Good morning and welcome to the Citizens JMP Virtual Hematology and Oncology Summit. My name is Silvan Türkcan, and I'm a senior analyst covering precision medicine. If you have any questions during today's Q&A, please email me at sylvan.turkcan@jmpsecurities.com. And now it's my pleasure to host Alex Nichols, President and COO of enGene. Thank you so much for joining us today. My pleasure. Happy to be here. Thank you. Great. Maybe we start off with some people who are unaware of your company and what you do. Can you please provide an overview of enGene and the lead asset, the detalimogene voraplasmid? Absolutely. Before I do, just a quick reminder that this conversation may contain some forward-looking statements, and you should not place undue reliance on those statements in making investment decisions. So enGene went public around 13 months ago. We're now a pre-commercial stage company with a unique and powerful platform for non-viral gene therapy, which we've developed in-house. And the crown jewel of this platform is our lead asset, detalimogene voraplasmid, which we're developing in a disease called high-risk non-muscle invasive bladder cancer, or NMIBC. And I'm hugely excited about this product and the opportunity for three reasons. The first is that the opportunity itself is massive. There's a big unmet need, and the market is going to explode. By some estimates, the overall opportunity size here will be north of $20 billion by 2040. So a really meaningful opportunity and an opportunity for patients as well. Second, we have a highly differentiated lead product. We have promising efficacy that we've observed from our data so far, potentially best-in-class safety, and importantly, we have a product profile that makes this extraordinarily easy to use for both physicians and extraordinarily easy to experience for the patients, and third, we're poised for market-inflecting growth in the near future. We have a BLA filing that we're guiding towards in mid-2026, so lots of reasons why we're really excited at this time at enGene and for the opportunity overall. All right. Thank you so much. And I think you kind of alluded to it, the opportunity and how things are changing in this NMIBC bladder cancer setting here. Could you just set the stage for us and highlight maybe the opportunity and how that may differ from some of these oncology therapies that we typically focus on, which are late-line metastatic? How this is different? Absolutely, so to start, bladder cancer, it's not widely appreciated, but it's a top 10 cancer in terms of incidence, and it's also among the most expensive cancers to treat on a per-patient basis, so there's a major healthcare economic impact here, but even if you put aside the incidence for a second, the prevalence burden of this disease is massive. By some estimates, around 730,000 patients per year are living with NMIBC in the United States, and the goal of care in this disease is, first off, to forestall the development of muscle-invasive disease, which generally has a worse prognosis and is more difficult to treat and can become metastatic, and then give patients more time before they have to have their bladder removed. We'll talk more about this later, but bladder removal is unfortunately still a mainstay of care for this indication. The goal of care at this stage in the non-muscle-invasive stage is to allow patients to have their bladder for longer. Importantly, this is a disease that's urologist-treated. It's not oncologist-treated, even though it is a cancer. Most urologists practice in a community setting and not an academic or major hospital setting. We know this from AUA data that they put out every year. So if you really want to develop a thoughtful product that will meet their needs, it has to be one that's suited for use in those community settings. Great. And so what is the standard of care for this population? Absolutely, so a typical patient will present to their urologist with hematuria, and their bladder will be examined by a cystoscope. It'll be biopsied, and if they're diagnosed with high-risk disease, the standard of care for the initial occurrence of this disease is a live-attenuated bacterium called BCG. It's actually the oldest form of immunotherapy, and it's been around for around 80 years. Now, BCG works very well, but it has two major problems. The first of those problems is that it can be difficult to get. It exists in a chronic state of global shortage that shows no signs of near-term resolution, so not all patients are getting it, and if patients are getting it, they're sometimes getting incomplete doses. The other problem is that, unfortunately, many patients will recur after they've been treated successfully with BCG, and that recurrence rate can be north of 50% within two years. That's what a patient first diagnosed with high-risk NMIBC is going to be receiving. After that, things can get a little bit murkier. The standard of care for recurrent BCG is unfortunately still radical cystectomy. This is complete removal of the bladder. In women, it involves a hysterectomy as well, and many can often involve a prostatectomy. As you can imagine, this is a life-altering surgery that leaves patients with a very different quality of life thereafter and has major complications and morbidity as well. The goal of care at this stage for patients is to push back that surgery as long as possible. Right now, there are three approved products for use in this context. Each of them has their own limitations. None of them have a product profile like detalimogene voraplasmid, but I'm going to take you through them. The first is Keytruda. Everyone's familiar with Keytruda. It's a systemic agent, but it's also systemic immunotherapy and has a systemic immunotherapy AE profile, which is something that your typical urologist doesn't want to have to manage. The second approved product is Adstiladrin. So this is a viral gene therapy. Viral gene therapies can be a little bit more difficult to work with, have a little more complex requirements in terms of handling and thawing and the operational aspect of giving that drug. And the third is Anktiva, which is a biologic that's administered in combination with BCG, which, as I mentioned, is in chronic short supply. So there's some challenges, I think, for all of these agents. But then importantly, 80% of patients who are diagnosed with NMIBC will be muscle-invasive bladder cancer free 10 years out. So we're looking at an opportunity to cycle through multiple treatment options before radical cystectomy occurs. And that really is the genesis of this growth opportunity within this indication, the opportunity to treat patients with multiple different agents. So I think we like to view this as a complementary evolving field where patients will have the benefit of having multiple therapies and moving between them. And we're positioning detalimogene voraplasmid to be one of the first therapies that physicians reach for. Great. So just maybe to summarize, so as you mentioned, the space is kind of like ripe for innovation, and there's a significant growth opportunity. So is that driven by these newer agents that will come online now and potentially in the future that will just keep patients on therapeutics versus surgery for a longer time that greatly expands this patient pool here? I think that's exactly right. The rate of progression is slower to NMIBC relative to other cancers. So patients, even if they have a recurrence, but they haven't progressed, they're eligible for potentially another round of treatment. And so that's the opportunity here. It's looking more like a prevalence-based indication as opposed to an incidence-based indication in terms of the treatment paradigm and the way they're going to be sequenced through therapies. Great. Thank you. And then maybe just shifting gears a little bit to your program, detalimogene voraplasmid. You're initially studying it in BCG unresponsive non-muscle-invasive bladder cancer with CIS. Could you just specifically walk us through that setting? What is with CIS and how is that managed specifically? Sure. CIS stands for carcinoma in situ. When a patient is diagnosed with high-risk disease, it basically can fall into one of two or three categories. You can have CIS disease, which is a flat sessile lesion, or you can have papillary disease, or you can have a combination of the two. But if you have CIS, it's generally considered to be a more difficult disease to treat. It can't be simply cut out like papillary disease can. That's where you find the greater unmet need. And that's why FDA, for example, has put out a guidance for industry in 2018, which they reaffirmed this year, that has created accelerated development opportunities for BCG unresponsive patients with CIS that allows for single-arm open-label studies, sometimes around 100 patients or so, to facilitate approval of new products in this field and to meet the unmet need for patients. That's a great example of regulators and industry working together to solve these problems. Great. Yeah. Since we're talking about the guidance, can you talk a little bit about the trials and maybe at a high level where you see this product going? So you said in BCG unresponsive CIS, you can have uncontrolled single-arm trials here. But in these kind of neighboring settings without CIS or papillary, what are your plans and what is the guidance here kind of to filing? Absolutely, so as you mentioned, the LEGEND study is the study in which we're studying detalimogene voraplasmid. The pivotal arm of the LEGEND study is for high-risk BCG unresponsive patients with carcinoma in situ. We also have other arms of the study, so a cohort two of this study is examining detalimogene voraplasmid in patients with BCG naive disease as well as BCG exposed disease, and these are patients who've had some BCG, but maybe not a complete course, so they don't qualify for this FDA guidance. We're also studying detalimogene voraplasmid in patients with papillary-only disease, so now this is the non-CIS version of high-risk BCG unresponsive disease, where it's given in more of an adjuvant context to a surgical removal of the papillary lesion. These cohorts are really important for us because we're generating data that will sort of span the arc, the continuum, if you will, of the real-world paradigms of NMIBC, what these real patients are diagnosed with, how the disease presents. By generating, we're hoping we'll give physicians the opportunity to make an informed decision about how this potential product could be helpful in treating those patients. Great. So talking about the LEGEND study, you've made some headway here and presented data. Could you just walk us through that data that was released in September? Absolutely. I'd be excited to talk about that. So to set the table, this is an open-label study where we've been conducting it generally in accordance with the FDA guidance. And the data I'm going to be talking about corresponds to the pivotal BCG unresponsive high-risk NMIBC with CIS category. So that's sort of the one that falls directly under the FDA guidance. And we released some preliminary data from this cohort in September. And we released data from 21 evaluable patients at three months and 17 patients at six months. So this is three months and six months since they've come on therapy. And we're delighted to see that we saw a 71% complete response rate at any time across all of these cohorts, which is a preliminary number, but we're absolutely thrilled about where it sits in the mix of approved and agents in development for these patients. When we look at three months, we saw a complete response rate of 67%. That was 47% when we went out to six months. For those of you who are more comfortable thinking through the lens of a Kaplan-Meier estimate, it corresponds to around 51%. We also had a glimpse of our safety. It continues to be generally favorable. In fact, as I mentioned earlier, it continues to trend generally best in class. 47% of our patients had a treatment-related adverse event, but they were all grade one or grade two, which is generally consistent with the mode of administration here. This is an intravesical agent, so it's instilled directly into the bladder via a catheter. That procedure alone tends to produce a series of low-level adverse events, which kind of fall under this grade one, grade two categorization. The other thing which I'll mention here that we announced in tandem with this data is that we'll be making several updates to our protocols, our clinical protocol for LEGEND, to better align with current standards of care and to give patients the potential to remain on the study longer and potentially benefit from detalimogene voraplasmid treatment on an ongoing basis. These protocol changes generally fall into kind of three categories. It's the way we treat patients prior to enrollment, where we treat patients at three months, and then again at six months. I'll talk through them sequentially. The first one, as I mentioned, takes place during screening. There's three different kinds of this disease that fall under this category. You have carcinoma in situ. You can have carcinoma in situ with papillary disease, so that's with Ta or T1 lesions. T1 lesions are considered to be the most aggressive, and there's a lot of data behind this, so they're the most ominous. Right now, if a patient has a T1 lesion at enrollment under our old protocol, that patient would be resected one time and would be allowed to enroll in the study. What we've come to appreciate is that there's tremendous benefits to actually having those patients undergo a secondary re-resection. And there's great data behind this as well. It's therapeutic for the patients, so they do better longitudinally. And we're going to be incorporating this into our protocol moving forward. So we're going to mandate that patients who have T1 disease undergo resection followed by a re-resection. And we have to ensure the physicians have to ensure that T1 disease is no longer present for them to continue with enrollment in the study. So that's going to give patients a better shot out of the gate. We're really excited about that protocol change. The second change takes place at three months. So under our former LEGEND protocol, a patient with Ta disease, so this is sort of a papillary lesion. Again, it's co-occurring with CIS. This would have previously been considered progressive disease. What we're allowing now is we're requiring physicians to resect that disease at three months so those patients can be re-induced with detalimogene voraplasmid and again continue to stay on treatment. So increasing the pathways through which a patient can continue on study. And the last of these is just tightening up the requirements for discontinuation at six months. Right now, under this revised protocol, if a patient is suspected of having carcinoma in situ at six months, they have to undergo a biopsy to confirm the presence of disease. This is because detalimogene voraplasmid is an immunotherapy. Even when it works, it can create some residual redness and inflammation in the bladder. Under our previous protocol, a physician could have conceivably looked at that and said, "This looks like disease now that needs to be confirmed by a biopsy." So we're really confident and we're hopeful that all these changes should help patients and also help the numbers going forward for our study. That's the reason we'd be excited here. Great. And obviously, that may or may not have an impact on the durability that you measure, obviously, with these changes. And we've looked across active clinical trials right now, and we've seen that a lot of these changes that you implemented are kind of like harmonizing your trial with what is out there, for example, by CG Oncology or others. Can you just quickly talk about why that was not initially implemented, or was it just to drive or get the trial off running and get people in there fast, and now you're harmonizing, or why is this happening? Yeah. I think when we started LEGEND, it was really a phase one first-in-human oncology study. Now it is a pivotal registration-enabling urology study. We have a urologist who's come on board as our chief medical officer. And I think we've just shifted the priorities towards making sure that now, as a registrational study, we understand what our competitors are doing. We understand how they're treating their patients. We want to make sure that we're giving patients similar opportunities and working to create more of an equal footing in terms of data comparison. Great. And then you mentioned the data that you've generated to date, which is pretty impressive. Could you just put that in context maybe with the FDA-approved options that you've mentioned previously and maybe also in context of some of these agents, next-generation viral gene therapies that may be upcoming on the horizon here and how that maybe leads to positioning just in terms of efficacy and safety, right? We can talk about some of the other parameters later. Sure. Right now, as I mentioned previously, Keytruda, Adstiladrin, and the Anktiva BCG combo are the only approved therapies for use in the BCG unresponsive with CIS category of high-risk disease. And generally, they saw lower CR or complete response rates at any time across the board. And they were 41%, 51%, and 62%, respectively. For the LEGEND study, our primary endpoint is the landmark complete response rate at 12 months. We haven't yet reported any data at 12 months. But again, if we look to what we know, the facts that are out there, these approved products saw a complete response rate of 19% for Keytruda, 24% for Adstiladrin, and 45% for the Anktiva BCG combo. So again, based on this initial data set, we feel very comfortable that we will fall above the bar for approval. As I mentioned, we anticipate that these protocol amendments will help bolster that and continue with the trajectory and the data that we're hoping for. In terms of tolerability and safety, as I mentioned, we continue to track best in class. We had no discontinuations due to treatment-related adverse events. In fact, we've had several of our investigators anecdotally compare giving detalimogene voraplasmid to giving saline, which is about the most benign thing you can administer to the bladder. I think this stands in contrast to some of the other agents out there, for example, TAR-200, which can be very irritating to the bladder, can be difficult for patients to tolerate. It's a foreign body that effectively just sits in your bladder all the time during the course of treatment. And they saw, for example, a six% discontinuation rate in treatment with TAR-200, which is quite high considering that these are motivated patients. They want to keep their bladders. There's nothing else available. And so they're basically looking at a surgery down the road. So for somebody to come off study and pursue that, I think that does speak to what the real-world profile is like for an indwelling device or something like TAR-200. Great. Yeah, maybe shifting gears from that to some of these other important characteristics outside of safety and efficacy that I think you already focused on for differentiation of detalimogene voraplasmid. Can you just address those and what we have to date that can incorporate your positioning here? Absolutely, and I know we're tight on time, so I'll be quick here. The physicians are the end users here and patients as well, so we wanted to create a product that's optimal for both of them. When you look at physicians practicing in these urology clinics, they value efficiency. They want what's best for their patients, but they also want to keep logistics as simple as possible and share time to a minimum, and the patients are in their mid-70s or older, and we believe that they'll really value the ease of experience and the experience that they have to go through in getting this drug instilled multiple times, and so we feel detalimogene voraplasmid is really well positioned to meet both of these criteria. From the physician perspective, you can store it in a refrigerator, not a deep freeze storage. It can be reconstituted in simple water on an open benchtop. It has no special handling. You don't have to decontaminate your patients or segregate them, and it has a shorter dwell time than BCG, which is two hours. We have a one-hour dwell time, which is how long the drug has to sit in the bladder once it's there. From the patient perspective, it's also easy to receive this treatment. As I mentioned, we've had fewer treatment-related adverse events so far, and so we're really excited about the generally favorable tolerability profile we've observed. We think patients are going to be able to get in and out of the office more quickly and just generally have fewer hoops to jump through when being given this agent, so we think ultimately this is going to be really impactful. Great. And can you talk maybe we've looked at the schedule, hypothetical schedule, a patient would come in in terms of frequency, right, with some of these agents coming out. How would you rank the detalimogene voraplasmid here, like were it to be approved within, let's say, six months or 12 months of treatment, how often you would have to come and how that compares to some of these other agents? Right. So the standard of care that's been established through BCG is one of induction and maintenance. When patients are coming in, they have a heavy treatment burden. They're basically dosed weekly. And we know that that is burdensome for patients. Some of these patients may be getting rides to the hospital. If they're going to an academic medical center, for example, they have to park, go in, they might have someone wait for them. So detalimogene voraplasmid has a four-time dosing frequency. So we're shaving some frequency off of that. And that's the same if you're being re-induced at three months. It's the same if you're in sustained remission down the road. So it's predictable, straightforward, and reduced in frequency compared to the induction burden of BCG. Great. And then what kind of data have you to corroborate the positioning that you have, right? You thought you brought a new medical officer on who is a urologist himself. But have you done some surveys either of patients or physicians that kind of tease out some of those details that you would have a real benefit here? We've focused both in the planning and development of detalimogene voraplasmid, and now it's later stage clinical development on really meeting the needs of community urologists. We've had multiple ongoing discussions with community urologists. They're part of our steering committees and advisory committees. They've all told us how excited they are to be getting access to detalimogene voraplasmid and to ultimately have access to detalimogene voraplasmid if it's approved. We're looking to be elevating their voices and making sure that they're represented in the materials that we put forward and the way we describe detalimogene voraplasmid and the opportunities and benefits of detalimogene voraplasmid in daily practice and in clinical care. Great. Thank you. And looking forward on the next data sets that are coming here, what are your expectations for the next interim for detalimogene voraplasmid and what have you guided to? So we haven't provided an exact update time, but we've said we'll be updating sometime in 2025. But beyond that, we haven't added more granularity at this point. Great. But in terms of maybe the efficacy data point, if you remain in line with what you've produced to date, you think that you will be happy with that? Is that what we're looking for? Should we look for an improvement over time? Well, I think we have an approvable product from where we sit today, which is a great position to be. And again, based on past regulatory precedent. And I think with the protocol changes that we've implemented, we feel confident that these numbers will continue to go up. I mean, in terms of what physicians look for, it roughly falls into two categories. There's the complete response rate at any time. 71% is a great place to be right there. And then there's durability, right? And as we've discussed, FDA has set the bar for what that 12-month response rate looks like. We're in the high teens and the 20s. And again, we feel pretty confident from where we are in the protocol changes we're implementing that these numbers can be viewed as kind of a floor. Great, and then also looking ahead, obviously, you're currently enrolling additional cohorts in the LEGEND study, cohorts 2A and B and 3. So those are BCG naive, exposed, and unresponsive with papillary only. Can you just describe the opportunities in each of those and why you're adding these cohorts? Absolutely. So simply put, these cohorts were designed to generate data across the spectrum of clinical contexts in which high-risk NMIBC will be treated. Cohort 2, as I mentioned before, this captures patients that have had different BCG exposure statuses, so naive patients who either haven't had BCG in a very long time or have never had BCG, and then exposed, which is those who've had some, but not enough to be technically deemed unresponsive in accordance with FDA guidance. Cohort number 3 is BCG unresponsive patients with papillary-only disease. So these are patients who don't have CIS, which again can co-occur with papillary disease or can occur separately. And there's quite a lot of these patients out there, right? This is the other kind of high-risk disease that occurs. So again, the goal here is to be generating data in these patients that will ultimately add to the body of understanding of detalimogene voraplasmid and how it performs across diverse patient groups with NMIBC. Great. Thanks. And what's the progress here? I think the guidance was to get them off the ground running by the end of the year, or have you started enrolling already? We haven't issued guidance here yet, but you should keep your eye out for an update from us later this year. I think we're very happy with where things stand today. Great. Thank you, Alex. Thank you so much for joining us today. It was a great discussion. Yeah, thanks again. Thank you very much.