And, welcome.
Pleasure to be here. Thank you very much for the invitation.
Well, thanks for coming back. I remember the conversation last year, and a lot has happened since.
It's been a busy year, that's for sure.
Absolutely. Maybe we can get started diving into the detalimogene program for non-muscle invasive bladder cancer. You made some pretty major amendment to the protocol that included the T1 re-resection and the TA reinduction. Those were key in terms of the advancement of the program. Can you maybe give us a sense of which of these changes do you believe contributed the most to the improvement that we saw in percentage point in the six months complete response rate?
I think the first thing is to kind of step back a little bit, right? When you think about the studies in NMIBC, you know, they're all roughly between 70 to 100 patients, right? If you impact even a handful of patients, it's a meaningful impact, right? I think the way that we think about our protocol change, the three being re-resection T1 patients, reinduction TA patients, and then biopsying patients before they leave the study, all of those things are just really standard of care, right? What we did was we brought our trial towards what urologists are doing, right? If you wrap that around the fact that our approach from a clinical operations perspective is totally different, right?
A team that's executing the trial in a different way with different oversight, that's where we believe the combination of those three, those three elements, plus better execution and a different approach to the clinical trial has made a meaningful difference in our response rates.
Okay, you think that it's more of like kind of a holistic, differentiated approach rather than a specific amendment that has led to the approximately 21% improvement in percentage point improvement that we saw?
Yeah, as I said, you know, these are, you know, these are major changes in a relatively small database, right? It doesn't take a lot. I, you know, trying to parse them apart, you know, I don't think that, you know, that's really helpful. I think it really is the combination of those things that work together, 'cause some patients have, you know, may have been impacted by two of those parameters, right?
Yeah.
It's a little bit more complicated than that.
Thinking of the amendment specifically to the assessment of this disease, obviously now it went from visual impression to biopsy, as you mentioned. How has this [audio distortion] continuation, right, so far?
Well, I think it kind of fits in that same bucket that I just talked about, right? You know, think about a, you know, from a logical perspective, you know, we were allowing doctors to take patients out of the study if they would look visually, and sometimes when you look in the bladder, like these are beaten up bladders, it's immunotherapy, sometimes that's red, right?
Mm-hmm.
Standard of care is before you take someone off a therapy, you know, you give them a biopsy. I think we're being more consistent with standard of care, and that's had a, you know, a good effect on our efficacy rates.
Great. Now thinking about the post-amendment cohorts, four patients converted from non-response at three months to complete response at six months. That was following reinduction. Can you just tell us more in terms of whether cycle patient can have?
Yeah, there is a limit, right? All patients are assessed at the three-month timeframe, and then all patients are given product at the six-month timeframe. If the three-month timeframe you're a responder, you would get treatment at the six-month timeframe. If you're a non-CR or a non-responder at three months, you would still get reinduced at the six-month timeframe. That's where the limit is. After that, it's only those individuals that are responders that have a CR that will continue to get therapy.
Okay. For the last data cutoff, there were 23 patients in the post-amendment cohort who achieved a six-month CR. Maybe could you give us a little more color in terms of the cadence for the nine months and the 12 months readout for those patients?
I'm sorry. The cadence of?
The nine months and twelve months read. We've seen the six months.
Yeah
for those patients who had a response. When can we expect potentially longer timeframe for this?
Okay. Sorry. Yeah. Sorry. We are pretty excited. We in our in our guidance, the 12-month data for the patients will be providing the second half of this year. You might or not have seen this morning that we announced that we plan an update at a-
Medical conference
... science conference
Yeah
... in the second quarter of this year.
Mm-hmm.
We're excited to provide an interim update to the market.
At the medical conference, should we expect nine months data? Should we expect 12 months data? Would all the patients that we've seen the six months data for so far have longer follow-up data at nine or 12 months?
Yeah, we have to work with the organizers of the medical conference to work through that. I think what we will do is we'll put all the patients together in an ITT population likely where you'll see the totality of the data at that time.
Thinking about totality of data and the study as a whole, there are obviously multiple cohorts. Obviously the focus has been on, you know, the pivotal, what could be the pivotal cohort. When could we get a first meaningful efficacy look to other cohort per se, the BCG-naive or BCG-exposed patients?
Yeah. For us, you know, the focus really is in the pivotal cohort. We wanna make sure that we're executing against that pivotal cohort, so we put a lot more effort to make sure that it's fully enrolled and it exceeded our objective enrollments and instead of 100 to 125 patients, so a lot of interest from the prescribing physicians. We're very focused on following those patients. The other cohorts have been, you know, a lower priority. You know, these are to provide information to the physicians over time. We're kind of going back to them now, and we're starting to do a little bit work on them. They are ongoing, but they're certainly not at the same level of priority as the pivotal cohort.
Maybe one last point on that cohort before we go back to, kind of the more pivotal cohorts. How should we think about the data translating from what we've seen in the pivotal cohort into this larger, like, subgroup of patients?
I think, you know, as we start to do market research, right? When you think about the patient population, For the physicians, it doesn't seem to be it's as clear, like the strict definition that our patients have, right? These are BCG-unresponsive patients that have had a full course of BCG. When you start talking to the prescribing doctors, they're a little more nuanced.
Mm
... than that, right? They have patients who they don't believe should get BCG, right? You know, are intolerant. They have patients that get partial doses of BCG, particularly because the issue of BCG shortages, right? Some of what we see in these additional cohorts, actually for the prescribing physician, is all sort of one big bucket. We would expect, you know, similar results right across there.
Yeah. Okay. Thank you for the color. Going back to the pivotal cohort, the pivotal design. Following FDA feedback, you shifted from the primary endpoint of the CR at six months to CR at any time. How does this change your internal bar for success compared to, you know, just looking at 12 months?
That change in primary endpoint really is just to align with the FDA wants, right?
Mm-hmm.
If you look at what they've approved other products, that's been the primary endpoint, CR at any time.
Any time.
We have a competitive CR at any time with the interim data that we've had. That's even in the 60s, right? And if you look across the agents that have been approved, they're roughly, you know, at 2/3 in that range. We feel very confident, you know, about our CR any time.
Great. Now thinking about pre-amendment and post-amendment cohorts and how much of the pre-amendment cohort could be kind of used for the data package. You'd mentioned that potentially some of the pre-amendment patient may be excluded. How should we think about the minimum N that the FDA would require, and how far are we?
Well, I think, you, when you think about the pre-amendment patients, there are 31 patients, right? Post is 94. We started to look at the data in totality, in reality, the pre-amendment patients are de minimis.
Mm.
Right? Because the size of the post-amendment population, 94, is so big, right? Now that being said, we are in a discussion with the FDA on a statistical analysis plan ( SAP), which is pretty standard once you fully enroll the study. We're kind of going back and forth with patient populations. That's a process that you try and get finished before you file the product, right?
Mm.
We anticipate some back and forth with the FDA. You know, in that, we anticipate that, you know, they will exclude some patients, which is quite common.
Yeah.
Which is quite common. Already at 31, it's de minimis on the impact, right? You know, I don't know what is de minimis less de minimis. It's probably poor English, right? Not very much of an impact.
We'll cut that in the conversation.
Yeah.
As you mentioned, you know, there's been over 100, more than that, patients that have been enrolled. In terms of the current safety database, do you expect that to be sufficient, or do you expect potentially having to provide additional, like, longer term safety follow-ups, or how should we think about that?
Well, the program that, you know, the LEGEND Cohort 1 program with detalimogene is the largest program in the space.
Right.
Right? At 125 patients, so it's by far the largest. I think we feel very comfortable that that's a sufficient database for safety. When you look at the other agents, you know, they've been approved in the lowest 7, you know, in the 70s, right?
Mm-hmm.
I think we feel really confident. The other aspect of it is if you look at our tolerability profile and safety profile, you know, it's trending towards best in class, particularly when you start looking at things like treatment interruptions and treatment discontinuations. You know, those are real measures of, like, are the patients taking the product? You know, will they show up for their treatments, you know? Ours are in the 1% to 2%, right?
Mm-hmm.
really great for patients and therefore really great for physicians as well.
Thinking about interaction with the regulatory agency, so beyond the statistical analysis plan discussions, can you maybe give us a little bit of understanding as to how RMAT guides your or helps the conversations with the agency?
We're just delighted with the interaction with the FDA overall. You know, and I think that we sit in a special place. You know, we start off with the fact that the FDA does not give guidance very often. You know, usually it's, you know, two studies, double blind, placebo, et cetera, et cetera. When they gave guidance in this NMIBC space, you know, for 100 patients, open label roughly, and you get a full approval, that's, you know, that's not commonly done. We feel very confident about it. On top of that, I think a measure of engagement and interest is the fact that the FDA gave us RMAT and CDRP.
Mm.
What does RMAT give us? RMAT, think of RMAT as kind of breakthrough, right? RMAT allows us much more dialogue with the FDA. Effectively what we do with the FDA is we line up what we have and what we're planning to submit, and they give us feedback early versus kind of throwing it over the fence. We're much more aligned, so we feel very comfortable about, you know, the potential for approval.
You also mentioned that the program is part of the CMC Development and Readiness Pilot, so the CDRP. Can you just maybe give us a little more color since it's a little less common, you know, than the RMATs?
Well, CDRP is a real honor, and again, I think is an indication of the engagement with the FDA. CDRP is given to one of nine companies. It's a pilot program, and it's to help you in the CMC space. If you look at CRLs, You know, CRLs used to be for clinical issues. More and more they've been for manufacturing issues, and it's plagued this category. CDRP is given to products that have special innovation and have a big impact on patients. A big criteria that goes with that. Effectively, what that does is allow us to, again, rather than throwing it over the fence, to go through all of our plans, all the data.
They give us some feedback and say, "More of this, less of that." Particularly in our case, where we're pretty much finished our PPQ or our validation batches, we'll be writing Module 3 very soon. It's timely to have CDRP and, you know, I think our product, you know, being, you know, made of smaller products that are readily available, the fact that we can make it at scale, our cost of goods are gonna be relatively low. It's a really competitive advantage to have CDRP and RMAT.
Looking beyond FDA interaction and into commercial strategies. As you mentioned previously, the data so far has shown a CR rate that is very competitive compared to all of the other programs that are in development.
Mm-hmm.
Can you maybe remind us some of the key commercial advantage that you see with the program compared to all of the competition that has a similar profile in terms of efficacy?
Well, I think let's just, you know, let's start with the lens of the physician, right?
Mm-hmm.
First of all, where are the patients? You know, the patients are with community urologists. Community urologists represent over 80% of the population, right? Most of the patients are there. We have a number of new agents, right, that have been approved. They're getting used, but are they getting used a lot? Probably not, right? Why aren't they getting used a lot, right? You look at the criteria for what the community urologist wants, when we look at our market research, obviously you want efficacy. They value tolerability and non-clinical benefits such as ease of use and how it factors into their practice flow equally. Like, literally, they're almost equal. What is the ideal profile?
The ideal profile is a product that has efficacy, which, you know, I think we've demonstrated competitive profile, that has tolerability, that where their patients don't complain. You look at our product, patients actually stay on their drug, don't discontinue, right? Slides into their practice, right? Slides efficiently into our practice. If you look at a non-viral gene therapy, which is unique, the non-viral gene therapy, first of all, sits in their freezer for years, regular freezer. Will sit in their fridge for months, right? It can be handled by anybody. It's very, you know, there's no. You don't need a special nurse. You don't need a hood. You don't need to decontaminate, right? That's very easy. There's no, you know, long thawing that goes with it.
For the patient experience and for the office itself, there's no pre-washes, right? In the clinical trial, you mix it with water and you instill it in the patient. We ask them to stay for an hour now to collect their urine. In real life, it's a five-minute administration and, you know, tap the person on the back and say, "You know, you can void at home. You don't need to bleach anything." For the amount of the number of times you have to come in, now these are, you know, in general, 75 to 80-year-old men, right? In general. For detalimogene, you come in for week one and two, week five and six, rinse, repeat 3 times the next, you know, that year.
Whereas for other agents, particularly if you get reinduce, you would come in for 12 weeks in a row, and you would, you may be exposed to probably 60 different bladder washes in that timeframe.
Yeah.
Right? If you then step back from the patient, much less burden, great tolerability, and then you step back from the practice, urology practice: no special equipment, no special staff, no special procedures. It doesn't cost them a lot of money to use this product. In fact, it's more, probably even more efficient than BCG.
Mm-hmm.
That's why we believe that detalimogene really fits the needs of those community urology practices.
Thinking about the community urologists, but also the maximization of the throughput, do you anticipate this to be a product that could be potentially administered by a medical assistant or a nurse? Is this something that you might want to think of during the clinical development to try and get to a label that would expand the provider that might be able to.
Well, we, so from a label perspective, we would expect that our label would not have any restrictions.
Mm
... right? That a APP or someone in the staff could administer it, this, whereas some of the other products, they absolutely have to be administered by a urologist. Getting back to the practice economics and practice dynamics.
Mm
... right? You think about urologists. Obviously they wanna do the best for their patients, right? They obviously wanna do the best for their give them the best therapy. Also, increasingly, these practices are owned by private equity, right? There's some pressure on them to perform.
Yeah.
Right? These agents will allow them to have buy and bill, right? Which will be a good source of revenue, but also, they don't wanna spend a lot of resource to-
Administer
... provide the medicine.
Yeah.
Right? In this case, you know, if I was your urologist, I would say, "I'm gonna start you on detalimogene," but then I would walk out of the room and do some other procedures and bill for those procedures. Someone from my staff will reach in the fridge, mix detalimogene, and I will bill for that instillation as well. Not only is it revenue generating for them, but it is also low on a cost perspective and easy for anyone in their offices to administer the product.
Thinking about that model, we recently hosted a KOL lunch at ASCO GU, talking specifically with bladder cancer physicians, and the understanding was that there has been a shift in terms of the number of patients that I seen in a research institute than those seen in the community, as you mentioned, and it seems like this is increasingly going toward people being seen in the community. Is this something that you also see in your market research? you know, within your research, what's the % of those, you know, physician practices that use a buy and bill model?
First of all, over 80% of urologists are community urologists.
Mm-hmm.
The vast majority of patients are there. That's where they are. Buy and bill, it's a great source of revenue for those practices. The number one users of buy and bill are oncologists, right?
Yeah.
Number two are urologists, right? They see this as a real growth opportunity for their practices, but I think they've been limited by the agents that have been available to them. It's just too hard for them. For some practices that are pretty sophisticated, they've been doing it quite regularly. We see this as a tremendous commercial opportunity to go to our doctors and say, "Look, here's detalimogene. This is gonna be great for your patients, but it's also gonna be great for you and your practice," right?
Yeah.
I think it really does fulfill an unmet need for the urologist. Detalimogene could really be the cornerstone of sort of the first choice therapy for these patients.
We've mentioned competition. Obviously, this has been a very competitive space. We've touched a little bit on the potentially different iating factors that kind of characterize the program specifically. With that in mind, how should we think about pricing?
Yeah. I think the first thing is I don't actually see this as competitive, right? Competitive suggests that there's a winner that takes all, right?
Mm.
It's a closed market. I actually see these as complementary medicines, because we believe that with products that have recurrence rates of anywhere ... approved products, right?
Yeah.
60%-80%, and with you know, the desire for physicians or for patients not to remove their bladders and physicians not to do that, right? These products are going to be sequenced. All of these products are going to be used, just a question of when and who, right? When and who. I see it as And frankly, that means the market is going to grow, right? to your question about pricing, I think you know, that's going to evolve, and for us, I think pricing is a real advantage, right? Because we have a non-viral approach, we use simple ingredients, right? We have the opportunity to see how the market, you know, starts to, you know, advance, right?
We can price at the higher level, the middle, or even lower if we wanted. Pricing is all. You know, I've priced lots of products in my life, right? You usually do it almost on the very last day, right?
Mm-hmm. Mm-hmm.
You're really trying to get every data point to see how you maximize value. We have a tremendous advantage there, and we will maximize value.
Thinking about a commercial strategy as we move toward BLA submission and pivot more toward commercial launch, how should we think about expenses, you know, in the next, you know, I would say 12 to 18 months as you ramp up production, but also as you kind of put together the commercial strategy?
Well, the early part of any. At this stage, right, of any biotech that is going to be a commercial biotech, right now and in previous years, we've been burning a tremendous amount of cash focused on the clinical program and focus on CMC. It's very heavy in that, in that timeframe, and G&A and commercial are relatively small. As we transition to a commercial company, our CMC spend actually goes down significantly, and our clinical spend will also go down significantly 'cause the pivotal cohort is the most expensive thing to do. That gets offset by, you know, G&A and commercial expenditures, and that starts to go up a little bit as well. That's the way to kinda think about that, you know, as we transition towards a commercial company, but we're in very good shape.
You know, the company has cash into the second half of 2028. You know, we expect a potential approval in 2027.
Mm-hmm.
You know, we're in very strong position from a clinical perspective, a cash perspective, and a readiness perspective to make this product a real success.
Great. Well, we look forward to the upcoming data at a medical conference and then to getting closer to BLA submission and potential approval.
It's an exciting year for us.
I'm gonna-
Thanks again for the opportunity.
I'm gonna scan the audience for any remaining question in the last few minutes we have. Otherwise, thank you so much for your time, and it was a pleasure to chat with you as always.
Pleasure to see you. Thanks again.
Thanks, everyone.