All right, welcome back to the Citizens Life Science Conference, day one. My name is Sylvan Turkan. I'm a senior analyst covering precision medicines, including enGene. It is my pleasure to host enGene Therapeutics. With me are Raj Pruthi, Chief Medical Officer, and Ryan Daws, CFO. Thank you so much for joining us today. Thank you for having us. Maybe you just, can you please set the stage and highlight the opportunity in non-muscle invasive bladder cancer for us and the kind of work that you're doing there? Yes, I think it's an exciting time for the space as a whole. I mean, for a while there, or up until recently, it was BCG, BCG, BCG, and then radical cystectomy, right? That's the removal of the bladder. Now, with the advent of a number of new therapies, a couple of which have been approved and a few more on the way, like ours, there's really the opportunity for patients to live longer with their bladder as they cycle through or sequence through these therapies post-BCG treatment. I think it's an exciting time for patients. Certainly, physicians now have additional potential treatment options in the armamentarium. From an investor perspective, this is an area that's been a challenge over the years. Now, all of a sudden, there's all of these hopefully approvable products in the pipeline. We see it as kind of what happened with AML almost a decade ago, where you had chemo and then it exploded with well over a dozen approved agents. It is a $20 billion market space now. I think it is an exciting time. If you don't mind, we just came back from our national meeting, the AUA, American Urological Association meeting. And I've had the opportunity or honor to be able to take care of these kinds of patients for 25 years. This is what I did sitting across from them. At the AUA, 15-20 years ago, it's exactly what Ryan said. We talked about BCG, more BCG, more, and cystectomy. Really, the conversation is, how do we best do a cystectomy, not how do we avoid it? I think you saw with the FDA in 2018, really a great opportunity of the FDA and industry partnering to say, how do we avoid that and come up with really a roadmap and guidelines that was really a single-arm pivotal study. I think that really is a great example. I think since then, you've seen Keytruda, Adstiladrin, and Anktiva plus BCG, all new opportunities. Now you're seeing ones in development. Again, as somebody who's taking care of these patients, this is a rising tide benefits all, especially for that patient. Does, I mean, just having additional options obviously expands use here, but it's also something about the shortage of BCG sometimes that comes into play here, or do you think it's just therapeutic options? Are you asking is shortage of having an alternative to BCG? An alternative, but also like BCG supply. Yeah, that problem's not going to go away. BCG is so difficult to make. It requires very difficult conditions. They can get super infected with fungal infections. I mean, we've seen more kind of a plant. I live in the Research Triangle Park, and it's up the road from me. I haven't really seen much on that. I don't think the BCG shortage is going away. I think if we do recombinant BCG or go other paths, I think that's more options for patients with BCG refractory. I think it's a little bit of both, Sylvain. Great. Great. Yeah. And BCG is not curative, right? So these patients will need another therapy, unfortunately. Great. Maybe can you talk to us about the standard of care in the high-risk population here and how you're planning on slotting in there or shifting it? I think it's a little bit like we said, the standard of care now is BCG, multiple rounds of BCG, and then potentially cystectomy. Now these new agents that we talked about. I think what we see with enGene and Detalimogene is the opportunity to slot in there, especially if you have an alternative that is patient-centric, friendly, with ease of use, that you can avoid cystectomy or even delay cystectomy. Remember, these patients are in their seventies when they're diagnosed. They have comorbidity. I think delay of cystectomy, and the FDA has even recognized this, is a worthy goal. Yeah. So there's a few, obviously, you hinted at that, a few therapies in development, some late stage, some earlier stage. What is Detalimogene and what makes it different than some of these assets that are in development? I'll touch a little bit on the science. It's important, a non-viral gene therapy. It's a gene therapy, but it's non-viral, which has benefits from cost of goods to handling to ease of use, a variety of different. What it does is it packages a DNA payload in a plasmid that targets mucosal cells, in this case, particular, the bladder urothelium. It's delivered intravesically. It's not a systemic agent and has a synergistic effect, anti-tumor effect, targeting both the innate and adaptive immune system, the innate immune system through targeting RIG-I and the adaptive through targeting IL-12. I think many of us know IL-12 is a potent anti-cancer therapy whose limitations are delivering it systemically and the systemic toxicity. Now we have an opportunity to actually deliver this locally. Great. Can you walk us through some of the initial data that we've seen with the Detalimogene that was released by you in September last year? Yes, at a high level. Last September, we provided a look into our pivotal cohort, so about 20% or 21 patients, very exciting CRNE, so 71%. Nearly three quarters of the patients in that look-in benefited from therapy with 67% at three months. A Kaplan-Meier estimate of about 51% or so at six months. I think we were excited by it because if you're a physician and you're trying to figure out where do I go next, what we offer is a product where their patients have a high likelihood of benefiting and some level of durability beyond that. What we've guided to is an update in the second half of this year. We'll do another look-in. We've made some protocol revisions to look at perhaps increasing that six-month CR rate to put it on par with CG Oncology's product and TAR-200. We're excited to see those kind of play out. We'll have an update in the second half of this year and then top-line data in the middle of next year. Great. Maybe can you just put the CR rates kind of like in perspective with the small patient numbers? Obviously, you hinted at some protocol changes. Where are you with respect to some of these other assets that are currently in clinical development? How important is the CR rate by itself versus the duration of CR rate at 12 months or longer? What are the important milestones here? Yeah, so maybe I'll put it in context and then Raj can kind of add on to it. I think from a CRNE, so are you likely to benefit as a patient, likely to benefit? It's on par with CG Oncology's product, which I think is 75% or right around there, and TAR-200, which is in the low 80%. I think from a physician's perspective, they're roughly comparable. I think where you start to see a little bit of differentiation from a CG or TAR-200 is at the six-month time point. I believe they're in the 60% and we're in right around 50%. There's a gap that we're trying to close. I will say that one of the things that when we talked about that first look-in of the data last September that we noticed is we had an overabundance of T1 patients. T1 patients, it's a form of papillary that's very difficult to treat. If you were to normalize for that, I think CG had six patients out of 110, we had three out of 21. If you normalize for that, we'd have had a Kaplan-Meier estimate in the high 50s, like 58%. I think one of the protocol amendments that we have instituted is really about aligning our trial with AUA guideline standard of care. That will essentially require that T1 patients coming onto the study are best positioned to benefit from the therapy. We think that piece alone will go a long way to closing that gap. We've got some other changes that we can talk about as well. We feel pretty comfortable that in the second half of this year when we do an update, we will be closing or have closed that gap. Yeah, I think Ryan, your point is, and it's something I saw as a urological oncologist coming in and seeing some of these things like resecting T1 tumors, which is I have the fortune to be part of the AUA guidelines, is something that we know we do in and of itself has therapeutic value and can increase your response rates fourfold. Doing that, we know is only going to improve that. Reinduction protocols, I think, which we now employ, because I've heard from investigators, the patient's doing real well. They have a little small tumor. Can I just snip it out and continue therapy? Others have. We hadn't until this point. I think we are now giving patients a lot of opportunities to have responses and stay on therapies. Yeah. Great. Obviously, some of your peers have gone through some of these transitions. You can see there's certainly a positive impact from these protocol changes, at least for them. Can you just walk us through some of the other important characteristics outside of the pure efficacy numbers that we've walked through that you can already observe in your trial? I'm thinking about preparation, storage, handling, all these kind of things that you already use in your clinical trial. I'm going to have you start with that and I'll. Yeah. I think one of the big benefits of our product is it was purpose-built for the community urologist office, right? There's no special handling. It's treated like BCG. It's a lyophilized powder. It's reconstituted in water. It's instilled directly in the patient, as Dr. Pruthi mentioned, via balloon catheter into the bladder. It has a dwell time of about an hour. They void and you leave. You don't have any of the usual like if you take BCG, you have urine bleaching requirements for 48 hours following treatment. You're asked to avoid contact with immunocompromised loved ones, right? These are elderly patients. They tend to have grandkids. They're thinking about, "Okay, well, I've got to go to the beach with my grandkids. I'm going to skip this appointment," right? We don't have any of those liabilities. Our viral competitors all have those as well, or we believe they will. We do not have cold chain storage. So within the facility, Detalimogene will sit in its bottle in their freezer for months, if not longer. We think it is just going to be easy to stock and have it sitting there waiting for them off the shelf. Cost of goods significantly lower than I believe our viral competitors. I think there are plenty of opportunities for us to think about how we can differentiate commercially in that regard. An important component of this is unlike, say, TAR-200, there is no doctor involvement, right? They see the patient. The conversation we imagine goes something like, "Bill, I am sorry, your cancer has returned. We can start you on Detalimogene today. You will be out of here in an hour. My nurse can get that started for you right now. Alternatively, we've got a couple of other therapeutic options, some of which will require trying to schedule a delivery of the vial just in time. We have to schedule that, and then we have to work on a six-week cycle. The other one is a medical instrument. I don't have time to do that today. I think with our, again, where it comes to our CRNE being so important, something where they have confidence that this gets them started, gives them a chance to benefit, see how durable the response is, and then in a thoughtful way kind of transition to other therapies down the line. There's no downside. I think we're seeing as people, as physicians experiment with different therapies, we're seeing some approved therapies coming into our study, and patients seem to respond well to them. Because you've used one therapy doesn't mean you'll not respond to another. I think that urgency is not there. I think one last thing about the space, which we probably should have touched on earlier, this is a space where 80% of patients will be muscle invasive bladder cancer free 10 years out, right? It's a 20%, said differently, it's a 20% risk of progression. This is a slow progressing disease and gives physicians an opportunity to cycle through. I think broadly, most physicians imagine a sequencing of four to five therapies before looking at radical cystectomy. If you don't mind, Sylvan, I could add on to that. I think when we talk about things like ease of use, to me, there's two constituents. One is the patient's ease of use, and the other is the practice, right? The patient's ease of use, and I think for me as a physician, that's the true north. When you now in medical schools, what students are taught is the first thing you ask when you walk in that room is, "What are your goals of therapy? What is it?" That's the conversation that's happening in that room. It might be CR, but it might also be, "I can't come here whatever number of times a week. I'm 73. I need my daughter, my granddaughter to drive me. How do I feel with this? Is it caustic? Can I tolerate it? Can I hold 100 ccs? I mean, there's a lot to this, right, that I think we have to be thinking of the patient and how they do. We have something to go back to CRs that has 100% CR. We've had it for a long time, and that's a cystectomy. We've made deliberate choices in our field to say, "We'll go down to these other competitors that are approved 20% or 30% because that's too much of a cost to me to have." I think for patients, that's an important thing and a trade-off that's made in the room. What are your goals? The other is, I think for the practice. For practice, I think Ryan mentioned it, 70-80% of these patients, I practice in academic centers, but are treated in the community. For that practice, they have to ask, "Does this change my practice? Do I have to buy a minus 80 freezer? Do I have to change the way my nurses and MAs handle it? Is it viral? Is it not? Do I need to book the cystoscopy room for procedural things?" These are things within the practice, not to mention even things like buy and bill and cost with it. I think that's where I think we probably thread a nice needle in being able to be able to say, as Ryan mentioned, if you walked in, Sylvan today, God forbid, and I said, "Sorry, your BCG didn't work. You got an hour." My MA can deliver that. I can actually leave and go into the next room and do a vasectomy or whatever do. You're thinking of efficiency of what you're doing and your opportunity cost, come back at the end and say, "I'll see you next week." Yeah. At AUA, we saw some of your competitors like CG Oncology, for example, trying to remove wash steps and doing just-in-time delivery and things like that. Did you think roughly maybe can you lay out back on the envelope, how much shorter is the, let's say, the time for the patient in the clinic versus your competitors? Is there any way that viral therapies could come on par with you or do you think that's just not because you're non-viral that you just have the advantage there? I think what you're seeing CG do is react to our talking points, right? They've tried just-in-time delivery to avoid the minus 80. They're now trying to take out bladder wash. These are important patient burdens, right? The time in the clinic is important both for the physician, right? The more rapidly a patient is out, the more they can do. I think what you're seeing is just that reaction. I think they're always going to be limited by the fact that it's a virus, right? It's an attenuating virus, so it can be a replicating virus, sorry. There is going to be some concern about it. I think those kind of hurdles are going to be things that are going to be part and parcel of that product and sort of how they handle it, whether they need, for example, a day where CG's product is administered and then they terminally decontaminate the room. These are things they're going to have to think through. We don't have those liabilities, so. Great. Have you done any physician surveys or what kind of type of work have you done to kind of corroborate the data that you have in-house or that you think your non-efficacy competitive advantages are? Have you presented them before? I can maybe address that a little bit. I think objectively, data-wise, Ryan shared in September in our early peak, we had no grade three, four, or five adverse events, zero, and no treatment-related discontinuations. That is data. That is well tolerated. I'll get into more subjective feedback that we've gotten, but that is kind of objectively from some of the—I previously worked at J&J, and I always hate to misspeak of sort of my former employer, but if you look at the data they presented at the AUA, they have an 80-plus% AENE, 15% grade three or higher. I do not know how many of those are fours and fives, which are hospitalization and death. So 15%. One of the cohort four had an 8% treatment discontinuation rate, which to me seems high for a clinical study, right? This is a clinical study where everyone is super motivated to keep that patient on study. That patient's worried about having their bladder removed. That's, I think, the objective data. Subjectively, we got back and interacted with our investigators, our KOLs, and we hear things. Again, this is more kind of soft points, but that these are patients heavily pretreated. Their bladders are really beaten up that it's like giving saline. It's like giving water. They tolerate it very, very well. It's not caustic. We've heard some of that ease of use even from academicians who sometimes are more sheltered from that. Great. Maybe thinking ahead a little bit about your expectations for the next interim release, right? So we got a little taste of your efficacy before. What kind of are you like, when are we getting it, if you can remind us, and what are you kind of guiding to? Yeah. So what we've said is that we'll provide a look in the second half. We haven't given any more granularity to that timeframe. I think Ron Cooper, our CEO, is very focused on making sure that investors see they learn something from this look-in. It's not going to be a small number of patients. The number of patients will obviously depend on kind of where they are, how many are at a certain point in time. The longer we wait into the year, the more patients we'll have. What I'd say is stay tuned. We'll provide an update down the road as I think to timing. I think what we're looking hopefully to see is that these protocol revisions have closed, if not eliminated, the gap with our competitors. If not, I think we'll reaffirm what we've shown already, and that will hopefully bring together some of the commercial work that we're doing as well to kind of demonstrate that the product attributes are very compelling for physicians and patients. There's a lot to see, a lot to look in. We're excited about the second half of this year and ultimately top-line data in the middle of next year. You're trying to basically on the efficacy front kind of go on par with some of the other leading investigations therapy, and then you have the other host of benefits that come with it. Yes, that's correct. I think just to reiterate the point, if you normalize our first look-in for those T1 patients that were not treated according to standard of care, we are at the upper 50s, right, at 58%. It is not a big gap. We think it is one that the protocol revisions that we made, as Dr. Pruthi mentioned, I think are really going to go a long way toward closing that gap. We are very optimistic that we will be in a good spot. The six-month CR rate, is that kind of what we should focus on? Yes, exactly. That comes up a bit. Great. Maybe talking about obviously your interactions with regulators, it's non-viral gene therapy, but what are kind of the next steps engaging with the regulators about moving this forward? What are your thoughts on the recent moves here at CBER and personnel decisions? Yeah. We interact with the agency all the time. So far, to your latter part of that question, so far we haven't seen any changes. Obviously, the head of CBER that they appointed yesterday, I'm blanking on his name, has made some statements in the past that you could read on an open-label single-arm study like what we're conducting. By and large, we haven't seen a change in posture at the agency. Most recent interactions have been on time. We're comfortable right now that we're in a good spot. Yeah. So I guess we can maybe read across what happens to CG Oncology's program. Yeah, they'll be there first, right? Okay. Great. Maybe looking ahead, you're currently enrolling additional cohorts in the Legend study. Can you maybe tell us about those cohorts and the importance of these? Yeah, I can talk about that. We have, if I may, Sylvan, I want to just for those in the room who are not as familiar with this space, and I think Ryan touched on this idea that these patients are going to be sequenced. That is the future. That is sort of the present and is the future. They probably will get four or five treatments. That is okay, right? Recurrence is not a bad thing as long as you do not progress. Again, 20% risk of progression at 10 years. We used to think the number was higher, and we kind of rushed them to cystectomy to be very honest, but it is not. As long as they do not progress, you have time to layer in multiple treatments, and there is nothing wrong with that. We have seen it. We have done it. Ryan mentioned we've seen patients in our studies that have seen approved agents Adstiladrin, Keytruda, and even other trials, CG, TAR-200, and so forth, and gemcitabine and so forth. I think this is going to be that. You're going to sequence three, four, five. I think the question will be, how do you sequence those? Will it be molecularly driven? I think what we may have a competitive advantage is that ease of use because I can start you today in something that's easy that gets you only one, two, five, and six. I think that might be it knowing that in all likelihood, I mean, hopefully you won't need a cystectomy, but you'll go on to other therapies. I did not mean to kind of take us down, but I think that is an important and actually the conversation you and I might have up here in two years is combination therapy. That will probably be the future. Anyway, to get back to your real question, which was the other cohorts. We have some other cohorts that include BCG naive, BCG exposed, and papillary only. BCG naive to me is very intellectually kind of appealing or compelling. Can you replace BCG, right? That is something that you addressed earlier with shortages and toxicity and so forth. It is exciting. It is interesting. The FDA also wanted to see that. We will get some signal on that, like where are we in these BCG naive patients? There still are locations, metro locations, Los Angeles, Philadelphia, where they have not seen BCG in years. It's a funny, the distribution of it's interesting thing. BCG exposed means you've gotten some, but maybe not the FDA's definition of what unresponsive is. That becomes blurry when in the community doctor, if you say, and it might be due to tolerability, just couldn't tolerate it. We'll get some information there. Papillary only is you don't have CIS. It's just a papillary tumor. We've seen other competitors or drugs actually get NCCN recognition for studies with less than 50 patients. We think that's an opportunity. Okay, great. Yeah, I think what's interesting here is that we're moving towards, and I think it's our last question here as we wrap up. It's like a semi-chronic setting here, and it makes sense to cycle through several options here before removing the bladder, which is probably very detrimental to the quality of life of patients. How do we measure benefit beyond just delay? Is there also maybe an opportunity on, let's say, on the price point because your cost is significantly cheaper? Is there an opportunity to maybe price cheaper or at least the whole cost with the provider and the time in hospital and steps like that to provide a product that's significantly cheaper? I'm going to let our Chief Financial Officer answer that, but I think you're right about issues, again, related to sequence that's going to become more of a prevalent population, right? It's not like pancreatic cancer or advanced lung cancer. We got one shot and you're done. I think we're going to see these patients that are going to continue to be out there. Yeah, I think it's far too early to speculate on price, but we certainly have that axis of competition. I think where it also could be important is in combination. As Dr. Pruthi mentioned, if the field goes that way, and we're certain it will, it's really tough to imagine Anktiva combining with anybody, right, at $500,000 a year. I think this provides us lots of flexibility to look for the most compelling combination partners and bring a combo product that still provides meaningful benefit to patients as well as lessens the financial toxicity that could potentially come with it. Great. Thank you so much for joining us today. Thank you. Yeah, hope you have a good day. Thanks for having us. Thanks. Thank you. Thanks so much.