Good morning, everyone, and thank you for joining day three of the H.C. Wainwright 26th Annual Global Investment Conference 2024 . My name is Daniel Smith, and I'm an H.C. Wainwright equity research associate in biotechnology. With that said, let me introduce our presenter for this session. I'd like to welcome Dr. Alex Nichols, President and COO of enGene, who are a clinical stage gene therapy company. enGene is traded on the Nasdaq under the ticker ENGN. The floor is yours.
Thank you, and thank you to H.C. Wainwright for the generous invitation to present today. I'm excited to talk about enGene and our new approach to developing practical and powerful non-viral genetic medicines for treating urological cancers. This worked just a moment ago. There we go. Okay, good. And just as a reminder, this presentation will contain forward-looking statements. So we've used our technology platform at enGene, which I'll talk more about in a minute, to create our crown jewel, which is detalimogene voraplasmid, a non-viral gene therapy that we're initially developing for non-muscle invasive bladder cancer, or NMIBC. And we've designed this to be a therapy, a potential therapy that can change practice, but that requires no change in practice for the urologists that are using it. And we're excited about it primarily for three reasons.
First is that if you're not familiar with the NMIBC market, it is poised for explosive and transformational growth. It's large today, but as new therapies continue to come onto the market, we expect that it will continue to expand and that patients will ultimately be treated with multiple therapies, leading to an overall market expansion. We're also excited because we have a product that will be highly differentiated within that space. That's actually a picture of it right there. It combines uniquely clinical activity, excellent tolerability, and really incredibly strong ease of use. It is incredibly straightforward use for both patients and urologists, and we'll talk more about that as well. And we're also excited because the opportunity for us to realize this is near term.
We have a BLA filing that we're guiding to Q2 or Q3 of 2026, and we're capitalized to achieve that with cash that we're projecting into 2027. So for those of you who may not be familiar with non-muscle invasive bladder cancer, it roughly tracks into two categories: non-muscle invasive disease and muscle invasive disease. The lion's share of patients have non-muscle invasive disease, or it's that 75%-80% of bladder cancer diagnoses. And for bladder cancer overall, we're talking about a prevalence of the disease of around 730,000 patients in the United States. So it's very large if you're not familiar with it. And within NMIBC, the disease roughly falls into kind of two broad buckets. The first is carcinoma in situ. So this is a flat lesion, shown here, that's aggressive.
It's not easily removed via surgery. Papillary disease, which represents outgrowths from the bladder surface, and both of these develop within the bladder and on the bladder surface. They can develop at the same time. They can develop separately. Bladder cancer itself is a high-incidence disease. You can see here. It's actually one of the top 10 cancers in the United States by incidence. It falls just behind melanoma, but it's also among the most expensive cancers to treat on a per patient basis. The reason for this really gets into the nuts and bolts of bladder cancer treatment. It requires cystoscopy, which is a procedure to monitor and measure the efficacy of these treatments. It also requires imaging visits and urine testing.
If, unfortunately, if it does progress to something like muscle-invasive disease, that's a costly, complex disease to treat. It can be treated surgically, and if it progresses to metastatic disease, then that's even worse. If you add all of this up, you're talking about an estimated total annual cost of around $6.5 billion, and that's today. Really unmet need here from a societal perspective. When you actually begin to look about the patient journey and the patient experience, I think the unmet need becomes even more acute. What we're looking at here is a typical course of treatment for a patient with high-risk NMIBC, which is one of the varieties of NMIBC, and it's one of the varieties on which we are most closely focused.
This is a disease that is managed by urologists, and most urologists, statistically speaking, around 80% of them, are practicing in community environments outside of academic medical centers. And so that's where the majority of these patients are treated. If you think about what the journey looks like, a patient will come in and be diagnosed with high-risk disease, and they're going to be treated with first-line therapy, which is intravesical BCG, which is actually the first immunotherapy. It's been the standard of this indication for decades. It's also in a chronic state of global shortage. BCG or some combination of chemotherapy, if the physician is unfortunate enough to not be able to get BCG, which many of them can't. Many of them are rationed.
Those therapies are efficacious, but they unfortunately suffer from a non-trivial recurrence rate of around 50% at two years. When a patient has BCG-unresponsive NMIBC, that's when they're going to enter sort of this cycle of second-line and beyond treatments, where the goal of care is to prolong the patient's time with their bladder, ideally cure their disease. If they can't do that, prolong the patient's time with their bladder, so that they'll eventually, hopefully, pass away from some other unrelated condition. Really, surgery here is a last resort, and I'll talk about why in just a second.
But if the disease does progress from here, this is the point at which the patient might be referred to an academic medical center or the medical oncology pathway, where they would be treated for their muscle-invasive bladder disease, which is sort of the definition of progression. And they might undergo a surgery called radical cystectomy, where the bladder is removed, and that's a very heavy surgery. We'll talk more about that in just a second. Actually, right now, if you find this image startling, you are certainly not alone. This is a life-transforming surgery that urologists and patients both view as a last resort for really patients who have no alternative. It's six to eight hours long. It has a considerable mortality rate, and very high complication rates and readmission rates, and importantly, the impact of this are obviously lifelong.
I mean, imagine living without your bladder. It has impact on sexual function, it makes the patients depressed. They have really dramatically lower quality of life. And you can see here under this towel, this is the urostomy site for the patient, so they're gonna be draining into a bag. Unfortunately, this still remains the standard of care for treating high-risk NMIBC with CIS. It's 100% effective, but it comes with a very high cost. And so our goal at enGene is to provide patients with a practical alternative to this and forestall the need for this surgery for as long as possible. And one of the reasons that we're focused on this is that there are, as I mentioned, non-surgical alternatives, but they all come with caveats and limitations. On a first-line context, so we have BCG.
It's been around for 70 years, but it is in a chronic state of global shortage, and alternatives to that are intravesical chemotherapy, which is really used as a backstop, but is difficult to work with. The efficacy is not great, and it's not particularly well-tolerated by the patients. When we go from first line to second line, there are, again, a number of treatment options that are available today. You have pembrolizumab. It's a systemic agent, not an intravesical agent, so it's given via IV infusion and not administered into the bladder as these other agents are, and it requires a multidisciplinary care team to manage these patients because of the serious immune-related adverse events, so urologists don't like using that. You also have nadofaragene firadenovec. It's a viral gene therapy. Well, it requires some complex handling.
And then Anktiva, which requires co-administration with BCG, which is in short supply. So major caveats on all of the options that are there. So we're really trying to provide a very practical alternative that will be powerful, and the first thing that urologists will reach for in treating these patients. And we're going into a very large market, and we're expecting that patients will ultimately be treated with all of these agents in some form or another, whether in a community clinic or an academic medical center, again, to prolong their time with the bladder. And against that framework, we designed detalimogene to be the first choice therapy for urologists and for their patients. We've demonstrated compelling clinical activity from our phase I LEGEND study. I'll talk about that in just a moment.
So we've also shown some strong durability as well. But what really sets us apart is our potential best-in-class ease of use. This is a non-viral genetic medicine, which means that we don't have many of the specialized handling concerns that one would typically attribute to a viral gene therapy, and that do come with viral gene therapies. We also have a very strong safety profile. We've had clinicians report that using this product is not that different than using, for example, administering saline intravesically. It's just very well tolerated by patients, and the AEs that you do see are largely attributable to the catheterization that's required to administer the product intravesically. And the manufacturing process is well characterized and scalable.
And again, for a gene therapy, that is really a strong point for us. We'll talk more about that as well. And so we believe that we'll be able to launch this product with full availability and really get. Our ambition is to get it to urologists and to patients as expeditiously as possible. So again, first choice, this is designed to be the first thing that urologists will reach for in helping patients through this multi-year, multi-drug journey if this product is approved. All right, so how does it work? I showed you a picture of the lyophilized vial. So there's a powder, and that powder is comprised of this DDX drug product here.
In the next slide, I'll show you how we make that, but it's effectively, it's comprised of our proprietary polymer into which we embed a DNA plasmid, and for the case of detalimogene, this plasmid encodes three different genetic cargos. So the technology allows for the nanoparticle to traverse the lumen of the bladder and the biochemical layers on the outside of the bladder urothelium, and then deliver its cargo inside, and that cargo encodes two double-stranded RNA agonists of the intracellular receptor RIG-I. This is designed primarily to stimulate the innate immune system, and we also encode a secreted IL-12, which is designed primarily to stimulate the adaptive immune system.
The idea is that this will transfect any urothelial tissue to which it comes into contact, so it's not tumor specific, and create a basically powerful yet anatomically localized anti-tumor microenvironment that we hope will eradicate tumors for patients. So it's really a precise sledgehammer that's delivering a one-two punch to the tumors within these patients' bladders. Now, of course, the other beautiful aspect of this technology is that it is a relatively straightforward manufacturing process that we can scale to an industrial level of commercial supply. So the process conceptually is very straightforward. You take the plasmid DNA, which is our drug substance, and then you mix that with our dually derivatized oligochitosan or DDX. So this is really the proprietary material that we've developed.
And then through this in-line mixing process, they combine to form this DDX nanoparticle here that is positively charged. We then passivate that positive charge with a PEG-PLE, and a simple, straightforward bulk mixing process that leads to now a PEGylated DDX nanoparticle, which is that, that lyophilized product that I showed you in that vial. Ultimately, when this is done, you can reach for it off a shelf, you can mix it with water and give it to the patient, and it's ready to go. The inputs here are, again, relatively straightforward, readily scalable, and there's no special delivery or handling requirements required. So, you know, unlike viral gene therapies, for example, you don't need cold chain storage. This can be shipped and stored in a very straightforward way....
We're excited to have taken this into a phase I study. The phase I study, which is again a first in human for this technology platform, was focused on BCG unresponsive, high-risk NMIBC patients with CIS. I'll talk why we are focused on this patient group in just a moment. It was fairly straightforward, otherwise. We explored two different dosing schedules and then three or four different dose levels. And the results that we saw speak to promising clinical activity. Looking at a complete response rate at any time across all doses of 73%, and now looking at our phase II dose, more specifically, a complete response rate at three months and six months of around, you know, 60%-70%, respectively.
So really encouraging from a first-in-human phase I study, signs of durability, and signs of efficacy. So we're excited about the clinical activity that we've observed through this. And as I mentioned, critically, this is paired with a highly favorable safety profile. So if you look, you'll see the majority of the AEs that our patients experienced were Grade One or Grade Two. Now, recall that this is an intravesical product, so it's administered by a catheter. And if you look across other intravesical products, you'll see a lot of these same AEs, and that's because they're generally attributable to the actual instrumentation and procedure itself, rather than the drug product. And then you also see we have one Grade Three AE. This was our only Grade Three AE.
It was a patient who experienced grade 3 renal failure. And we subsequently realized this patient had a history of renal failure, and we amended our protocols going forward to exclude patients with that medical history at the recommendation of our DSMB. And all these AEs were reversible. So we chose BCG unresponsive NMIBC with CIS because we recognized there was a real unmet need there. We are also fortunate in that FDA recognized there's an unmet need there, and in 2018, they put forward a guidance that specifies that because of this unmet need and the absence of a pharmacological comparator, that a single-arm, open-label study is sufficient for full approval in this indication.
And they actually recently came out in 2024, August, reaffirming this guidance, which we were really excited about, and I think is great news for patients. So coming in through this guidance, there's been several products, pembrolizumab, as I mentioned, Adstiladrin, and then most recently, Anktiva. And so if you kind of look at what the floor here is in terms of approvable twelve-month complete response rate, you know, you'll see it's in the 19%-24% range. So you know, again, really strong data points for us, and also a great example of regulators working in concert with physicians, patients, and industry, right, to help bring new therapies to markets that have the potential to transform this disease.
So we have used that guidance toto yu design our registrational study, which is again in BCG-unresponsive high-risk patients with CIS. It's a global study. We're enrolling-- we're targeting a hundred patients for total enrollment, and we are-- we have a BLA filing that we're guiding towards in Q2 or Q3 of twenty twenty-six, with a primary endpoint of complete response rate at twelve months. We are further excited about the potential of detalimogene voraplasmid outside of this cohort, however, and as you'll see, we've recently launched several additional cohorts, all high-risk NMIBC. So we're studying this in BCG-naive patients who have CIS. You know, these patients may not be able to get access to BCG, or the urologist may not be able to access BCG. We're also looking at BCG-exposed patients.
So these are patients who have gotten some BCG, maybe they've had some chemotherapy, but they don't qualify under the FDA guidance as fully BCG unresponsive. It's a very large group of patients for whom there still exists a significant unmet need. And then, of course, papillary-only patients who do not have CIS, and therefore don't qualify under the guidance, but who still have a you know, papillary lesion that needs additional treatment so that they can be spared a radical cystectomy. And of course, we are planning on releasing some preliminary data later this month in this cohort, which we hope will provide some comfort that we are, we have clinical activity and remain on this path to approval.
So again, taking a step back and thinking about the design attributes of detalimogene that make it so well suited for busy urology practices. You know, it's really about five buckets. We have promising clinical activity and evidence of durability from our phase I study. It's easy for patients to take this product, and certainly in a relative sense. It's straightforward for clinicians to use the product and administer it. They can store it without any sort of specialized equipment or freezers. And the AE profile that we've observed so far has been highly favorable. Now take a look at that from the urologist's perspective and think about how detalimogene might stack up against some of the other agents, you know, that are in development a couple of years from now, if they're approved.
And again, our perspective is that all these agents will be used, which will accrue to the benefit of patients. But if you think about which one a urologist might reach to first, right? I mean, you've got some viral gene therapy agents, some of which are oncolytic viruses that, you know, may require elevated levels of biosafety. Patients need to decontaminate their urine for a long time after being treated. You have to store it in minus 80, and maybe you have to thaw it for 3-10 hours. Or you've got a drug device that requires a consent and a procedure room to administer, and that might have higher rates of, you know, urosepsis. Versus something like detalimogene, right?
Where it can be administered in a very straightforward way, and you can take it out of your fridge, mix it with water on your desktop, all right, and then administer it to a patient. So it slots in very nicely in terms of product profiles that urologists are used to dealing with. And then think about it from the patient perspective as well. So for some of these viral gene therapy products, because they need to be thawed, and that can take hours, the patients need to show up early in the clinic and then wait around, right? And keep in mind that the average patient here is going to be in their seventies or eighties. I believe it's in the mid-seventies is the average age. So they're they may be getting driven to the clinic by their loved ones.
They may not wanna spend that time there, and they may not wanna have to deal with some of the exposure precautions that are required or expected to be required for some of the viral gene therapies. They may not wanna bleach their urine or have to avoid contact if they have any family members, you know, that shouldn't be exposed to those viruses. And then, of course, you know, if you think about what it's like to have a drug device inside of your bladder, you know, maybe you can feel it, so you can feel it when you're urinating. Again, not a pleasant sensation, so these are some of the reasons why a patient might bias towards a product like detalimogene.
One-hour administration time, you don't have to worry about your post-treatment experience, and you don't have to sit in the chair and endure a series of bladder washes, you know, to be treated. So taking one further step back and thinking about where this field will move, we have products emerging across a number of different modalities and therapeutic categories, viral gene therapies, you know, CPIs, bacterial immunotherapy, and we think that this is gonna be a wonderful transformational event for patients. We're gonna be moving from a treatment paradigm that's dominated by radical cystectomy, towards one where patients are going to be cycling actively through these mechanistically complementary therapies, and again, hopefully have many more years of time with their bladders.
And the result in this is that the bladder, the NMIBC market in particular, and the bladder cancer market, will just continue to grow and grow and grow, in an analogous way to the multiple myeloma market, as these basically will transform into a more of a chronic disease-type management paradigm. So we're. We also have a fantastic team supporting the company. Ron Cooper just joined us as our Chief Executive Officer. He's done dozens of product launches in Bristol-Myers Squibb and had a successful stint as the CEO of Albireo. Raj Pruthi also joined us as a Chief Medical Officer. He's a recognized global thought leader in NMIBC, and a practicing urologist who's, you know, seen thousands and thousands of patients and is deeply dedicated to advancing the standard of care.
And Ryan Daws, our Chief Financial Officer, very experienced in public markets, also brings a banking background. So with that, I'll just summarize by reinforcing, you know, these three primary reasons why we're so excited about this product. It's an exploding and growing market opportunity. There's nothing like the product that's on the market or that we're expecting to come onto the market that combines this activity and tolerability and ease of use. And we're poised from a cash perspective and a BLA filing perspective, in order to take advantage of it near term. And so with that, I'll stop, see if there are any questions.
I wanna thank Dr. Nichols for that awesome presentation. I think-