Okay. Let's go ahead and get started. My name is Ally Bratzel, a biotech analyst here at Piper Sandler. Thanks for joining us at our healthcare conference. It's my pleasure now to introduce enGene. Joining us today for our fireside, we have Chief Strategy and Operations Officer Alex Nichols.
This is meant to be, you know, informal. If anyone in the audience has a question, just raise your hand and we'll get to it. But just kinda jumping into the Q&A, you know, we know enGene develops non-viral gene therapies for delivery to mucosal or other tissues or other organs. Based on your proprietary platform, lead asset detalimogene, focus on NMIBC, can you just give us a high-level overview of that platform, detalimogene MOA, and just where else you can apply this?
Sure. Before I do, let me just thank you for the invitation and also just remind anyone listening that this discussion may contain some forward-looking statements, which they should not rely on in making their investment decisions.
So your question was about the DDX platform. DDX, the DDX technology, is a proprietary approach that we've developed based on effectively a proprietary sugar polymer that allows us to make non-viral gene therapy delivery nanoparticles that are non-integrating, non-viral, non-immunogenic, and also redosable. And so basically, we can formulate that and integrate an arbitrary DNA plasmid, or RNA plasmid for that matter, and achieve local delivery of powerful gene therapies.
So our main focus is the bladder. It's obviously a great opportunity for this kind of platform because it's an easily accessible tissue, and also the DDX platform is uniquely able to transfect mucosal tissues. That's in fact what it's designed to do. It can survive the biochemical journey across those mucosal tissues while remaining intact.
In the case of detalimogene , the cargo is a single DNA plasmid encoding three genes, so two of those are double-stranded RNA agonists of the intracellular receptor RIG-I. So those primarily stimulate the innate immune system, and then the other cargo is a secreted form of IL-12, which primarily stimulates the adaptive immune system.
A nd so the idea is that when this is infused into the bladder, it will transfect all tissues into which it comes into contact, creating a powerful inflammatory and anti-tumor environment that is also localized to the bladder, therefore avoiding some of the systemic exposure consequences that have been traditionally associated with cytokines like IL-12, for example.
Excellent. Maybe zooming in now a bit on NMIBC. I think we all know this has become a little crowded, in terms of, you know, the development landscape. Maybe help us understand how detalimogene is differentiated. And, you know, in your view, what factors are gonna actually determine how urologists adopt these, you know, new therapies, either newly approved or, you know, late-stage clinical development?
Absolutely. So I'd be happy to talk about detalimogene's differentiation. I think it is really a unique product within the space. I think its most differentiating aspect is its overall product profile in terms of the way it's used and administered. We designed it from the beginning to be a product that's useful in a community context.
And maybe if I take one step back, the majority of patients with non-muscle invasive bladder cancer, which is what detalimogene is treating, are treated in community clinics. So if you look at the American Urological Association, for example, they run census data every year on where urologists are practicing. 70% of them are practicing outside of major medical centers in these community-type clinics. Someone recently also reported some data from a survey showing that even though some of these larger clinics that are, you know, closer to major metropolitan areas, have more urologists practicing, they are actually seeing fewer NMIBC patients.
What that tells us is that the majority of these patients are being treated in community clinics, and that's where, you know, we really have to have a product that's suitable for those sorts of use conditions. Detalimogene is a product that's really easy to use. It can be reconstituted in water. It's a lyophilized drug product. You can just take the vial, you add water, you can administer it into the patient, and there's no sort of pre-treatment protocols or post-treatment protocols. They can keep it in their bladder for 60 minutes and go home. You don't require cold chain storage, BSL2 handling, anything like that.
So that is really, I think, one of the areas in which detalimogene stands alone. But we also have a generally favorable safety profile that's been observed so far. I could say it's trending best in class. We have a treatment-related adverse event rate that's in the 40s. You know, some of our peers are closer to the 60s. And we've actually had some of our investigators say it's almost like giving saline. It's so well tolerated. And then, of course, the efficacy as well. You know, with a 71% complete response rate at any time, you know, it's really sitting right there in the mix in terms of efficacy.
And we're overall really excited by the holistic data package that's coming together. We feel like it's going to be a really great proposition for your everyday users that are really focused on volume, clinical experience, and patient experience.
Excellent. Building off that, a couple weeks ago, you had interim data from LEGEND. Walk us through the highlights of that data, kinda what you view as most compelling from that readout and just, you know, why that interim look was derisking for the full data.
Sure. Absolutely. So we were really excited about the data set. J ust to, if anyone's less familiar with it, we had the opportunity to read out from our open-label registrational study, which is single-arm. We looked at 21 patients in a preliminary look-in, which we announced in September. 21 of those patients had data going out to three months. 17 of those patients had data going out to six months. So relatively early data set, but we were able to get a pretty compelling look at the way detalimogene is performing.
As I mentioned, we saw a complete response rate at any time of 71%, which we were absolutely delighted by. It sits, you know, again, very favorably in with a mix of competitors, especially on top of the overall product profile. And that corresponds at three months to a 67% complete response rate and then at six months a 47% complete response rate, y ou know, which again, for a data set, that's this early, we're just really, really excited about.
And of course, the safety piece of it as well, as I already mentioned, you know, we're looking at a treatment-related adverse event rate of 48% from this patient group, all grade 1, all grade 2 AEs. They're generally consistent with catheterization because this is an intravesical product that's administered directly into the bladder. So, really compelling data look for us.
I think you also announced some protocol amendments in LEGEND. Just walk us through those, you know, briefly, like the rationale for them and then, you know, what that could mean for the remaining patients to be enrolled in the registrational cohort.
Absolutely. So we announced these protocol amendments concomitantly with this data update. And we kinda focus on three different time points for patients and physicians. The first is how the patients are treated pre-enrollment and during the screening phase. The second is at the three-month phase. And then the third is at their six-month evaluation. And actually, I think it extends a little bit more broadly than that as well.
So currently, as you know, high-risk non-muscle invasive bladder cancer with CIS can present as CIS-only or you can also have concomitant or co-occurring papillary lesions. So you can have Ta or T1 lesions. Currently, under our old protocol, during the screening process, if a patient had a Ta or a T1 lesion, that lesion would be surgically removed via TURBT and during one procedure, and then they would enter the study, be treated with detalimogene .
What we've come to appreciate, in particular, after bringing on board Dr. Raj Pruthi, who's our Chief Medical Officer, is that, particularly when you focus on the T1 patients, it's become well established now that if you re-resect that lesion, so you go back to the same place where that lesion was, and you cut it out a second time, that has a dramatic effect on the way that the patient performs. They do much better if you do this re-resection.
It has independent therapeutic value, and it has really become sort of standard clinical practice. So we are now implementing that and requiring that all of our T1 patients at screening have this therapeutic re-resection because we think it will allow them to do better longitudinally and give them a better outcome.
The other consequence of that is that during that re-resection, they can go back and take a look at the stage, they can restage the tumor. If the tumor is still a T1 lesion, those patients will no longer be eligible to enroll because at that point that's a very ominous lesion, and those patients should be discussing with their doctors potential alternatives such as radical cystectomy.
Mm-hmm.
Or the full removal of the bladder, which is really what all of these therapies are designed to avoid. But at that point, it's just becoming a much more risky situation and proposition for the patient.
Excellent. So I think later this week, another player in the NMIBC space is going to be presenting phase III data at SUO, CG Oncology. So assuming that data is comparable to what we've seen in prior data cuts, I guess, what does that mean for detalimogene and enGene's opportunity here?
I think largely we don't think it's gonna be entirely consequential for detalimogene and our overall hypothesis. I mean the product profile of cretostimogene is really pretty significantly different than that of detalimogene , so you know, I think more or less we're not expecting it to move dramatically, and I think it won't have really much of an impact on our thinking around detalimogene .
I mean it's a very different product. As I mentioned, you know, we're really positioning this for use in the community setting where the majority of these patients are treated. We want it to be one of the first things that urologists will reach for because of its ease of use.
You know, cretostimogene is a much more complex administration process. There's five different steps. You have multiple pre-washes. It's an oncolytic virus, which is kind of elevates the level of biosafety and introduces some potential, you know, additional handling considerations that community clinics are probably not gonna wanna get involved in.
I mean, a lot of these clinics, many of them are private equity-owned in the community setting. The physicians are interested in giving their patients the very best that they can, but they also wanna, you know, make sure that the patients can move quickly through the clinic so that they can see the volume. That's allowed them to see, you know, more patients, as I just cited.
So, I think they're very different products. We think products like cretostimogene will be beneficial for patients, but they're probably gonna be reserved for when those patients are handed off to the academic medical centers further on in the course of the treatment.
Okay. Maybe a question on endpoints. You know, there's a couple endpoints we look at: CR at any time, at six months, at 12 months. CR at any time seems to be what FDA cares about most. It puts on the labels of approved drugs. I guess, in your experience, what do docs care about, you know, the most? And, you know, what would they view as a meaningful difference on, you know, say, 12-month CR rate? You know, would a, say, 30% versus a 40% 12-month CR rate actually affect decision-making?
Yeah. That's a great question. So I think when a lot of doctors are looking to prescribe a product in this space, they kind of ask two questions. How likely are my patients to respond to the therapy? And then how durable is that therapy likely to be?
And if you're asking me to choose which one I would think is probably a little more important, it's that first one because it's sort of the overarching question, right? Are my patients going to respond to this therapy? So with a CR rate of 71% at any time, again, I think we're really well positioned there, you know, based on this preliminary data set.
Now looking out to the second question of how durable is this response going to be. If you talk to community practitioners, you know, most of them aren't going to say that there's a very large or appreciable difference, you know, between three out of four patients making it out to 12, three out of 10 patients or four out of 10 patients making it out to 12 months, particularly when we have an emerging landscape of therapies that's going to allow for sequential treatment through mechanistically complementary, you know, therapeutic modalities.
Remember that 10 years out from their initial diagnosis of NMIBC, only 20% of these patients have actually progressed to NMIBC or to metastatic disease. So there's a very long treatment horizon through which these patients can be treated with multiple therapies. And that's why we feel that probably the most important figure is are my patients going to respond. And then what is the experience like for them? And then what is the experience like for my clinic when I'm thinking about which product I wanna be investing in and learning how to use?
Okay. Excellent. You know, thinking ahead to 2025, I know you've guided to an update. Can you just frame for us what that could look like? You know, would it be reasonable to expect updated six-month data at a medical meeting? O r just, you know, what kind of update should we be looking for and, you know, and what kind of venue?
Yeah. Unfortunately, there's not much more I can say at this point other than I think, you know, folks can be expecting a data update in 2025, b ut we haven't added much more color on that. I think we'll do so in the, you know, the months to come.
Okay. Then, you know, in terms of the other LEGEND cohorts, you know, you're planning on starting enrollment in three other cohorts. Just explain the rationale there, you know. I s the idea that each cohort opens up an opportunity for specific, you know, label expansion? And maybe building on that, you know, like, is there, how should we think about those indications being included in a potential, you know, BLA filing? What could that look like?
Right. So we have just to lay the land. We have three cohorts for this study. We have our registrational cohort for BCG- unresponsive NMIBC patients with CIS. These are patients who've received adequate BCG and are, you know, classified as unresponsive. This is all laid out in the FDA guidance.
Cohort two for us has now been split into BCG- naive patients and BCG- exposed patients. Exposed patients are patients who've had some BCG but who don't meet the formal criteria of adequate BCG to qualify as BCG unresponsive. And that's a very large group of patients. And then the third cohort is high-risk BCG- unresponsive papillary-only patients. So these are patients who do not have CIS and who have papillary lesions. Again, this is a very large group of patients.
And the thinking here with these cohorts, with respect to cohort two, early in our dialogue with FDA, they actually asked us to enroll patients who were BCG naive or who had been inadequately treated. Now, we've adapted and updated our protocol to reflect the BCG exposed nomenclature. And our idea is, you know, at this point, is to be generating data and generating evidence that physicians can, you know, use to better understand how this product might perform for those patients.
We think this is gonna be also particularly relevant because , as you know, there is a BCG shortage, and that shows no sign of abating in the near future. You know, likewise for papillary-only, again, it's a really meaningful group of patients. It's a single-arm study. A nd the idea is just to be generating some data about how detalimogene can perform and potentially be of benefit for these patients.
Great. So in building on some of your comments on BCG, I guess, how do you envision, you know, detalimogene , you know, ultimately changing standard of care? Is the idea here to displace BCG, be first-line post, you know, BCG?
And then in terms of supply, I know that, you know, BCG shortage has just been a long-standing issue here. You know, I guess it's our understanding there will be some, you know, new, a new manufacturing site coming online relatively near term. You know, what's your sense there? Does that matter? How does that affect how the, you know, NMIBC treatment landscape evolves?
Right. So let me begin with the latter part of your question or the second part of your question. Merck has provided an update this year, in early 2024, that they're expecting their new BCG plant to go online sometime in 2025 or 2026. They're not being particularly granular about that.
We know that that's been a very difficult product for them. It's hard to make. It's not particularly lucrative. It's not particularly well reimbursed. And they've also said that they're expecting supply to increase gradually, s o I think one can reasonably interpret that as meaning that the BCG shortage is not going to abate anytime reasonably soon, so the, you know, the current state of affairs will remain as it is for some time.
That being said, BCG is a product that has a deep history of use in bladder cancer. It's actually the first immunotherapy. As you know, it's been basically used since the 1920s. It predates the modern notions of biosafety. It predates a modern label.
So it's been around a very long time, and urologists use it widely, s o I don't think our expectation is that we will be realistically displacing BCG. I think we could be potentially offering, you know, in some cases perhaps an alternative down the road, you know, depending upon, you know, how our data evolves.
I think maybe, to answer the other part of your question, as we think about the positioning for detalimogene f or patients with BCG- unresponsive disease with CIS, if the product is approved, I think we'd like to position this as the product for which urologists would reach for first, right?
Given the spectrum of potential products that would be available at that point in time, given the spectrum of complexity and AE profile and patient experience, you know, with the safety profile that we have, this doesn't. It's not an indwelling device. It doesn't reside in the bladder. You know, I think that this is something that we really want physicians to feel comfortable discussing with their patients as one of the first options when BCG fails.
Excellent. Something you've touched on, you know, is, in terms of the BCG- naive population, you know, what would a path to approval in that population look like? You know, I think thinking is it would be more complicated than, you know, FDA set the pretty straightforward guidance on how to get approved in refractory patients, b ut just kind of talk to what you might expect there and how you might take detalimogene forward there.
In the BCG naive context? Yeah. You know, we haven't provided a lot of additional color on that. I think our ambition at this point in time, you know, is in response to FDA's request, we wanna just continue developing this data set, you know, see how it matures.
You know, again, as I said, I think it's going to be a heavy lift to really fully displace BCG, but continuing to generate some evidence that this could potentially be a viable alternative, you know, will be adding more tools to the urologist's armamentarium, you know, should we continue to pursue this path.
Excellent. Maybe turning more towards the market opportunity here. You know, I think, at least investors and analysts, we like to just kind of make data tables and compare and try and prognosticate that way on who, you know, kind of who's gonna be the winner here.
So I guess the question is, you know, is NMIBC a winner-take-all market? You know, I guess, from my standpoint, it doesn't seem like that would completely make sense. Just, you know, how do, I guess, how do you envision this kind of working out with the sequencing of therapies?
Right.
You know, patients, you know, maybe staying longer in the community clinics versus going to academic centers. Yeah, just kind of walk me through how you kind of envision this all kind of evolving.
Right. So to offer a very definitive answer to a comment you made, no, we do not think that this is going to be a winner-take-all opportunity. And the rationale behind that thinking is, again, going back to my point, 10 years out from their initial diagnosis with high-risk NMIBC, the vast majority of these patients have not progressed.
So what does that mean? It means that if you have a series of therapies that are mechanistically distinct, i.e., there's reason to believe that if a patient fails one, that they could stand to benefit from another, that we'll be shifting from a paradigm where, I mean, right now, the standard of care is radical cystectomy, full removal of the bladder. It's a horrible procedure. It has 9%-10% morbidity on its own, six-eight-hour procedure.
Everybody wants to avoid that and give patients more time with their bladders. And so having multiple tools in the urologist's armamentarium is really going to accrue to the benefit of patients and allow them to achieve this goal of care of giving patients more meaningful time with their bladder.
You know, as to where we think about the opportunity, it's really about, I mean, one lens through which to view it is the breakout between community use and academic medical center use, you know. A nd again, we're positioning detalimogene as a product of choice for academic, sorry, for community users.
The fact is most radical cystectomies are now done in the academic setting. It's not a particularly lucrative surgery. It's not particularly well reimbursed. And as I mentioned, it takes a long time, s o, you know, for the urologist to treat a patient, you know, through one- two rounds of therapy post BCG failure in a community setting and then hand them off for maybe an additional round of therapy, you know, with something like Adstiladrin or cretostimogene , for example, in a facility that has more infrastructure to accommodate that, you know, I think is a paradigm that we could be working towards.
Okay. Makes sense. You know, I think it's pretty clear you're in line with FDA guidance on NMIBC, so I guess, just expand on that, you know, what gives you confidence there? And then, you know, what makes you comfortable that the approval bar is going to kind of remain the same as additional therapies are approved in BCG refractory NMIBC?
Right. So for your first question on the FDA guidance is obviously referring to the 2018 guidance that FDA put out that allows for single-arm open- label studies to be registrational in the BCG-unresponsive with CIS population.
FDA actually put out an update in 2024 on this guidance where they basically reaffirmed their position that this is a path. There's still an unmet need here. And that's significant for us because this is after we've had several approvals, Adstiladrin and now Anktiva, and, you know, frankly, Keytruda as well, right?
So FDA clearly perceives that there's still an unmet need here. They made one minor tweak to the biopsy requirement at 12 months, you know, with which we've had productive conversations and which we're compliant. So, you know, we've basically been engaging with FDA from the start. You know, we've been structuring our trial to be in line with this guidance, and we feel confident that, particularly with the update in 2024, that they're standing behind it.
Perfect. And it looks like we have less than a minute, s o maybe one last question just on the finance side. Remind us of your pro forma cash balance and runway expectations.
We have a $315 million pro forma cash balance and runway into 2027.
Excellent. And looks like we are basically up on time. So, thanks for stopping by the conference and discussing all the [audio distortion].