Ron, maybe just to start out with, for those that may be less familiar with enGene, can you just provide us a quick introduction of the company and opportunity for your lead asset?
I think the most important thing about our lead asset, detalimogene , is that we're in a pivotal program that we're currently enrolling around a regulatory path that's pretty clear in a growing market. I think it's an attractive opportunity. If I step back, you know, what is detalimogene ? Detal imogene comes from our DDX platform. It's a non-viral gene therapy that's administered intravesically. We're developing for non-muscle invasive bladder cancer, where the unmet need is pretty high. I think forecasts suggest that the market will go from $2 billion to about $20 billion. Unmet need, very high. As I said before, detalimogene is an exciting, pivotal program. I think, you know, we see detalimogene and where we are with enGene as a product and a company that has relatively low risk going forward, but a lot of upside as well.
All right, so maybe just to set the stage on the non-muscle invasive bladder cancer landscape, so there's been some evolution in recent days and months, and so maybe just remind us where detalimogene sort of sits now relative to other therapies and perhaps in a post-BCG setting, where we have now three approved therapies and others in development.
Yeah, I think the recently released FDA updated draft guidance sort of is telltale for us. So the FDA came forward with guidance in non-muscle invasive bladder cancer in 2018, said, you know, look, you know, this is serious disease. There's not enough treatment options. We're going to change the regulatory guidance to say, if you do a single study, open label of sufficient size, that would be great for approval. Since that time, you know, three agents have been approved. And then the FDA brought forward new guidance this past summer, updated draft guidance. And the updated draft guidance had some refinements, but essentially said the regulatory path was the same. That suggests to me that the FDA, in consultation with patient groups and with manufacturers, would suggest the unmet need is still pretty high. And we would agree with that.
You know, the current agents and the new agents add, but aren't enough. The reality of it is non-muscle invasive bladder cancer is really about BCG, more BCG, and then removal of the bladder. And so the opportunity, we believe, with a product like detalimogene and other products to really make an impact on patients and fundamentally change the size of this market is pretty significant.
Great, and then maybe just sort of, again, more sort of understanding that opportunity, so can you talk a bit about how patients are treated, perhaps in the community relative to academic centers, and, you know, how does that affect the choice of available therapy, perhaps?
Yeah, I think there's a bit of a misconception about, you know, NMIBC, right? Because you think it's cancer. So cancer, people go to these academic centers. But remember for NMIBC that these patients have a 20% chance of progressing over a 10-year time frame. So the majority of the patients, you know, 70%-80% of the patients are in community urologists, community urology practices. Now, I've worked in multiple therapeutic areas, and community urology is often different than other therapeutic areas. You know, these are really little businesses, very entrepreneurial. And so, you know, when they think about treatments, they think about treatments differently than, you know, perhaps at an academic center. So it's a combination of you need products that are efficacious, right?
But you also need products that the patients are really interested in having and tolerating it, because given that this is a disease that progresses slowly, and convenience is a big factor in choice. So those three things circulate and are really big drivers of choices of therapies in the community urology setting.
Right, and so, detalimogene , so how does it really address that, you know, that context?
We actually believe that detalimogene will be a first choice therapy for urologists based upon three factors. First of all, the efficacy that we've demonstrated thus far, so we're in an open-label study. We've announced some preliminary data, and the efficacy is as good, if not better, than agents at the same level, so number one, we have the drug works, and we know it works. Second, it appears to have best-in-class tolerability, and so it's very easy for the patients. It's a one-hour instillation with no pre-washes and nothing afterwards from a bladder perspective, so very convenient and well tolerated for patients, and the last aspect is the convenience both for the physicians and for the patients.
The physicians are used to BCG, where they administer it every week for six weeks in a row, and then the patients, if they don't respond, come back for another six weeks. You know, our instillations are week one and two, week five and six. It doesn't require any special handling, no cold chain storage, no extra hoods, no extra personnel being trained to administer specialized drugs. So it's easy for the doctors and as well easy for the patients because of that short instillation. So I think it really does address the unmet medical need in the community urology setting.
And so, yeah, you did obviously recently report early interim data from your pivotal LEGEND study in 21 patients. Just remind us of the takeaways from that data disclosure and perhaps how, yeah, you mentioned it, how it compares to other imaging therapies.
Yeah. So I think, you know, number one, we're absolutely delighted with the preliminary data. Why were we delighted? Well, first, I think we showed tremendous efficacy. Any- time CR rate of 71%, right? So that efficacy compares very well to any of the other agents at the same time, at the same time in their Phase 2 study. So we're delighted about that. So from an efficacy standpoint, check. But then we're equally delighted about the tolerability profile. So treatment-related AEs were in the 40s, right? Whereas for other agents, it ranges between the 60s and 80s. All of our AEs were Grade 1 or 2, so relatively mild and pretty much associated with catheterization, to be honest. They were reversible. We had no grade three, grade no four, no grade two, sorry, no grade three, no four. So no serious AEs.
And I think the real proof in the pudding comes within the discontinuation, right? We had zero patients that discontinued from the study from a, you know, because of side effects, right? So the preliminary data for us, you know, both from an efficacy standpoint, met and exceeded our expectations, but also from a tolerability standpoint as well.
Right. And then, you know, you did talk about some protocol amendments for the study. So remind us just what are you planning to change and how that might impact the outcomes?
Yeah, maybe Raj, you want to take those?
Yeah, thanks, Michael. That's a great question. I think just kind of to frame it, I think we are taking a study that was probably more of a Phase 1 oncology study to a Phase 2 urology study. And I'm a urologic oncologist by training and really adapting to that and the standards within that practice. Just to touch on a couple of them, one is we allowed for a re-induction paradigm. And so patients, if they had a Ta tumor and recurred at three months, we allowed those patients to have that tumor removed and stay on study and allow their CIS, which is really the goal of therapy, to be treated with an immunotherapy for a longer period of time. And this is fairly standard practice for BCG, for Anktiva in clinical practice.
So this is really adopting standard clinical practice to our protocol, allowing patients to stay on study. And we heard this even from investigators saying, "The patient's doing very well. Can't I just remove that little small tumor and stay on study?" Another amendment was re-resecting T1 tumors even before they enter the study. So that's a tumor that's starting to grow within the bladder wall. And the re-resection is part of the guidelines of care. And in fact, just irrespective of further therapies, re-resecting itself reduces the recurrences by a quarter, to a quarter of that. So it's therapeutic in and of itself. So now what we're doing is allowing patients to see the benefits of that re-resection before they even enter on study. And third is allowing for a much more objective assessment of responses with a biopsy.
All of these we feel allow patients to stay on study, benefit from the drug, and I think we're going to see better response rates with them.
Okay. And then I think to what degree have those, you know, those characteristics been incorporated into other clinical trials? And as we compare, you know, your data perhaps to other emerging studies like the CG product or others, the TAR-200, you know, how does study conduct, I guess, or protocol compare across to those?
Yeah. Again, another great question. It's sort of the art of the trial, right? And to use a specific example, I think reinduction has been adapted to Anktiva, which is already approved. And even for CG's trials, they went from B OND-2 to B OND-3, actually had reinduction. So also they saw an evolution as well and saw improvement in their six-month CR rates as well.
Yeah, so I think the way to think about it is the preliminary data set that we announced is analogous to what occurred in B OND-2. And what we expect with these protocol changes that Dr. Pruthi and the team are implementing, that we would have a protocol that would be more similar to B OND-3.
Makes sense. And then, you know, one question we've been getting is, as you're implementing those changes in the ongoing study, I mean, how does that affect, you know, timelines in a number one for enrollment and then ultimately results? And also, you know, as you assess outcomes, you know, does it affect in any way how the outcomes are being assessed, given that obviously you have a mixed protocol at the end of the day in the population?
Yes. So thanks for that, Michael. So our guidance is a filing, you know, relatively soon. So mid-2026 is when we expect to, you know, file detalimogene . As we've made these protocol changes, it's not like we've stopped enrollment in the study. So the study has continued on, and we're enrolling patients, you know, every week. So I think, you know, we feel pretty comfortable, you know, with that guidance. I think the second part of it is probably a little, you know, probably a bit unknown, right? But I would say virtually every Phase 3 program has multiple protocol amendments that people don't hear about. So what we're doing is actually quite common, quite common, but we just chose to speak about it a little bit more.
So we anticipate that, you know, these protocol amendments will actually help us with enrollment because it's going to be easier to enroll patients, and it'll be clearer. We believe the protocol amendments actually help us with our CR rates. And, you know, we're excited to be able to be on track to finish the study and file in mid-2026.
Right. And then, is there still FDA feedback pending, or are you good to go on the changes that this?
So we've submitted this to the FDA and are not waiting on anything that's been being implemented at our sites. And, you know, these things are, as Ron mentioned, relatively common. We're not changing the drug or the dosing, so we don't anticipate. It's just more of the process.
Right. So the next update from the LEGEND study then would essentially be the final analysis at some point, or will there be other disclosures before completing enrollment?
We're still working our way through our disclosures, but I think there's a lot of things to think about in the near future to get excited about. So sometime next year, we'll have, you know, full enrollment of the LEGEND study. We're planning on providing another preliminary data update next year as well. Then, of course, there's the completion of the study, the announcement of the study results, then the filing in mid-2026, and of course, the subsequent approval. So we're in a period of where there's a lot going to happen with detalimogene and with enGene.
And so that additional data look next year, will that include, you know, some patients that have experienced the protocol change, for example?
We would anticipate that to be the case, yes.
Right. And then how do you think about other opportunities for detalimogene in BCG-naive patients and/or in other areas potentially?
So we, as part of the protocol amendment, we are also having other cohorts. One is, as you mentioned, BCG naive. The FDA was interested in seeing, and I think they're broadly interested in seeing some other experiences with that given the shortages. So we'll have a BCG naive and a BCG experience cohort, which is a kind of a new terminology, somewhere between naive and refractory. You know, maybe you've got some BCG, but not all of it due to shortage or tolerability. Then the third cohort we're going to have is a BCG refractory papillary-only cohort. So there's not the guidance that exists for CIS. But the papillary cohort, I think that, again, we're just trying to create some clinical evidence for the urologists, maybe for guidelines inclusion for use.
Okay. And then, yeah, can you talk a bit more about the BCG naive study and some of your plans there?
Yeah. So I think for us, you know, that is part of the protocol amendment. So that's up and going as we're speaking, like literally right now, we're probably beginning to enroll patients. And I think that we're pretty excited about this particular cohort, you know, given the shortages of BCG and given the unmet medical need. And then the profile of detalimogene , as I said earlier, you know, detalimogene has good efficacy, great tolerability, but the convenience of even going from an instillation six weeks in a row, because, and remember that, you know, these patients are in their mid-70s, right? So it's usually daughter or granddaughter, you know, driving, grandma or grandpa. So it's not that convenient, right? Whereas something that, you know, like detalimogene would be week one and two, week five and six, well tolerated, efficacious, could really play an important role.
Right. And then maybe just one commercial question. It's early since, you know, the study's done, the LEGEND study's done enrolling, but how do you think about accessing this global opportunity relative to the U.S. opportunity?
Yeah. So in fact, there is a large global opportunity. We've been heavily focused in the U.S. because of, you know, the regulatory guidance and the clarity of the path. But we do see an opportunity, you know, in Europe and in the rest of the world. So we're working our way through both the regulatory and clinical aspects of that. And at the same time, you know, we'll think about our go-to-market strategy. I think our early thinking in the U.S., our go-to-market strategy would be one where we would go directly, you know, because it's probably going to require, you know, somewhere in the order of 40 to 50 sales representatives manageable for a biotech company. And particularly given, you know, my expertise in launching products around the world, I think it's a good fit.
I think the rest of the world, we're going to kind of look at, you know, the cost-benefit of perhaps partners.