enGene Holdings Inc. ($ENGN)

Great. Thanks, everyone. My name is Etzer Darout, senior biotech analyst at Barclays. It's my pleasure to have enGene with us this morning, CEO, Ronald Cooper. Ron, maybe if you can just give us an introduction of enGene for those that are less familiar with the story, and then we'd take it from there.

Well, enGene is a unique company with unique technology at actually a really unique time, right? So our technology is called the DDX platform. It's a proprietary sugar platform that we developed ourselves over many years. The lead asset from our platform is a product called detalimogene, which we're developing for non-muscle invasive bladder cancer. And we're right in the middle of an open-label pivotal study. And so it's an exciting time. Detalimogene itself is a nonviral gene therapy. So that confers a lot of benefits, very unique. And this year is a pretty exciting year for us in that first off -- first up in Q2 of this year and spring of this year, we will be providing -- we plan a data update at an upcoming scientific conference. In the second half of this year, we plan to share the long-term data, 12-month data for our pivotal study, which is fully enrolled. So we'll have the final results of our pivotal study. We have a planned filing of the BLA, and we expect an approval in 2027, you wrap that up, a company that has cash is over $300 million. We have cash in the second part of 2028. That's why I said it's a unique company, unique technology at a very unique time.

Awesome. Great. Based on our conversation with KOLs, non-muscle invasive bladder cancer feels potentially larger, I think, than I think the market assumes certainly higher unmet need. Maybe if you can comment on sort of the disconnect, if you will, between sort of how the market views this opportunity and sort of how key opinion leaders are talking about it.

Yes, this is a market that's undergoing a lot of transformation. So the first misnomer is that people are very focused in on breast and lung as big cancers. But first of all, bladder cancer is #6. So it's a top 10 cancer, right? So it's pretty large. And then NMIBC within that is 700 and prevalence is around 740,000 in the U.S. So that's quite large as well. What people are not quite understanding or the transformation that's occurring is when you think about NMIBC, traditionally, if you were diagnosed with that, the only real treatments that you had were BCG and removal of the bladder. And urologist said, well, you have cancer. If you fail BCG, we're going to take your bladder out. Increasingly, though, it's understood that NMIBC is a slow progressing disease. So progress is about 20% over 10 years and maybe even lower than that. So now all of a sudden, the treatment paradigm is changing. But with this slow progression, there were no treatments, right? And so now there are a number of new treatments that have been approved and that are in the pipeline to be approved. And so what's going to fundamentally change is products are going to be sequenced out for each other because these products they have -- they kind of wear out a year later, right? There are recurrence rates anywhere from 60% to 80%, right? So quite significant. So they will be sequenced. The patients don't progress, but they recur. The analogy that I would use for this is a little bit like the multiple myeloma market, right? When Revlimid was launched, it was a $1 billion market. You add a dozen-plus new products, it's a $20-plus billion market as products are being sequenced. I think the same thing is going to happen here. The bladder cancer market is about a $2 billion market. It's projected to be a $20 billion plus because of the reasons I just talked about.

Right. And sort of with that, can you just highlight, obviously, this is sort of a space where competition is growing. If you can highlight detalimogene's differentiation relative to what we sort of see from other molecules and maybe also describe the mechanism of action and how that relates to the differentiation here.

Well, first of all, as I said, we're the only nonviral gene therapy. So by itself, it is super differentiated and super unique. And that confers a lot of interesting benefits. I think the way to think about that, first of all, is let's flip it around from the customer perspective. The majority of the patients are with community urologists. When you ask community urologists, what do they want? What do they need? Obviously, they need products that have efficacy. They need products that are highly tolerable because these patients are generally -- and this is underappreciated, are 75- to 80-year-old smoking men with comorbidities, it's tough to get them on treatments. They don't really want to bother with this sort of slow cancer. So tolerability is important. But the third thing that's important are some of the nonclinical benefits, how easy it slides into their practice does it consume resources. So when you think of detalimogene, it's probably the only product that delivers all 3, right? So it -- our preliminary data shows that we have a CR rate that's very competitive, good efficacy. We have probably best-in-class tolerability, very low discontinuations, very low treatment interruptions. But in particular, community urologists, because we have a nonviral approach, our product can be stored in a regular freezer for many years, in the regular fridge for many months. There's no special handling. So if you compare this to some of the other products, right, that require special handling that require prewashes, that require decontamination of rooms, that require hoods, right, that require procedure rooms, right? We don't have any of those things, right? So detalimogene is a really unique product because it provides the efficacy that doctors want, probably best-in-class tolerability. Most of the patients don't discontinue, most of the patients don't have treatment interruptions and probably best-in-class handling and ease of sliding into those practices.

And with that, when you think about sort of your go-to-market strategy and how you plan to sort of reach those community docs? Is there any education that needs to go on given that it's a slow progressing disease? How are you thinking about that?

Well, I think, first of all, from a go-to-market strategy, we think about geographies first, right? And in the U.S., we believe that we'll need 40 to 60 sales representatives, which is very manageable for a company like ours. So we're ready to go. In Europe, our go-to-market strategy, we're still evaluating. I and a lot of other members of our team have a lot of experience in Europe, and that will be a financial decision, whether we go on our own or whether a partner and the rest of the world will partner. So then within the U.S. itself, how do we think about this? Well, within these community practices are often organized in what I call LUGPA's, right, which are a collection of practices. But within a LUGPA, there are usually a handful of doctors that are really focused in on bladder cancer. So we will be targeting them, right? We also have to really think differently about our targeting from how the practices work. And I'll tell you why, right? Because in the U.S., the #1 specialty that does buy and bill is oncology, right, number one. The second one is urology, right? So this is a big source of revenue for their practices. But when you segment the practices, some practices are very sophisticated in what they do and they do a lot of buy and bill. Some practices would really like to do that. But right now, the technologies that have been -- the first-generation products are just clunky for community urologists. And detalimogene is a next-gen product. So it's really going to slide in [ lower ]. And then there's a third group that really haven't explored buy-and-bill and do a lot of referring. So we will be, first of all, targeting the first 2 groups, and we think we can really activate the community urologists because we have a next-gen product that really fits our needs as I talked about earlier.

Great. And then maybe -- sorry, with the registration study, first announced data in 2024 sort of for LEGEND and sort of the amended protocol for the study. Can you talk about sort of maybe a little bit more around that amendment, what it entailed and sort of walk us through now the sort of the next data update and what we can expect from that?

Yes. So the journey for us in our pivotal cohorts, the pivotal study is the LEGEND program. Cohort 1 is the pivotal cohort. When it was designed, it was designed by a CMO who is an oncologist. And we just realized we're going to be a urology company, better have some urologists here, right? So the team figured that out, which is terrific, right? But urologists said like, okay, like why are you making this harder run yourselves? You're not even applying standard of care for these patients, right? So we had some good data, initial data in 2024, but then we made 3 pretty significant protocol changes that brought us in line with standard of care. First one being is before patients even got into the study, the T1 patients, so the T1 patients are higher risk, standard of care is to resect their T1, that lesion and then do a second time. And we weren't doing the second one. Now they all have to get that second resection. The second thing is that as patients got to 3 months, if you had a little TA growth and papillary growth, we said you're out of the study. And the doctor said it's just a little growth. There's nothing happening with cyst. We just cut it out. That's standard of care. Now we allow them to do that. And the third thing that we do is we ask for biopsies before patients come on before doctors would look and say, "Oh, it looks like it's progressing." But sometimes with immunotherapies, the bladder gets red. So it's a much more objective or subjective approach. You take that and you wrap it around the fact that our -- again, with a different approach of doing the study, we brought in a very strong clinical operations team that if you take those protocol changes, mixed with better execution, better follow-up there you go. And the results that we shared late last year are really compelling and much better, frankly. And then what we're expecting is a data update at a major congress in the spring of this year, that's planned. And there, what we hope to do is really focus in on the primary endpoint, which is complete response at any time. So it's 3 and 6 months for us. So that will be locked in because we have about 125 patients and most of those patients would have reached their 6-month time frame. So it's a pretty exciting time.

Good. And I guess the obligatory question these days is sort of alignment with the FDA on the protocol change. And I guess as well as sort of how you're kind of thinking about the pivotal readout and whether or not, again, the FDA sort of you and the FDA are aligned with that. And again, also, how does that compare to sort of peers, if you will, in terms of their pivotals?

Well, the FDA has been terrific with us. Now remember, when you think of the FDA, very rarely do they have guidance in there. They recognize the need in NMIBC, right? And so the guidance that they originally put on 2018 and then reiterated draft guidance in 2024 that if you do 100 patients or so open label, you'll get a complete approval. And what's nice is that a number of products have even recently have got that. So it's pretty rare in all of the things that they do, and I would call that rock solid. We've had a good dialogue with the FDA. And the FDA has provided us a number of important designations. So we have Fast Track, we have RMAT, we have CGRP. And I don't think they give those to companies unless they are serious about working with us to bring this product across the line. So we've had very constructive dialogue with them. We shared our preliminary data with them, which has resulted in some of these special designations. So I think we feel pretty good about being on track for working through the filing in the second half of this year.

Great. And how does the protocol compared to other programs, this is bond program, SunRISe, how does the protocol compared to...

Well, I think I'm always -- I always caution people to make comparisons, right? So first of all, we do not have access to their protocols, right? So we don't know for a fact. But from their publicly disclosed information, what you see is many of the changes that we've done seem to be similarly done with them. But I always caution people to compare against these particular -- I know it's human nature to compare. But first of all, the patient population, inclusion criteria, patient populations are very heterogeneous, right? So NMIBC patients are very different. I believe the protocols are different. And then in these studies of 100 patients or less, right, you can see a lot of swings. So I believe that we're roughly aligned with others. But again, I would just caution individuals to make comparisons between the study, even though it's human nature because there are different patient populations often and often different protocols.

Great. Yes. And then maybe another change if you could comment on, is there a meaningful difference or maybe the reason driving the change from complete response at 12 months to sort of complete response at any time? Like what's -- is there a meaningful difference there? And then maybe what was the motivating factor for that change?

Well, that's just sort of standard discussion that we started in a particular area. We started to talk to the FDA. And the FDA said, look, this is the primary endpoint for all the other products that we've approved. So we would expect that to align. So primary endpoint is CR any time and the key secondary endpoint is duration of response.

Right. And how -- with the potential for sequencing of these different therapies, I guess, how do you see the NMIBC space evolving over time? And where do you think your program fits into that sort of paradigm?

Well, again, I believe this is a real transformation that's going to occur. First of all, you have to think about the customer groups, right? You think about where are the patients. Over 80% of the patients are in the community, right? About 17% from our market research are in the academic centers. In the academic centers, these are places where they remove bladders and they're really focused on efficacy, and they have the resources to use some of these new technologies, right? So some of the newer products that are approved and the products that have come along actually sit very well there. But these new next-gen products where we lead with detalimogene are actually ideal for the community. And right now, most of the new products just don't work very well for the community flow, right? So what we see is in the community that patients will be diagnosed because that's where the patients are. Well, they'll start with BCG if they could get them. Then a nonviral approach like detalimogene because it's just so easy in their office, right? We'll have a product sitting in the fridge. Literally, anyone in the practice can take it out of the fridge, mix with water, regular catheter, instill it into the patient 5 or 10 minutes they're out, right? That's a lot simpler than a lot of the other technologies. So we believe there's going to be a transformation with these next-gen products and some of these other newer products will continue to be used in the smaller specialty area.

Got it. And for detalimogene, do you think about opportunities for the program beyond BCG unresponsive NMIBC with CIS? What where else can this program go?

Well, I think what's really exciting about our -- first of all, our platform is -- our platform can be applied in many areas. Our technology can be applied in many areas. Detalimogene specifically, we've already started a couple of additional cohorts in patients that are naive to BCG, those that are exposed to BCG and those that have papillary only and don't have cyst. So those cohorts are ongoing. And we're also looking at some of the other areas as well because one of the nice things about our product is being a nonviral gene therapy is the only one. It can be -- being a nonviral product and not being an LNP, the cost of goods in manufacturing this is actually relatively low. So that allows you to go to a wider range of diseases. And because the handling is a lot easier as well. It also allows you to go to a wider range. The potential for detalimogene outside of its first indication is pretty significant.

Right. And you just talked about sort of manufacturing. You're participating in the CDRP pilot program. Maybe you can describe what that is? And then also sort of, again, as you kind of talked about before, the differentiation of detalimogene from just historical NMIBC program that has sometimes struggled with manufacturing.

Yes, really great question. Well, first of all, we're very honored the FDA granted us CDRP. It's a pilot program, 1 of 9 companies. It's given on the basis of great innovation, but also clinical data and clinical need. And to your point, when you think about in the old days, complete response letters were for clinical reasons, now they're mostly for manufacturing, and it's been more so in this category. Effectively, what this means though, rather than taking module 3, the CMC module and kind of throwing it over the fence when we file, we actually start engaging in an early dialogue with the FDA. We open the kimono, we say, here's what we're planning. They give us feedback more, there's a little less of that, et cetera, et cetera. And that will significantly reduce the risk of CRLs. Now we always thought because, a, we've been manufacturing at scale. We're pretty much finished our PPQ batches, our validation batches. So we'll be writing module 3 very soon. And because our product takes readily available ingredients and there is no -- it's not a virus, it's not an LNP, we lined up with a product that has relatively low cost of goods. And because it's not a virus, the handling is a lot easier as well. So it makes it very competitive. So I think CDRP is a real help for us and certainly reduces any risk that we might have on the manufacturing front.

Great. And what type of feedback have you gotten from key opinion leaders in bladder cancer around the detalimogene as well as sort of how it sort of compares to competitors?

Yes. Well, first off, I actually never consider them to be competitors, right? These are complementary medicines. And the reason I say that is if there was a product that had a 12-month complete response rate of 80% to 90%, that would be a competitor. That would be the #1 product that's being used. But most of these products have an anytime CR rate of around 2/3, somewhere in that range. And the products have a 12-month rate of 20% to 40%, which means patients are going to recur. So all these products are going to be used. They're just going to be used in different places and in different sequence. We just believe that when you think about the needs of the community urologists, the first-gen products, they're not really using very much because they just don't fit their needs. They're just too clunky to use, right? These next-gen products where detalimogene is leading, I think, really fits to where the patients are and are going to -- it's going to transform -- be able to start the transformation of this marketplace.

Yes. Great. And then obviously, for your upcoming data disclosures, if you can just talk through what good looks like in terms of benchmarks or hurdle rates when you think about sort of what is a good data set, what is not a good data set as you think about sort of these upcoming disclosures?

Well, these are experiments, right? So you never know exactly where you're going to land up. But I think in our spring conference, right, if we -- that's where we'll be focusing in on the CR any because most of the 125 patients would have hit the 6-month time frame, right? And if you look at the range of products in that, they range from sort of 50 to 60, 70 range of CR any time. So let's see where we land up. We had a CR rate of any time, 63 on the preliminary. So if we're within that range, I think that sounds good to me, right? And then in the second part of the year, we expect to have the 125 patients, the majority of them would have reached the 12-month time frame. And again, it's an experiment. And the range there is 20 to 40, right? We think we're going to be competitive on both ends. So I think that we feel pretty confident this being an immunotherapy in our durability as well.

Great. I was beyond CR, right, obviously, sometimes you kind of have trade-offs and efficacy, safety and convenience as well as just think about other parts of sort of this data set that beyond CRs that you're going to be looking at and trying to educate investors about.

Yes. That's a very good point. I almost skipped over probably one of the most important things, right, is the tolerability, right? Again, think of these patients, 75- to 80-year-old smoking comorbid men, right? They don't want to have a hassle, right? And if you look at our clinical trials thus far, we have a discontinuation rate in the very low single digits. We have treatment interruption rates very low, where other products are in the 40s and above. So the tolerability for us is going to be very competitive. And that's going to be important. And I think what Wall Street is missing is that particularly for where the patients are in the community, these newer products are just too difficult for them to use to get into their practice flow, cost them too much money and too much resource. Our product is going to differentiate so nicely. It's going to slide right into the practices. In fact, it's going to be easier than what they've been using in BCG. So that's going to be a big benefit.

Yes. And it looks like we're up on our time. But, Ron, thank you so much for your time today. Thank you for our listeners, and we'll be back soon with our next session.

Great. Appreciate the opportunity. Thank you.