit about the side effects. The dosing of this medication also is a little bit less intense than we have for BCG and for some of the others. Perhaps not as less intense as Adstiladrin at once in a quarter. But still, it seems like from what I can tell, as we enroll patients, it’s the week 1 and 2 and week 5 and 6 et cetera. Tell me a little bit about what you all have seen in terms of side effect profile, dosing, et cetera.

Vikram Narayan: So as you said, the thing that’s unique about this that’s a little bit different from what we’re used to—it’s not a straight induction and maintenance. Or it’s not the quarterly dosing. As you said, you can think of it on a quarterly basis given at weeks 1, 2, 5, and 6. It’s done with the catheter. It’s done intravesically. The patients have—I would say if they do have symptoms, the typical ones that we saw in the phase I were things like hematuria, urgency, dysuria. A subset of patients.

And these are mostly grade 1 and 2 issues. So there were no, for instance, grade 4 or 5 adverse events reported in the phase I. And the most common side effect or issue was hematuria and all of that. There are three cases that were all grade 1, which is not surprising given the—so it’s really what you expect.

But like I said, I think that the lack of a detergent or a biologically—I guess I shouldn’t say biologically active, but more like a virus or bacteria, likely contributes to that reduced irritability in patients. And that’s what we’ve seen. I don’t know if that’s been your experience, Sam, but—

Sam Chang: Yeah, I think so far, we’ve just enrolled a few as the phase I/II starts enrolling more with the rollout. We’ve seen great tolerance. And patients definitely do like the decreased dosing burden as well. The fact that you have this combination of a unique platform with perhaps long-term benefit—although we’ve got to see that in the data. And there might be more maintenance, et cetera.

Obviously, anytime you see that rechallenge data where tumors don’t grow where they’d grown before and you could see in the naive how the tumors grow. You look at other tumors. They grew. But in these specific bladder cancers, they didn’t grow as they were rechallenged. I think that always gives us an idea that something is going on that’s learned in some way by the immune system.

Now, we look forward, Vik, so much to—as we gather more data with these different options. Again, so many variables impact on success. But also, so many variables are going to impact on ultimate usage and patients’ desires in terms of what types of therapy. And so I look forward to your continued research, involvement in these clinical trials. And thanks again for spending some time with us here. You’ve got, I guess, one last slide here, Vik.

Vikram Narayan: Well, I appreciate that, Sam, as always. Yeah, I was just going to share the LEGEND study and how there are several cohorts. And I don’t know how you guys are faring up at Vanderbilt with BCG supply, but as you know, it remains problematic. And for example, here at Emory, we’ve recently run out of BCG as of a few weeks ago. And we’re waiting on more supply.

And one of the things that I’ll call out here is that there are cohorts in this study—there is a BCG naive cohort as well as a BCG exposed cohort. So it’s not just BCG unresponsive that’s being looked at. And I know the company also has interest in the intermediate risk space, as a lot of the companies these days are.

So just calling that out as well for folks who may be listening, who are looking potentially for an option of how to treat patients who may not—and if they don’t have easy access to BCG, one potential option is this trial, particularly if that patient has CIS. And that’s the one thing that I’ll call out. If they have papillary only disease, they wouldn’t be eligible for that cohort 2. But that’s one thing that we’re also—we’ve enrolled a number of additional patients on study because of that.

Sam Chang: And actually, a really good point, because real world, very important because of the uncertainty in many places still of BCG supply. But then, secondly, as we see these patients, we now can offer them truly options of clinical trial versus other agents. And I think, again, it’s a very exciting time for clinicians, and hopefully a very hopeful time for patients. So, Vik, I do want to thank you again for your efforts. And look forward to future presentations as we gather more data for this agent and for others as well.

Vikram Narayan: Absolutely, Sam. Thank you again for highlighting the work, and for all of your support.