Great. Good morning, everyone, or good afternoon, depending where you may be. Welcome back to another session here at Oppenheimer's 35th Annual Healthcare Life Sciences Conference. I'm Leland Gershell, one of the biotech analysts here on the research team, and delighted to have with us as our next company, enGene. enGene is a company that is working in the area of non-muscle invasive bladder cancer and NMIBC.
It's become a very dynamic area among investor investment interest, and we've been covering enGene now for almost a year and have an outperform rating. We like the story very much for its differentiation. From enGene, we have Alex Nichols, Chief Strategy Officer, as well as Ryan Daws, who's the CFO. With that, I'll turn the mic over to Alex for the presentation. Thank you.
Thank you, Leland. I would like to start by thanking you and Oppenheimer for the invitation to present today. We are very happy to be here and tell our story. Oops. Before I begin, as a reminder, this presentation may contain forward-looking statements. You should not place undue reliance in those statements in making an investment decision. I am here because I am excited to share our work in advancing non-viral genetic medicines to the forefront of care for patients suffering from urological tumors. At enGene, our crown jewel in this effort is detalimogene voraplasmid, which is a unique and powerful non-viral genetic medicine for patients with non-muscle invasive bladder cancer, or NMIBC for short. We are excited about this opportunity chiefly for three reasons. The first is because we are entering a market that is poised for explosive growth.
We're witnessing a paradigm shift in the care for these patients from a surgical paradigm towards a medical or intravesical paradigm, and that comes with a very large increase in projected market size by some measures upwards of $20 billion. This translates into an exciting near-term commercial opportunity for enGene. We have multiple exciting milestones coming up on the horizon with an update from our pivotal cohort in the second half of 2025, along with updates on cohorts two and three as well. We're guiding towards a BLA filing mid-2026 towards a potential launch in 2027. Of course, underpinning all of this is detalimogene, which is a highly differentiated investigational product. That's an actual picture of it there on the right.
You can see it's a very simple lyophilized powder, and it brings to our clinicians a unique combination of activity, tolerability, and really differentiated ease of use. It was designed for use in any urology clinic across the country, and we will talk more about that as well. We have the capital to execute on this plan with runway projected into 2027. Now, for those of you who may be less familiar with NMIBC, let me just take a quick step back at bladder cancer overall. Bladder cancer roughly falls into two or three buckets. There is non-invasive bladder cancer, which is what we are going to talk about. This corresponds to approximately 80% of the newly diagnosed patients in the United States, or 65,000 cases per year.
This can come in a couple of different varieties, but by definition, this is a cancer that has not yet invaded the tissues of the muscle in the bladder. You can see the three types we'll be talking about today. The first is carcinoma in situ, or CIS. This is a non-invasive, flat cancer that's not easily removed. We also are talking about papillary tumors, which are more sort of finger-like outgrowths from the bladder surface into the lumen of the bladder, which are classified as Ta and T1, depending upon their level of invasiveness. There is also muscle invasive disease and metastatic disease, but those are the kinds of disease that we seek to avoid with the treatments we'll be talking about today. Bladder cancer, although you may not think about it as much, is actually a top 10 cancer by indication.
There is a real cost to society, $6.5 billion estimated annual cost in the United States. It is among the most expensive cancers to manage on a per-patient basis. The reason for that becomes clear when you actually begin to think about the journey that a typical patient experiences while being diagnosed and treated with NMIBC. This is a multi-year journey that is typically quarterbacked in the community setting by their urologist. A typical patient will present to a urologist with a symptom set such as hematuria or blood in the urine. They will be diagnosed with high-risk disease, and they will begin what has been the mainstay of treatment for high-risk NMIBC for decades, which is intravesical BCG. BCG is an attenuated bacterium. It is actually one of the oldest immunotherapies. It has been in use for decades, and it works very well for first-line treatment of this disease.
It comes with two major caveats. The first caveat is that, unfortunately, 50% of patients will recur within two years. There's a need for additional therapies afterwards. The other major caveat is that it exists in a chronic state of short supply, particularly within the United States. Not a lot of patients can get it. There's an unmet need both on the supply side as well as in the downstream care side. When these patients recur after BCG treatment, that's where they enter a region of care where there's less clear standard of care and where it's evolving. For decades, the mainstay of care has been surgical treatment. We'll talk more about why that's undesirable in just a minute.
Most clinicians really want to avoid surgery because it's permanent and disfiguring, and will prefer to treat patients with an intravesical or medical option to forestall the further development of their tumor. Basically, they want to exhaust all non-surgical options with the goal of preventing progression to muscle invasive disease, which is a slow process, can take place over 10 years, and with the goal of avoiding radical cystectomy, which is the bladder removal surgery I'll talk more about in just a minute. I think the other important point to take away from this is that this is a disease that is treated by urologists, and the overwhelming majority of urologists are practicing in community clinics.
If you want to build a product that's going to have an impact here, you need to build a product that's going to be amenable for use in those sorts of clinical contexts. The other goal beyond avoiding MIBC or muscle invasive disease is avoiding radical cystectomy. Radical cystectomy is a surgery that's the complete removal of the bladder. In women, this involves a hysterectomy, and in men, it involves a prostatectomy as well. It's an extremely morbid, life-transforming surgery. It's a 10% mortality rate. It can take six to eight hours with a high number of complications, including sexual dysfunction, mental disfigurement, and depression. Unfortunately, it remains the standard of care because it is curative, but it's something that patients don't want to do and that urologists would prefer to have a medical alternative.
Our goal at enGene is to provide patients with better alternatives to radical cystectomy that will allow them to live longer, healthier lives, holding on to their bladders. There are non-surgical treatments that are available today in both a first-line setting and a second-line setting. They all, unfortunately, suffer from substantial limitations. We talked about BCG. It works, but it is in chronic global shortage. When BCG is not available, clinicians can give intravesical chemo. There are second-line treatments as well. Keytruda was approved in this indication. It is a systemic agent, so it is not given in the bladder like the other agents we will be talking about today. That requires a multidisciplinary care team to manage these patients and therefore is likely utilized because that is not something urologists typically want to deal with. There are also a number of viral gene therapies that are recently approved.
Adstiladrin is one of them. This is a complex therapy with complex handling and storage. It launched with a history of limited availability. There are also other products like Cretostimogene, which requires co-administration with BCG per its label. Remember, BCG is in a state of chronic shortage and rationing. It has some problems in terms of practical utilization on all fronts there. Now we come to detalimogene. Detalimogene, we designed to be the first choice agent that physicians will reach for in treating this disease. Again, the care paradigm here is shifting from surgery towards a series of intravesical treatments to forestall the development of muscle invasive bladder disease. We want detalimogene to be the first agent that urologists reach for. We've demonstrated the clinical activity of detalimogene in our LEGEND study, which we'll talk more about in just a second.
This is a registration-enabling study, so we're very excited about it. We've shown a favorable safety profile with an adverse event profile that is generally consistent with instrumentation. Recall that this is an intravesical agent, so it's instilled directly into the bladder via a catheter. The AEs that we see are largely consistent with that. Where we really stand apart is in our ease of use. This is critically a non-viral genetic medicine. It requires no special handling, does not require cold chain storage on the site of administration. It's really something that a physician can take off the shelf, pull out of the refrigerator, mix with water, administer to their patient the same day that they come into the office. It's very straightforward, requires little advanced planning. We designed it that way from the start.
Along with that comes the benefit of a well-characterized and scalable manufacturing process. Basically, we have a cost-effective process that we're confident will support wide availability. That is our goal, to make this available for everyone. In summary, we designed this to be the first choice agent for urologists. We anticipate that urologists will ultimately use multiple agents to manage this disease. We think this is going to be one of the ones that they reach for first in the patient journey if it's approved. Detalimogene is built off of enGene's proprietary DDX technology, which allows for non-viral transfection of mucosal tissues with genetic cargoes. I'll talk a little bit more about how that works and how Detalimogene works. The drug product in this case, what's in that actual white powder, is a nanoparticle comprised of DDX.
I'll show you what that looks like in just a second. What that's designed to do is to traverse the biochemical layers of the mucosal tissue, in this case, the bladder, while remaining intact and non-aggregated, but then to break up when it interacts with the tissue on the other side to deliver its genetic cargo. In this case, the genetic cargo is a single DNA plasmid encoding three genes. Two of those genes are double-stranded RNA agonists of the intracellular receptor RIG-I. This is designed primarily to stimulate the innate immune system. The other cargo is a secreted form of IL-12, which is designed primarily to stimulate the adaptive immune system.
The idea is that these cargoes will interact synergistically with the immune system to create a powerful but yet localized immune response that drives the anti-tumor effect, but also reduces the risk of systemic toxicities because it's only administered locally into the bladder. It is a true platform in the sense that we can encode an arbitrary gene cargo. In fact, we can go above and beyond what typical genetic medicine vectors such as AAVs can do. We can encode much larger and more complex gene therapies. A really exciting platform. It also lends itself nicely and naturally towards an industrialized scale-up. It's a simplified version, but it is a really straightforward process. We take our plasmid DNA, which is negatively charged. We mix it with our proprietary DDX polymer, which is positively charged, to create effectively a DDX DNA polyplex.
In step three, we passivate the surface of that polyplex with a PEG-PLE, which is effectively an excipient. We get from that a PEGylated DDX or DNA nanoparticle, which we then lyophilize to create our drug product. Robust, straightforward, and amenable to scale-up. We're really excited to be demonstrating the potential of detalimogene in the clinic. Right now, the tip of the spear for us is the LEGEND study, which is a multi-cohort study with a registrational arm focused on demonstrating the potential of detalimogene across high-risk NMIBC patients with and without CIS. Our pivotal cohort here, which is the one shown in blue, are BCG-unresponsive NMIBC patients with carcinoma in situ. These patients have an unmet need that's so substantial that the FDA has issued guidance that allows us to run a single-arm registrational study here.
We'll talk more about that in just a second. Again, we're guiding towards a data update here in the second half of 2025 and a BLA filing in mid-2026. We're also enrolling patients who are BCG naive with CIS and who are BCG exposed with CIS. Both of those are real-world patients where there exists an unmet need. We're looking at patients who do not have CIS but have high-risk BCG unresponsive papillary-only disease, which is another meaningful market segment where we want to demonstrate the potential of detalimogene. We're also looking at some exciting applications of the DDX platform more generally, but we won't be talking about those today. Now to talk about the pivotal arm of the LEGEND study. Again, we're looking at BCG unresponsive high-risk NMIBC patients with CIS, where we have an approximate enrollment target of around 100 patients.
It's a global study, single-arm and open label. The dosing PET scheme that you'll see when we put up our tumor plot, patients are dosed four times in a three-month cycle during year one. That three-month cycle is very typical of this disease. A patient comes in, they'll receive detalimogene at weeks one, two, five, and six. If they're responding, they will stay on study and be redosed in another three-month cycle after that. Four doses every three months for the first year, as long as they remain on study. At the end of the first year, they enter a dose-reduced maintenance period. Now that four times per cycle drops to two times per cycle at weeks one and two. Patients have the ability to stay on that for up to three years.
The primary endpoints that we're looking at here are the complete response rate at 12 months, as well as safety. The patients you'll be seeing here are pretty typical of NMIBC patients. They're generally male, generally older, in their mid-70s. There's really nothing remarkable about our patient group. You can note down at the bottom that for the patients we'll be seeing, 71% of these patients have CIS only, and approximately 30% have CIS with concomitant papillary disease. Look particularly at that T1 number because I'm going to come back to T1 patients. They're a very difficult-to-treat patient group, and we've modified our protocol to give those patients a better opportunity to respond and benefit from the standard of care here. As I mentioned from before, we have a great tolerability profile.
When you look at our treatment-related adverse event rate, you see a rate of 47%, which trends very favorably across the competitive landscape. We see no grade three or grade four or five AEs. The majority of AEs that we see are consistent with the catheterization and instrumentation process. You will see this set of AEs across intravesical therapies because you have to put a catheter into the bladder, and some of these are just associated with that process. We are really excited about the tolerability profile that we have seen so far. It stacks up nicely against the competitive landscape. You can see some of the other players in late-stage development, detalimogene voraplasmid, TAR-200. We are right where we want to be, and we are really excited about not only the number of adverse events overall, but the lack of grade threes.
I am really excited to talk about our data that we released in September, September 13th of last year, which is preliminary data from the pivotal arm of the LEGEND study. Again, these are BCG unresponsive patients with carcinoma in situ. You can see we have 21 patients' worth of data here, of whom 17 have made it out to six months. This corresponds to a complete response rate at any time of 71%. At three months, we have a complete response rate of 67%. Out at six months, we are at a complete response rate of 47%. For those of you who might be more comfortable with Kaplan-Meier estimates, that corresponds to a six-month Kaplan-Meier estimate of a 51% complete response rate. We are really excited about this data. We feel it shows a compelling activity, efficacy, and it is a great preliminary look.
Now, around the same time as we compiled this data, we also implemented some key changes to the LEGEND pivotal protocol, which were designed to align the protocol with the standard of care and with our understanding of the practices of other late-stage companies that are developing in this indication space. I mentioned those T1 lesions before, or patients with CIS and T1 disease. These are the hardest patients and the hardest lesions to treat. Previously, these patients would undergo a single surgical resection prior to treatment with detalimogene in the LEGEND protocol. We now know that these patients do dramatically better if they undergo not one, but two surgical resections prior to intravesical treatment. That is now required under some revisions that we have implemented to the LEGEND protocol. The next change occurs for how patients with recurrent Ta disease are treated at three months.
Previously, only patients with recurrent CIS at three months were eligible to be retreated with detalimogene. If you had Ta disease at three months, you were not eligible and had to come off of study. In reality, recurrent Ta patients would have their lesions removed, and they would be retreated. Effectively, that disease would be managed surgically. We now allow for that. That, again, is consistent with standard of care, with what clinicians are doing, and with what our peers are doing in their clinical protocols to the best of our understanding. The other focus area is out at six months, or really whenever anyone's coming off of the study. Previously, you could come off of study based on visual perception of CIS only. A biopsy was not required.
However, after speaking with urologists, we realized that this introduced subjectivity into the protocol, as many times a lesion that had responded to therapy can appear visually similar to one that has not and can appear visually similar to a recurrent lesion. A biopsy is now required, which should reduce false negatives. In sum total, although these are some technical points, we now require that patients coming into the study have had the full benefit of evidence-based medicine and are thus poised for success once enrolled. We are also trying to decrease the chances for a patient to discontinue the study prematurely or via a false positive. All else held constant, this should strengthen our results going forward.
To position the preliminary data against the landscape, I feel like our efficacy rate is really right where we want it to be and favors very strongly against the competitive landscape overall. With these changes to the protocol, we're excited to see how our data at later time points continue to evolve as well. Just by way of background, I mentioned that the reason we can perform a single-arm open label study for full registrational approval is because of the unmet need here in this indication. FDA issued guidance in 2018 that allows for trials of that structure to support full registration. They went on to reaffirm that guidance in August of 2024 in a guidance update that they put out. These are approvals that, to our knowledge, have been made under this guidance.
To get a sense for what the 12-month complete response rate is, we see 19%, 24%, and 45% for Anktiva, which is co-administered in combination with BCG. All very similar. We follow this guidance very carefully to be consistent with the pathway that FDA has laid forward. To summarize, we designed detalimogene to be the urologist and the patient's first choice when treating high-risk NMIBC. It's practical. It's designed for use in busy clinics where time is at a premium, where chair time is at a premium. We've shown clinical activity, and we've shown we have a generally favorable adverse event profile. It's really designed to be easy to use. Just to very quickly think about what that looks like from the urologist's perspective, they're thinking about what to recommend to their patients.
They may have other agents that are available that have a more complex storage process, that have more need for biosafety, facilities, decontamination, may require more resources, such as a procedure room or cystoscopy or more planning around the thawing of the vial. You do not have to worry about that with detalimogene. It is just easy to grab off the shelf and administer. From the patient's perspective, those factors can have an impact as well. Viral exposure precautions can affect the way you can interact with your family at home. With detalimogene, there is no need for that, right? It is a reasonable time in the chair, currently one hour. There is no need to bleach your urine to contain any sort of viral therapy on the other end. There is no intense induction period as there might be for something like BCG or some other therapies in development.
To summarize where we see this market is going, there are multiple agents in development. We feel that's a great thing for patients, again, because in a second-line context, the goal of urologists will be to push off radical cystectomy for as long as possible and give patients as much time with their bladder as possible. We see a future where all of these agents will be used in some form. Patients will cycle through them provided that they're mechanistically complementary and that the patient continues to receive benefit.
Because remember, this is a slow-progressing disease, and the goal is to give the patient as much quality of life for as long as they can. This is the change that's going to be underpinning the growth in the market. Our ambition here is to be one of the first things, if not the first agent, that urologists and patients reach for in treating this disease. I'm going to stop there. We're working on this with a great team, and I'm going to see if there are any questions that I can answer.
Great. Thanks. Thanks so much, Alex. I guess a few questions here. As you've modified the inclusion criteria, obviously, it looks like that's aligning more with current standard practice. Would we expect any impact on enrollment, whether plus or minus from enGene's perspective?
I think, first off, a lot of the pivotal studies that are enrolling similar patients, some of those are winding down. That all should help enrollment. I think, if anything, it's difficult to say, but we would expect that it would be largely enrollment neutral. We could have potentially a benefit to enrollment overall, but I would not expect it to have a huge impact one way or the other. We are very focused on enrollment and getting as many patients into the LEGEND study as possible.
Got it. Clearly, there is an ease of use advantage with enGene's technology versus the viral agents. Also, the cost of goods, not only with respect to the material itself, but also the whole logistics, the cold chain. Can you maybe just sort of, without having to be too quantitative, but just qualitatively maybe give us a sense of what that difference may look like and how that could benefit the company, which presumably has to shoulder the costs of all those requirements?
Yeah. I mean, you are absolutely right. We view this as being a strong point of differentiation for detalimogene. When you think about what it takes to potentially administer a viral gene therapy, and there have been urologists who practice in high-throughput clinics who've talked about this in Urology Times videos, right? You want to be thinking about, how can I minimize a patient's chair time? How can I minimize the time that requires a procedure room or a complex team?
You do not want to have to be thinking about things like decontamination of the room or, am I going to have to be reserving an OR to go in and remove a device? Could there be complications from that? The ability to have a therapy that you can take out and store in a regular fridge, take out of that fridge whenever your patient is in the facility is a real plus for high-volume, busy practices.
Instead of having to tell a patient, "Well, you can come back on Friday because Friday is the day we're going to dose all of our viral gene therapy patients. We can offer this to you today so you don't have to make another trip." Remember that you're talking about a care paradigm where patients may have to come in four, six times in a three-month period for an indefinite period of time, right?
The ability to save another trip to the office is really meaningful. Some of these patients may be requesting rides from loved ones. The logistics can kind of compound. That is why having something that's straightforward to use, does not require cold chain storage, does not require thaw or sophisticated handling, is a real plus for us. Of course, the ability to manufacture it at scale in a robust process just gives us lots of flexibility in terms of how we can interact with physicians and payers.
Yeah, no, that's very helpful. Clearly, the registration arm is BCG unresponsive with CIS, but you have other cohorts as well. Should we think of those as being kind of filling out the database to support future use? Will there be formal label expansions to include those? Yeah, how do we think about the utility of those other cohorts?
Yeah. I think at this point, you can think of them as an opportunity to demonstrate the potential of detalimogene within those patient cohorts. Those are real-world, meaningful cohorts, right? BCG exposed patients, these are patients who haven't formally met the FDA's guidance in terms of BCG doses to qualify as BCG unresponsive per se.
What matters because there is an ongoing BCG shortage, right? A lot of patients are getting split doses. We hope that this data will give physicians information about how this potential product performs in that patient group. The same thing with papillary-only patients. We note that products like Adstiladrin, for example, have achieved NCCN guideline inclusion on the basis of single-arm data sets, for example, in papillary-only high-risk BCG unresponsive disease. I think, but generally, the idea is we haven't talked specifically about our interactions with the agency, but the goal is just to tell a fulsome story about how detalimogene voraplasmid performs in patients with high-risk disease.
Great. Finally, it just seems like there's a great value proposition here. Some of your other companies in the space, CG Oncology and so forth, they seem to trade at a much higher valuation. Just maybe you can share with us kind of what investors may be missing with respect to enGene, given clearly the operational advantages of the technology and what looks to be also a very viable kind of efficacy safety profile.
Yeah, Ryan, would you like to take that one?
Sorry, Leland. Could you repeat it?
Oh, yeah. Just with respect to kind of what investors are missing here. You've got a good technology that's showing very encouraging efficacy, clearly safety, much better handling and logistics, but clearly not as well-valued by the markets as, let's say, CG. Just maybe what do you think are kind of the key points of what investors may be missing here that could change over the next year?
Yeah. I think, look, it's a little bit less mature of a data set compared to, say, CG and J&J, right? There is that component of it. I think, as Alex mentioned earlier, we have a little bit of catch-up to do from a CR rate at six months, which is the comparable data point that we've shared so far from our data release in September. The protocol revisions that we've made, and as Alex walked everyone through, we believe will help close that gap, if not erase it.
I think the big picture is, from my perspective, investors are singularly focused on that CR rate and kind of are missing the best-in-class product profile that we've got in favor of what they believe is a CR rate above which you're not going to get, below which you won't be prescribed. That's kind of the dynamic that we're working through. As Alex also mentioned, we'll have an update on that data in the second half of this year that I think will surprise a lot of folks and will be well-positioned after that.
Yep. No, looking forward to the update. With that, I think we'll conclude here. Thanks to you both, Alex and Ryan. Thank you all for zooming into our session with enGene. Thank you.