Morning everyone. We apologize for our technical difficulty, but we are up and running now. Welcome to the enGene Therapeutics webinar to discuss the preclinical work supporting its lead investigational therapy, detalimogene voraplasmid, plus a surfactant bladder rinse, as well to discuss the clinical case studies. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentation. As a reminder, this call is being recorded, and a replay will be made available on the enGene website following the conclusion of the event. I'd now like to turn the call over to Lauren Hopfer, Executive Director of Investor Relations at enGene Therapeutics. Please go ahead, Lauren.
Thank you. Good morning, everyone, and thank you for joining. With me on today's call are Ron Cooper, CEO, Anthony Cheung, enGene's Co-founder, and we're pleased to welcome Doctors Suzanne Merrill and David Cahn of Colorado Urology. Before we begin, I would like to remind you that during our prepared remarks and Q&A session to follow, we may make forward-looking statements for purposes of U.S. and Canadian securities laws.
These statements include, but are not limited to, our current expectations regarding the potential benefits of detalimogene voraplasmid or detalimogene, the efficacy, safety, and product profile of detalimogene, potential impacts of incorporating a surfactant bladder rinse prior to treatment with detalimogene, timing of clinical data, timing of regulatory submission, prospects for regulatory approval of detalimogene, projections of market opportunity and market share, anticipated market acceptance of detalimogene, if approved, our current views and market research on NMIBC bladder cancer implications or takeaways from our market research, estimates, projections, or forecasts of payer coverage of therapies, expectations regarding how detalimogene may be used by healthcare providers or sequencing of products.
They involve risk, uncertainties and assumptions that are difficult to predict and may not prove to be accurate. These statements should be considered only in conjunction with the information in our filings made with Canadian and American securities regulators, including our Risk Factors section of our annual report on Form 10-K. At this time, I'll turn the call over to Ron Cooper, enGene's President and CEO. Ron?
Great. Thanks, Lauren. Thank you all for joining us this morning. You see here on slide three is an overview of this morning's agenda. Before we begin the formal presentation, I'll start by reiterating that we believe the NMIBC market is fundamentally changing as next generation medicines meet the different needs of community urologists, and that detalimogene is uniquely suited to address the combined efficacy, tolerability, and logistical challenges of community urologists.
First, we believe that the NMIBC market is still immature and that the advent of more options for patients will drive an increase in the prevalent population through increased sequencing of therapies to grow the overall market and create room for multiple therapies. This is not going to be a winner-take-all market. Second, we believe that detalimogene's clinical profile to date is compelling.
Our most recent interim data update for the LEGEND pivotal cohort, which has studied detalimogene without a surfactant, was in May of this year. While our long-term durability data was still immature, with a median follow-up of just five point five months for all patients, we were encouraged that our study's primary endpoint, complete response at any time, was 54%, within the range of products already approved for this indication.
Even more encouraging was detalimogene's tolerability profile, which we believe is trending towards best in class. Rates of treatment-related adverse events leading to dose interruption or discontinuation were only 2.4%, respectively. Third, detalimogene was designed with our non-viral DDX technology, which uses low-cost, readily available components supporting both scalable manufacturing and simplified storage and handling, which makes it viable for all practices and should allow for broad adoption in any practice setting.
Fourth, we're already thinking about lifecycle management through the incorporation of a surfactant bladder rinse. Our pre-clinical data suggests that this approach may improve both the efficacy of detalimogene and reduce dwell time, another potential advantage to patients and providers. Importantly, we remain well-funded to accomplish all our upcoming milestones and through potential approval in 2027. Now, before handing it over to our community urology experts, I'd like to review highlights from market research that give insight into the new dynamics impacting the NMIBC market.
First, with next gen therapies, we believe the community urology market will begin to unlock, and the prevalent market should grow with increased sequencing. We also outlined the evolving pricing dynamics over the course of several years, with the most recent group products launching in the range of $500K-$700K per year and with little payer pushback. Importantly, 40% of patients are being treated in community practices that are either resource-limited, workflow-constrained, or economics-focused.
These are practices looking to balance efficacy, safety, resources, and economics when making treatment recommendations. Given these constraints, there's a continued need for new bladder-sparing treatments, and detalimogene as a next gen product has the potential to unlock these segments as a workflow-friendly option. I've shared with you market research highlights, but there's nothing better than hearing from physicians that are on the front line treating these patients. With us today to shed light on these aspects are two leading community urologists from Colorado Urology, Dr. David Cahn and Dr. Suzanne Merrill. With that, I'll turn it over to Doctors Merrill and Cahn to introduce themselves, their practice, and review illustrative patient cases
Thank you, Ron. I am Dr. Suzanne Merrill, and it is a pleasure to be with you today. Following my fellowship in urologic oncology at the Mayo Clinic, I spent six years in academic medicine as an associate professor of urologic oncology and residency program director at Penn State Hershey Medical Center. I then transitioned to private practice at Colorado Urology just over five years ago. I would like to take this opportunity to tell you a little bit more about my practice before diving into a case study discussing the real-world management of non-muscle invasive bladder cancer.
With my background, I have unique insights into the differences in academic and community urology. Colorado Urology is a large group practice in Denver. We are part of a larger national group, commonly called LUGPA, that has multiple practice sites across our nation and employs over 220 providers. At Colorado Urology, we have over 30 urologists and 20 advanced practice providers serving 18 locations through the greater Denver and Boulder metropolitan areas, which collectively serve close to 130,000 patients.
Our practice is structured similarly to other LUGPAs across the nation. However, there are still many smaller, independent community practices that are different from our organization. Many such large practices have provider champions for specific urologic disease states, and I lead our Colorado Bladder Cancer program, where we look to offer patients access to the most cutting-edge bladder cancer treatments as well as clinical trials. I will let Dr. Cahn, our director of clinical research, tell you a bit more about that. David?
Thanks, Suzanne. I completed my residency in urology at Montefiore Medical Center and a fellowship at University of Colorado, and I have been in private practice since 1998. In 2000, I founded Foothills Urology, which became Colorado Urology. I have always had a passion for clinical research, and I have the pleasure of leading the practice's clinical trial program. At present, we have 38 active trials ongoing, and I have served as the PI on more than 70 clinical trials. What we look forward to speaking to is the often long and burdensome patient journey and the continued need for additional therapies in the BCG unresponsive space. With that, I would like to turn to our patient case studies to shed some light on the various treatments and lifestyle considerations impacting treatment decision. Let me turn it back over to you, Suzanne.
Our first case involves an 82-year-old male named Walter, a retired veteran who moved into an apartment down the street from his daughter and three grandchildren after his wife passed. Walter is a long-term smoker with a history of peripheral vascular disease, coronary artery disease, COPD, and atrial fibrillation, who experiences urinary frequency and urgency, which are currently managed with Myrbetriq. His cardiologist has prescribed him Eliquis. Walter's initial presentation starts in January of 2022, where he develops gross hematuria or blood in the urine, and his urine cytology was found to be positive with a normal CT scan.
Using cystoscopy, we saw diffuse erythema, which means severe redness within his bladder, and thus we performed a TURBT, which pathology confirmed multifocal carcinoma in situ. As a standard for NMIBC with CIS, Walter began BCG induction. With traffic, though, this is a 45-minute drive to and from the office for him and his daughter, who accompanies him, and presents significant scheduling and childcare challenges for the family. Following induction, we find persistence of CIS, and reinduction with BCG is recommended. Walter does respond following reinduction and enters into a maintenance period with BCG for one year.
However, in July of 2023, at a quarterly surveillance appointment, we see a papillary lesion and another TURBT is performed with path-confirming CIS plus high-grade Ta papillary disease. Based on this, Walter is now considered BCG unresponsive, high-risk NMIBC. At this time, given his more advanced age, continued health challenges with COPD and heart disease, Walter is a poor candidate for cystectomy. At this time, only Keytruda has been approved for BCG unresponsive CIS, for which potential side effects could be significant and difficult to manage for him and his caregiver.
While Adstiladrin was approved in 2022, it did not yet have its J code, which meant reimbursement would be a challenge. Although resolved in recent years, manufacturing issues ultimately made this drug initially widely unavailable for commercial use. So we settled on treating Walter with Gem/Doce, which is successful, and he undergoes monthly maintenance for the next year. His next recurrence is in September of 2024. With cystoscopy, we see a lesion and then perform TURBT again with pathology confirming CIS plus high-grade Ta disease. Walter is now 85 years old. His health is continuing to decline, and after his last recurrence, he has moved in with his daughter and grandchildren.
With his ongoing comorbidities, he is not a candidate for cystectomy and now is developing worsening urinary urgency and incontinence. At this point, both he and his daughter are looking for something that is going to offer less frequent dosing and be overall more tolerable with his declining bladder function. At this time, the treatment discussion moves to one which requires balancing his multi-recurrent disease, his age, comorbidities, and bladder symptoms.
Since we have already used sequential gemcitabine and docetaxel, we would not recommend treatment with additional chemotherapy due to a similar mechanism of action, nor would we recommend other available agents due to their frequent dosing schedule on account of his poor bladder function. Now that he is sharing a bathroom with four other people, his daughter feels uncomfortable with clinical trials or products involving viral agents due to the need for urine bleaching, as well as the need to do separate loads of laundry for her father's clothes for a period of time after exposure to such agents.
If detalimogene were available as an option, it would be attractive alternative for the following reasons. First, being a non-viral gene therapy, it would be a different mechanistic approach than what Walter has experienced in his past. Second, in an aging patient with worsening bladder symptoms, we need a treatment that provides both a strong tolerability profile and reasonable chance of achieving a complete response. Finally, given the less intense dosing schedule and lack of post-treatment bleaching or contact precautions, detalimogene would be an attractive next treatment for Walter. And with that, I'll turn it over to David to review another case.
Thanks, Suzanne. Our next patient is quite a bit different. A 70-year-old newly diagnosed Albert is an active, otherwise healthy former business executive who travels frequently. He is on an advisory board. He visits family on both the East and West coasts. Albert plays golf and tennis weekly, and he has no significant medical comorbidities. Otherwise, in great health, his diagnosis of bladder cancer is both a shock and viewed as a major inconvenience. That said, Albert is initially a motivated patient, and he wants to address this issue as quickly as possible.
Albert's initial presentation in January 2024 was gross hematuria, which is quite typical. He had positive cytology, and a cystoscopy revealed multifocal lesions. Pathology confirms high-grade Ta NMIBC. He immediately begins a BCG induction. During the induction cycle, he misses a family reunion but is relieved to have a complete response. He then undergoes one maintenance cycle. At his next disease assessment in July of 2024, he is still in response and decides to discontinue therapy. Albert is lost to follow up for a year.
Once again, in June 2025, Albert presents with blood in his urine and comes into the office. We confirm recurrent multifocal high-grade Ta disease. Given the time from his last BCG, he is technically classified as BCG exposed. We discuss a few options with him, including cystectomy, which he refuses. As no approved products have NCCN 2A guideline inclusion for papillary-only disease at this time, which presents reimbursement issues, some clinical trials are discussed given my interest in clinical research. He is not interested in these. So we move to discussing gem/doce, and he agrees to this.
We begin the induction course, and he really struggles with severe bladder burning, which results in his inability to hold each drug more than 30 minutes. Once Albert moves to the monthly maintenance, it is slightly more manageable, and he is able to complete two maintenance cycles before he recurs again in November 2025, this time with a high-grade Ta lesion. At this point, he is eligible once again to undergo BCG, still cystectomy, or a clinical trial.
He is reluctant, but given his past success and time between exposures, he once again chooses BCG and completes both induction and two maintenance cycles, despite once again experiencing burning and difficulty holding BCG for the recommended two-hour dwell time. Thankfully, this time he is not lost to follow-up, and a TURBT during routine surveillance in September of this year, we uncover CIS. He is now officially deemed BCG unresponsive.
Albert once again refuses cystectomy, and he's hesitant to begin chemo given his experience with gemcitabine, but he agrees to try INLEXZO, given his strong complete response at any time. We insert the pretzel. About a week later, he calls our office complaining about urinary burning and the sensation of having to urinate frequently, particularly bothers him during his tennis matches, and he wants the device removed. Our staff counsels him to continue on the therapy, and he agrees.
About a week later, he calls back and demands that the pretzel be removed. Albert is a very active guy, and his NMIBC has recurred but has not progressed. I would like to give him something else, but need a viable option. In this case, I'm looking for something that is different, has efficacy, and will be convenient for Albert, and something that also offers a strong tolerability profile, given his difficulty holding BCG and chemotherapy for the recommended dwell times. Based on detalimogene's profile to date, if it were available, this would be an attractive choice for Albert.
Ultimately, both cases highlight joint decision-making and the need for additional bladder-sparing options, whether because a patient forgoes radical cystectomy to maintain their current lifestyle or because patients are simply a poor candidate for the procedure. Patients are often trying to balance everyday life, management of comorbidities, and bladder symptoms with the degree of treatment burden and the hope for treatment success. There is certainly no one-size-fits-all option for each patient, and as clinicians, we are excited by the continued innovation in the high-risk NMIBC space and look forward to the ability to offer our patients additional bladder-sparing options.
Right. Great. Well, thank you. Thank you very much, Dr. Cahn and Dr. Merrill, for your comments. Let me turn it over to Anthony, our founder, to talk about detalimogene and surfactant.
Great. Thank you, Ron. I am excited today to provide you with a deeper look at what is next for detalimogene. I will walk through the scientific rationale for combining detalimogene with a surfactant bladder rinse and answer a number of questions we continue to receive but have not covered in detail until today. I will walk through this rationale in three parts. First, I will review the scientific rationale for using a surfactant with an intravesical gene therapy.
Second, I will describe how we selected polidocanol and summarize the preclinical evidence supporting its use in clinical development. Finally, I will discuss how these findings have informed the clinical surfactant cohort that is now underway with the LEGEND trial. Let us begin with the scientific rationale. To understand why improved penetration and distribution of detalimogene throughout the bladder may matter, it is helpful to revisit detalimogene's mechanism of action.
detalimogene is a non-viral, plasmid-based gene therapy designed to deliver DNA encoding three genes into cells lining the bladder. Together, these components are designed to locally stimulate complementary arms of the immune system. RIG-I activation initiates innate immune signaling and support recruitment of NK cells and T cells to the bladder. Local IL-12 expression then promotes Th1 polarization of the indwelling T cells, creating a strong antitumor response, cytokine production, and potential formation of durable immune memory.
Essentially, we are aiming to create a strong adjuvant effect with detalimogene. Decades of vaccine biology shows that the strength of the adjuvant effect determines whether the immune response is robust and durable. The question we asked ourselves was straightforward: How do we increase the level of transgene expression from detalimogene? While an intuitive way to increase gene expression would be to administer a higher dose of detalimogene, our phase I data indicate that the relationship between dose and gene expression is sigmoidal rather than linear.
These sigmoidal dose response findings are consistent across gene therapies. In terms of dose response, you can see that we observe a substantial increase in urinary IL-12 when the dose increased from 250 to 800 micrograms per milliliter. But when the dose increased further to 2,500 micrograms per milliliter, expression appeared to plateau. This pattern was also consistent with other preclinical models. It suggests that increasing the dose alone is unlikely to produce a proportional increase in therapeutic gene expression. That is why 800 micrograms per milliliter was selected as recommended phase II dose.
We also spaced the two-weekly administration in each treatment cycle to help avoid saturating the host transcriptional machinery. This observation led us to explore a different strategy. We asked, instead of giving more drugs, could we increase IL-12 expression by allowing the existing dose to reach larger number of receptive cells? Looking at other gene therapies in the NMIBC space, we found meaningful precedent for incorporating a surfactant bladder rinse prior to administration of therapeutic agents.
As shown here in this slide, preclinical work with viral gene therapies, for example, cretostimogene and [Esilgan], these agents demonstrated relatively limited urothelial transfection without a surfactant pretreatment. After incorporating a surfactant pretreatment, transfection increased substantially and extended across broader portion of the urothelium. Although the specific vectors, payloads, and surfactants shown here differ from detalimogene, these findings support the broader biological principle that a surfactant can help a gene therapy overcome the urothelial barrier and improve access to target cells.
With that reasoning, we move into preclinical development and surfactant selection. Our goal was not to simply identify the agent that produced the largest signal in an experiment. We wanted a surfactant that could ultimately support clinical development and broad commercial use. We established three principal selection criteria. First, the surfactant needed to be commercially available so that we could have immediate and uninterrupted access to supply. Second, it needed to be available as cGMP-grade material at scale and at a practical cost, and in regions where clinical sites would operate. Third, it needed an extensive existing safety database.
detalimogene has demonstrated a favorable tolerability profile, and we did not want the addition of a surfactant bladder rinse to compromise that important attribute. These requirements narrow the field to agents with both scientific potential and a practical path into clinical and commercial use. Nonoxynol-9 was initially selected because it has been widely used for many years as a spermicidal agent in contraceptive products.
Consequently, it was commercially available and supported by an extensive body of safety data. DDM was used as a benchmark for our preclinical studies. DDM is a non-ionic surfactant used in another investigational bladder gene therapy product. We did not consider using DDM because it has not been widely used clinically and it is not available as a commercial product. Here you can see Nonoxynol-9 produced gene transfer comparable to DDM.
However, we later learned that there are supply chain constraints which make Nonoxynol-9 less attractive for continued development. We then evaluated polidocanol. polidocanol produced a greater increase in gene transfer and offered broader regulatory and commercial access. Based on the totality of these datas, including performance, supply, safety history, and development practicality, we selected polidocanol for the clinical surfactant rinse program. polidocanol met each of our core criteria. It also has an established history of clinical and consumer use at concentrations well above the 0.25% concentration being evaluated in our bladder rinse cohort.
Clinically, polidocanol has been used at concentrations of 1% to 4% as an intravenous sclerosing agent for conditions such as varicose veins and hemorrhoids. It is also used at approximately 1% concentration in shampoos and other consumer products. Having selected polidocanol, the next question was whether the surfactant rinse could meaningfully improve the performance of detalimogene in preclinical models.
In this slide, these images illustrate the effect of the surfactant rinse on tissue penetration in mouse models. Without surfactant, detalimogene is concentrated primarily near the luminal surface. With the surfactant rinse, the nanoparticles appear to reach cells in the intermediate and basal layers of urothelium. That distinction is very important because cells closer to the basal lamina are more metabolically and endocytically active.
Once a vector enters those cells, their biology may better support nuclear transport and transgene expression, and therefore has the potential to increase both the magnitude and duration of localized gene expression, which may ultimately translate into improved efficacy and durability. The murine studies provided evidence that this deeper penetration had functional consequences.
On the left, the surfactant rinse appears to have broken the sigmoidal response seen with detalimogene alone, having generated a greater than tenfold increase in localized IL-12 expression and maintained expression for a longer period. On the right, we deliberately used a suboptimal dose of detalimogene to test whether the surfactant could improve biological activity. You can see here a brief five minute bladder rinse restored efficacy in that model.
Taken together, these findings suggest that the surfactant is doing more than simply changing distribution. It is increasing expression of the therapeutic cytokine and improving antitumor activity in preclinical models. The surfactant rinse may also enable a more convenient administration experience. In this preclinical experiment, a five minute rinse allowed detalimogene to be administered with a 15-minute dwell time to generate substantially greater IL-12 expression than detalimogene alone with a 60-minute dwell time in the bladder.
Notably, we are not carrying the 15-minute step detalimogene dwell time directly into the current clinical study. Instead, we selected 30-minute dwell time to provide an additional margin for patients' potential inability to tolerate holding liquid instilled into the bladder. This is an issue overviewed by Dr. Cahn in his case study. A shorter dwell time could be meaningful for patients with irritated or overactive bladder who may find it difficult to retain an intravesical therapy for a full hour. It could also reduce chair time and improve treatment capacity within community urology practices.
Next, the biological response we are generating is also relevant to established bladder cancer treatment. IL-12, interferon gamma, and CXCL10 are all important mediators of antitumor immunity within the bladder. These same targets are upregulated by BCG, which remains to be the standard of care in the high-risk NMIBC setting. BCG-established clinical activity provides support for the relevance of this immune axis. Detalimogene is designed to engage that biology through a differentiated, targeted, and localized approach via IL-12 expression and RIG-I activation.
These data show that the effect in preclinical models extends beyond the initial increase in IL-12 expression. With the surfactant rinse and a shorter detalimogene dwell time, we observe increased and prolonged expression of IL-12 in murine models. We also observe sustained enhancement of interferon gamma and CXCL10 production. This is very important because it suggests that the surfactant-mediated increase in delivery produces a broader and more sustained response across multiple key anti-cancer biomarkers. An important development objective was to preserve the procedural simplicity of detalimogene. Some surfactant can interfere with the stability or potency of a subsequently administered drug.
If that occurs here, the surfactant would need to be washed out with saline before detalimogene administration, adding another step to the procedure. Our studies show that potential residual surfactant volume in the bladder or catheter at levels of up to 10% did not have any impact whatsoever on detalimogene stability or potency. As a result, the rinse can be removed, and detalimogene can be administered through the same catheter without an intervening saline wash. This helps preserve a straightforward single catheterization workflow.
We also evaluated whether the surfactant rinse produced local bladder toxicity or systemic exposure. In the murine model, bladder weight is used as a sensitive marker of inflammation or toxicity. As shown in the figure on the left, bladder weight remained unchanged following treatment. We also evaluated plasma DNA and IL-12 levels in plasma and observed no evidence of systemic exposure.
Next, we moved to validate these findings in non-human primates, whose bladder anatomy and biology provides a relevant larger animal model. As shown in the figure on the left, the combination of a five-minute polidocanol rinse followed by a 15-minute detalimogene dwell produced approximately nine-fold higher mean human IL-12 expression than detalimogene alone with a 60-minute dwell. The proportion of positive tissue samples also increased from 29% to 81%.
This suggests improvement in both the magnitude of expression and its distribution across the bladder urothelium. Importantly, we observed no systemic distribution of polidocanol following administration, as shown in the figure on the right. The non-human primate results, therefore, reinforce the two central findings from the murine work. That is, pre-rinsing the bladder with polidocanol significantly enhanced localized gene expression in the bladder with an encouraging preclinical safety profile.
The consistency of these findings across multiple preclinical models gave us the confidence to move into clinical study. in May of this year, we announced the initiation of a new cohort in the LEGEND trial evaluating a surfactant bladder rinse plus detalimogene in patients with BCG unresponsive, high-risk NMIBC with carcinoma in situ, with or without papillary disease. The clinical procedures uses a single catheterization.
Patient receives a five-minute bladder rinse with 50 milliliters of 0.25% polidocanol, followed by detalimogene. Detalimogene dwell time has been reduced from 60 minutes to 30 minutes in this cohort of the study. The safety run-in is now complete, with no dose-limiting toxicity observed, and the efficacy portion is now in progress.
The cohort may enroll up to 80 patients and will assess whether the increased gene expression and favorable administration profile seen clinically can be translated into improved clinical activity, durability, tolerability, and a more convenient patient and practice experience. For the surfactant cohort specifically, we expect to provide a six-month complete response update on approximately 20 patients in mid-2027. With that, I'll turn the call back to Ron.
Great. Thanks very much, Anthony. In conclusion, we believe that within the growing NMIBC market, detalimogene alone may offer a differentiated total product profile that can address the needs of a large swath of private community urology practices with its balance of efficacy, tolerability, and a streamlined experience for both patients and practices. At the same time, we're actively investigating future life cycle management and our ability to improve efficacy, maintain tolerability, and reduce burden to both patients and urologists with our surfactant bladder rinse.
We're now approaching important near-term milestones in Q4. We're planning to provide updated data from our pivotal cohort. Our key primary endpoint, CR at any time of 54%, is likely not to change significantly. The key secondary endpoint, durability after 12 months, will still be immature, but we plan to provide an estimate. We expect tolerability to hold even with increased exposures. Additionally, we expect to have the vast majority of 12-month landmark data, and based on the data we presented in May, we expect to have in-class efficacy, best-in-class tolerability, handling, ease of use, and cost of goods. Last, we expect to initiate our BLA submission for detalimogene.
Next year, we are tracking towards both potential approval for detalimogene as well as a clinical data update mid-year on our detalimogene plus surfactant bladder rinse cohort. So it is really an exciting time for enGene and detalimogene. We apologize for the technical challenges. Hope you can stay with us as we open up the call for questions.
Great. Thank you, Ron, and thank you to our speakers. So at this time, we will be conducting a Q&A session. Please hold for a brief moment while we pull for questions. Our first question comes from Maury Raycroft at Jefferies. Please go ahead, Maury.
Great. Thanks for doing this call. The event has been really helpful, and thanks to the KOLs as well. Maybe just starting off for just how representative are these case studies, or what proportion of patients fit this general profile where the KOLs would use detalimogene? As the HR-NMIBC treatment landscape expands, how do the KOLs rank the available options and which factors drive their preferred treatment choice?
Maybe, Dr. Merrill, you want to start with a little bit on how these cases generalize to your population and talk through that question. Maybe David, you could add a few comments on that as well.
Sure thing. These cases are pretty representative in regards that we see a spectrum of patients from age and comorbidities. We gave you that spectrum of a younger patient diagnosed with disease, still very active in their lifestyle and with their professional life, that dealing with intravesical therapies can be a challenge when they're very frequent dosing and the problems they can pose when they cause symptoms. Then we gave you the other end of the spectrum of the elderly patient, as they've been sequenced already through many therapies, and their bladder symptoms are really driving a lot of our choices into that next line, as they've already passed the threshold of not being safe to take for a cystectomy. In regards to that second question of our ranking of the therapies available for BCG unresponsive disease, ultimately, what drives the decision, unfortunately, is multiple-fold.
It has to deal with certainly efficacy, but also very much close-knit is what is going to be tolerable for that patient. So involving, again, what bladder symptoms they have, any issues with, of course, traveling to these locations where we can administer these therapies. Then certainly their, again, bladder symptoms, et cetera. A lot of things play into that decision beyond just efficacy of what we use. It's really important to have a lot of options. As what Ron said really rings true to us, that it is not one drug fits all patients. It's really nice to have a lot of options to really individualize our treatments to that patient's needs.
If I may add, and thank you, Suzanne, and I was going to reference what Ron said as well, that it's not just a one size fits all. If you think about it, these patients have a disease in their bladder. First line of treatment for most of them now and into the foreseeable future is going to be BCG, which can be very toxic to the bladder. Just as Suzanne said, we're going to be focusing as much on tolerability as efficacy, because we're asking these patients with compromised organs to hold these agents in their bladder for efficacy.
The fact that we have an agent here in detalimogene that potentially is efficacious and well-tolerated, and now with a shorter dwell time, is quite important. I can just say anecdotally, my clinical coordinators have noted a difference in the tolerability with this shorter dwell time. It's encouraging, and we're excited to see what the data shows.
Got it. All really helpful perspective. Maybe just one more technical question, and I'll hop back in the queue. You mentioned a sigmoidal dose-response relationship. Do you think the surfactant meaningfully increases the effective drug dose delivered to the tumor? If so, should greater tumor exposure, I guess, translate into a proportional improvement in tumor suppression, or would you expect the benefit to plateau beyond a certain exposure level?
Thank you for the question. This is Anthony. Let me just clarify one point. I just want to make sure that we understand that detalimogene doesn't need to get the gene expressed in the tumor cell specifically. It can express anywhere in the urothelium, and the effect that we're trying to achieve would come about. That's number one. It doesn't need to get to the cell specifically. The question is whether we expect to see higher.
Certainly the preclinical data that we're seeing, we're seeing very, very consistent across multiple animal models that the expression of these transgenes carried by detalimogene is all increased in 9 to 10-folds level. Based on the mechanism of action that I reviewed earlier, we do believe that that would translate into better response. At least we've seen it in animals, and certainly we need to wait for the data in humans and see how that plays out.
Yeah. I think we're pretty excited that detalimogene on its own, we get pretty good expression. You saw that in the animal models. The addition of polidocanol surfactant really adds potential in two parts. Better expression as well as reduced dwell times. Thanks for the questions, Maury.
Thank you. Thanks.
Great. Yes. Thank you, Maury, for the questions. Our next question comes from Lili Nsongo at Leerink. Please go ahead, Lili.
Hi. Thank you for the event today, and thank you for the KOL perspective. I had a question regarding the surfactant cohorts. Can you maybe give us a little more color on how you think about the potential regulatory path for surfactant specifically? Basically, do you anticipate that this will fit into the current framework that you are working on with the FDA, or might we expect a separate registrational study for detalimogene plus surfactant? Thank you.
Yeah, thanks for the question, Lili. We've had a lot of interactions with the FDA. As we said, we have a planned BLA meeting for this quarter. We expect a filing. We're going to very much focus on detalimogene on its own, on the basis of cohort 1, and we expect approval on that basis sometime next year. As it relates to the addition of the surfactant pivotal cohort, that'll be something that we'll continue to dialogue with the FDA path forward. But we would anticipate that that would be part of a supplementary following the approval of detalimogene on its own.
Great. Thank you.
Thanks for the question, Lili. Our next question comes from Andres Maldonado at H.C. Wainwright. Please go ahead, Andres.
Hi, everybody. Thanks for hosting this, and thanks for taking my questions. Just two from us. One for management. I guess, can you help me reconcile in the case where you're introducing the surfactant and you're theoretically increasing the levels of IL-12 in the bladder, how does that reconcile on the safety side? Understand in the mice models it looks clean, but just help me reconcile how having increased levels of IL-12 can hopefully maintain the good safety that you guys have previously reported.
Then follow up for the KOLs, if you can maybe speak to when you treat a patient with NMIBC, obviously you're adherent to very strict algorithms within the guidelines, but in your practice, in your experience, have your patients ever had concerns when you said either chemotherapy or gene therapy to the point where it would influence the algorithm of how you deploy those therapies? Thank you.
Great, Andres. Why don't you take the first question, and Dr. Cahn, maybe you can start with the second question, and then if Dr. Merrill would like to add something.
The question was whether surfactant.
Safety.
Was it a safety question? Sorry.
Yes.
Yes.
Yeah. As you mentioned from the preclinical studies, we got really great data. We are also very happy that we took this very carefully into patients. We had to do a safety run-in one patient at a time, and we are happy to report that that is completed. We did not observe any dose-limiting toxicity, and that is why we are opening up that study to a wider patient population and look at efficacy. From that point, I think we can say that it translates quite well from preclinical to patients right now, and we did not see any increased toxicity or AE events with the use of pre-treatment, pre-rinse with surfactant.
And remember, Andres, remember we are using 0.25 polidocanol. In shampoos you are using up to 1%, so it is a very light bladder rinse and as Anthony has indicated, we are pretty pleased to have made it through the safety run-in with no dose-limiting toxicity. Thanks for that question. Maybe turn it over to you, Dr. Cahn.
Well, I think one of the things that we emphasize with our patients when we are treating them with intravesical therapy is that the bladder is a bit of a sanctuary organ. It is designed to hold waste, so it protects the body from the urine, which contains high concentrations of agents that we are filtering out. Similarly, it is a sanctuary that we are able to provide therapy within the bladder, and there is a low systemic response. Yes, particularly since the pandemic, we had patients who are against the idea of gene therapy and have all kinds of skepticism. But also these are highly motivated patients who want to preserve their bladder. So if we are able to present somebody with data that suggests efficacy and low systemic absorption, they are motivated. Suzanne, you treat more patients than I do with bladder cancer. What has your experience been?
Yeah. Thanks, David. I do think that there is quite a frequent amount of patients that have kind of a negative, at least initial response when we say that we are going to use these big words of chemotherapy or a viral-based therapy in the bladder. So I do think having an offering available of a non-viral therapy would ultimately mute out those concerns initially. But as David said, again, these treatments are overall contained in that bladder, but we do get some initial responses which are very hesitant by the patients when we define some of these therapies as chemotherapy and viral agents.
Great. Thank you very much.
Thanks, Andres. Our next question comes from Chiara Montironi at Kempen. Please go ahead, Chiara.
You might be on mute, Chiara.
Hello, can you hear me now?
Yes, we can.
Yeah, sorry. Thank you for the very helpful event and KOL's perspective. I have two questions. The first one for the docs, maybe just thinking about the detalimogene only data that we get in H2 2026, anything that we should be looking at that could impact the decision-making in clinic after a potential approval? The second one for the company, exciting to hear that we will see first data for the surfactant cohort already next year. I was wondering for the first 20 patients, can you give us a sense of on which kind of metrics we will be able to see at that time?
Maybe I'll take the second question first, and I'll hand it over to Dr. Merrill for the first question. I think we're still determining that, Chiara, but expect to see something along the lines of CR any time and where we are from a tolerability standpoint. But we're looking forward to sharing that data with you, and we're pretty pleased to have gotten through this safety run-in period, and enrollment is proceeding quite nicely. Dr. Merrill, do you want to take the second question in regards to the data? As we said, we expect later on from a data perspective to report where we are with CR any. Probably we'll be reporting something around an estimate on durability, an update on tolerability, and then we'll probably be sharing the majority of landmark 12-month data at that time. Dr. Merrill, I don't know if you have a comment on that.
Yes. Thank you. Ultimately, out in practice, we're always interested in that kind of landmark 12-month data and durability. The hope here is that detalimogene will kind of come in to around the ranks of where we see some of the current FDA-approved drugs. Ultimately, Keytruda is what set the stage way back when in 2022, I guess, in BCG responses, and one that a lot of us actually don't use that drug in this space because of mostly the side effect profile, for one, the difference in administration being IV, and then its durability data and efficacy.
But ultimately with all our intravesical drugs, there is a variety in range in efficacy and durability that we see, and the hope is that detalimogene will come into where that current range of intravesical therapies is. I believe if it does with its, again, side effect profile, its kind of novel mechanistic approach being non-viral, its infrequent dosing and tolerability, I think it will fit nicely into the portfolio of what we will be able to use for these patients that is an ever-growing pool now.
Thank you. Very helpful.
Thanks, Chiara. Our next question comes from [Jacob Orquiz] at Raymond James. Please go ahead, Jacob.
Hi. Jacob Orquiz here on for Sean McCutcheon. Thanks for the question. Just a quick one from us with maybe a quick follow-up. With the addition of the surfactant, have you given any thought to or are you open to exploring different dosing schema, for instance, doing a more intensive induction? Or are you confident that the treatment cycle as it stands is already optimized? As a follow-up as well, is there any potential for the surfactant concentration to be adjusted as well from 0.25%? Thanks.
No, I think in both cases, we're really confident about the preclinical work to give us a sense that we've optimized the dose and we've optimized the percentage of polidocanol. They're really well studied, and so I think we're excited to put it into patients, and we'll see what the clinical results are. Thanks for the question, Jacob.
Great. Understood. Thanks.
Thanks for the questions, Jacob. Our next question comes from Silvan Türkcan at Citizens. Please go ahead, Silvan.
Hey, good morning, and thanks for putting on this event, and thanks for taking my question. I just wanted to know maybe if you could just summarize maybe the rationale again of the impact of the surfactant wash specifically on any time CR rates or efficacy measures, right? Any time CR and 12 months CR rates. And then on that slide where you show the selection of the surfactants, on one side you measure IL-12 levels, and then I think glucuronic on the other side.
Could you just help us understand why the N9 performs well on the one measure and then poloxamer on the other measure, and perhaps what that means about CG Oncology picking one surfactant and you picking another surfactant. Are they all roughly the same or is it really about other factors that you've outlined here, such as global access, et cetera? Thank you.
The first question is about the. I think the best way to answer this is go back to the mechanism of action, what we are trying to do with detalimogene. As I covered in my presentation, the effect that we are trying to generate is to create a strong adjuvant effect so that the immune system could be fired up more actively, more robustly to go after the tumor cells. That is why from what we learned from vaccine biology, if you can get the level up high enough, you can potentially create a stronger and a more robust activity.
That actually came through for us in all the preclinical studies, and that is the reason why we have confidence that if we can achieve that it could translate into better treatment, better response and also longer durability as well. Your second question is about the DDM. From what we can see, DDM work as well. The reason, as I said in my presentation, that we did not go with DDM is because it is still an investigational product, and there is no commercial source for it as well. It also does not have a lot of safety data available at the moment for that product.
Yeah. I guess just, Silvan, just the way that we are thinking about things, the emerging profile for detalimogene on its own, we believe it is a competitive profile, very useful. Community urologists kind of reiterated by our two community KOLs. Then we see the work with the surfactant bladder rinse is really a life cycle play that just improves what we already have in two dimensions. I do not want to lose the dimension of the reduced dwell time is a real benefit to patients, particularly being able to hold things in. Then, we have seen that the use of surfactant has improved the efficacy of other viral gene therapies. We would expect that this will have an impact on patients based on our preclinical data.
Great. Thanks for taking my questions.
Thank you, Silvan. Our final question comes from Peter Spanogiannopoulos at Piper Sandler. Please go ahead, Peter.
Hi there. This is Peter Spanogiannopoulos for Allison Bratzel. A couple for us, if we may. The first one's for the docs. After a patient becomes BCG unresponsive, how many lines of bladder-preserving therapy do they typically receive before moving on to radical cystectomy today? As more options become available, do you expect community practices to offer all these options, or do you think they will focus on a small number that they're more comfortable using?
You had a second question? Or were those the two questions?
The second question is for management. I'm just wondering if you're measuring IL-12 expression or another transfection biomarker in the bladder wash cohort, and if you can use that data to assess whether transfection might correlate with response or no response, and whether any biomarkers are being measured in the pivotal cohort. Thank you.
Why don't we answer that second question quickly, and then I'll let Dr. Merrill and Dr. Cahn comment on your first question.
Yeah. We are collecting data. We're collecting exploratory biomarker data, specifically around the level of the IL-12 and also the downstream effector molecule, the chemokine called CXCL10. We'll be measuring those in patients' urine samples, and we'll look at before and after treatment. Then we'll also be able to compare it to the current cohort 1 patients, which were given detalimogene without the surfactant rinse. They give us an idea whether the increased expression of the transgene and engagement of the downstream molecule would be similar to what we've seen in the preclinical models.
All right. That's going to be a pretty important PD marker that we're excited to share with you in the future. Maybe over to you, Dr. Cahn, and then over to you, Dr. Merrill, on the concept of current lines and how you see that going in the future.
Sure. Well, it's a very good question. It's important because this is a brave new world. We did not have this variety of options previously. The approval of Keytruda and Adstiladrin, and the other agents are the INLEXZO and ImmunityBio product. These are all relatively new. We can see that patients are going to be going through potentially three or four different drug regimes. Potentially. Also, there's going to be a push for bladder preservation. Again, I don't think every practice is going to be offering every therapy. Part of the issue is going to be difficulty with administration. Suzanne touched on this with Keytruda. It's not only the difficulty with administration, it's the management. Now it can be done sub-Q, so it doesn't need an infusion, but we're still dealing with the immunologic side effects of a checkpoint inhibitor.
Similarly, drugs such as Imlygic cause. There is difficulty with managing these patients. That is time for the physician, so there is going to be potentially a disincentive to use those agents. If a drug needs to be stored at a cold temperature, then that is also another obstacle. There are lots of factors as to which therapy is going to be chosen. In terms of the number, I do not have a good number on that. We have some reasonably good data that these therapies have not resulted in higher rates of systemic disease. We are not necessarily putting our patients at increased risk by giving them sequential therapies. Suzanne, what do you think?
Thanks, David. I would just add a couple points. Currently, right now, there is no guidance as to how many therapies we can sequence a patient through. We ultimately use our clinical judgment, evaluation with scans, cystoscopy, and then, of course, what the patient desires as to how many we can safely cycle through. As, again, there is now more drugs available. Patients have always wanted a bladder-sparing approach. We are right now cycling through the majority of them before we really get to a lack of options, upon which then we often discuss cystectomy. It is a rare situation that we see actually, like David said, disease progression to where then we are discussing cystectomy. Cystectomy was obviously used more earlier on just because we did not have options.
As Ron said, the pool of patients in this space is going to ever expand, and the need for additional therapies is going to be present as we are going to be able to continue to safely cycle these patients through a number of therapies, and be able to avoid cystectomy, which is definitely a patient-centric desire. In regards to if all practices are going to be able to use or access all these therapies, that certainly is not the case.
Even a lot of your LUGPAs are not using all these therapies because of workflow issues that each of them have to beholden to themselves. An agent that is easily able to be stored in the fridge, okay, easily able to be administered without requiring any additional procedures, that is familiar to the staff, is going to be more uptake by a majority of practices than agents that have unique administration requirements.
All right, great. Well, thank you, Dr. Cahn and Dr. Merrill. Thank you, Anthony. Thank you all for attending. We hope that you found today's discussion informative and look forward to providing you additional clinical and regulatory updates this quarter. Thanks a lot.