Good afternoon, and welcome to the Aura Biosciences Virtual Urologic Oncology Investor Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Aura website following the conclusion of the event. I'd now like to turn the call over to Jill Hopkins, Chief Medical Officer and President of Research and Development at Aura Biosciences. Please go ahead, Jill.
Thank you, Tara. Thank you, everyone, and welcome to the Investor Event. If you move to the next slide, we are very excited today to share with you updates on our bladder program. We're joined by key opinion leaders, three outstanding leaders in the field: Jennifer Linehan from St. John's Cancer Institute, Dr. Neal Shore at Carolina Urologic Research Center, and Dr. Gary Steinberg from Rush University, who will be sharing their thoughts on the data that was just recently presented. Our Aura leadership today includes Sabine Brookman-May, who is our Senior Vice President and Therapeutic Head of Urologic Oncology at Aura, Ellie de los Pinos, who's our Founder and CEO, myself, and Joseph McQuaid, who is our Executive Medical Director heading up clinical development in urology.
We are thrilled to share our goal of having Bel-sar seek to redefine the treatment of bladder cancer, and we have a novel and disruptive approach. You'll see that the bladder data we'll share today, if you go to the next slide, builds upon the work we're doing already in Aura with Bel-sar as a unique platform technology, and we're excited by the potential for this to be applicable across multiple cancers, multiple solid tumors. We are in ocular oncology in phase III in choroidal melanoma, the most common primary intraocular tumor that we are now globally enrolling. We have a SPA with the FDA, and this was based on positive phase II clinical data showing durability of response at 12 months in patients with choroidal melanoma treated with Bel-sar.
We've also initiated a phase II trial in metastases to the choroid, and we're in pre-IND work in both cancers of the ocular surface and retinal blastoma. A broad ocular oncology franchise is actively being developed. As we'll hear more today, the bladder cancer space, both NMIBC and MIBC, are the next area of major development for us. We have positive phase I data in NMIBC. We'll talk about our multiple CRs and the important histopathologic confirmation of our mechanism that we have. We see the potential to expand to MIBC and other urologic cancers, potentially with next-generation combinations. That opens other cancers in the future for us in terms of CNS or GI, head and neck, breast, lung, or cutaneous melanoma, all of which we have key foundational science coming out of NIH.
The broad potential for a platform here, very exciting at the work we're doing at Aura. Today, I'll hand over to Sabina Brookman-May, who will take us in on the bladder cancer space.
Yeah, thank you, Jill. Before going into more details about AU-011 and bladder cancer, and also before we will show the data of the current phase I study, I would like to give some background also on bladder cancer epidemiology. Bladder cancer is the ninth most common cancer worldwide, with more than 600,000 cases per year globally, and it is also one of the cancers with the highest lifetime treatment costs, not only in the U.S., but also in other regions. Most of the patients are diagnosed in the local disease setting, and 75% have non-muscle-invasive bladder cancer, 25% have muscle-invasive disease. The current standard of care and the conventional bladder cancer treatments are suboptimal.
We have the resection of the tumor as the first step of the treatment, followed by multiple cycles of adjuvant treatment, and both have considerable impact on quality of life for the patients with short and long-term side effects. In addition, we see inadequate efficacy. Patients need multiple TURBT surgeries, and nonetheless, they have in the end still the risk of repeat recurrences, and also progression of disease, potentially even with metastatic disease in a high-risk setting, and the risk to lose their bladder by radical cystectomy. As you can see here as well, about 84% of patients are not finishing treatment, which is also another reason why the treatment has not the highest efficacy that is possible. Bel-sar has now an innovative dual mechanism of action that would be ideal for the treatment of bladder cancer.
It is designed to increase the chance of bladder preservation and bladder function preservation and to reduce the risk of recurrence and treatment burden to the patient. The dual mechanism of action consists of two aspects. The first part is a robust targeted cytotoxicity designed to rapidly destroy cancer cells. The second part is the initiation of a long-term anti-tumor immune memory that has the potential to provide an immune surveillance, a urothelial field effect, and to prevent recurrence of bladder cancer. We have three main key advantages. One is the focal administration that treats only the tumor, but not the entire urothelium, which also makes the side effects profile excellent. There is no need for general anesthesia, as the administration is aligned with current urologic office practice, and it can be done with local anesthesia. The procedure is brief.
We have less than 15 minutes for both injection and light activation, and the procedures are familiar to urologists using cystoscopy needles for injection and common techniques for laser application. The current treatment paradigm in NMIBC, and this is what you see here, is based on upfront resection that still results in the fact that these patients have recurrences again and again. The field of NMIBC is split in different risk categories. On the one hand, we use grading based on low grade and high grade from the pathology assessment, and then we have three different risk categories: low risk, intermediate risk, and high risk. The current mainstay of treatment is, as said already before, the TURBT, the surgical resection first, followed by adjuvant therapy with BCG or intravesical chemotherapy. Nonetheless, these patients have recurrences again and again.
Most of the patients have recurrent disease not only once in their life, but several times in their life, and they again need the same cycle of treatment with surgical resection and adjuvant treatment. The high recurrence rates in the end lead to an incredible patient burden. I would like to outline here now also how Bel-sar differentiates from the current standard of care. What you see on the left-hand side is the current standard of care. First, the resection of the tumor is done, and then adjuvant treatment with BCG or intravesical chemotherapy is added. That causes a high treatment burden to the patients, and patients need a maintenance treatment for 12 months or in the high-risk setting, even up to two or three years. Bel-sar now has an immune-mediated mechanism of action, and we have the dual mechanism of action.
What we are planning, or we are currently developing, is upfront treatment of Bel-sar or AU-011 as long as the tumor is still in place. The tumor needs to be injected with AU-011, and then it is light activated. With that, you get the first cytotoxic effect and then a subsequent immune effect initiated that causes an anti-tumor-specific immune response, and that has the potential to provide immune surveillance and long-term protection. Again, I would like to outline it needs to be done upfront. Bel-sar also has the potential to be developed as a standalone Immunoablative therapy. The other second approach is the potential to develop as a neoadjuvant treatment prior to TURBT, which is quite a unique treatment approach that nobody else is currently doing.
When you look on the top, you see the Immunoablative approach that has been explored already in the current phase I study, where you would inject the tumor as a prior treatment, and then the immune response gets activated, as outlined before. That could be an approach for low-risk and intermediate-risk patients, where you want to avoid TURBT as far as possible. With such an approach, the treatment with AU-011 could potentially replace the need for TURBT. When you look at the bottom, this is the neoadjuvant approach or multimodal approach I was talking about, where AU-011 would be injected also again when the tumor is still in place. The tumor is not resected first. We have an upfront treatment with AU-011 first.
The immune response gets initiated after the cytotoxic effect, and you could still remove the tumor subsequently with TURBT, which is especially a potential approach in high risk, where you want to have the tumor completely resected. With the initiation of the specific immune response, there is a chance to subsequently reduce the risk of recurrence in these patients and to minimize the treatment burden after TURBT and potentially avoid adjuvant treatments following TURBT. Bel-sar has the potential to transform with these approaches the disease trajectory for intermediate-risk and high-risk patients. Let's again look at the intermediate-risk patients. Here again, the goal is to have a frontline immune ablative treatment and move away from a resection-based treatment, what is the current standard of care, and get the immune-based tumor ablation in as a first frontline ablative therapy without tumor resection.
With the treatment with AU-011, tumor cells are destroyed and targeted, and this induces the immune response, and we have the potential to prevent recurrence with minor treatment intervention in these low-grade intermediate-risk patients. The other potential pathway, as already shown, is the multimodal neoadjuvant approach in intermediate-risk or high-risk patients. Again, that would be a paradigm shift compared also to the current standard of care, again away from a resection-based upfront treatment with adjuvant treatments following it to an immune-based neoadjuvant multimodal approach. Bel-sar would again be injected before the TURBT when the tumor is in place to have the highest immune response possible. Then the tumor would get resected, but the need for adjuvant treatments following would be reduced after the resection.
With such an approach, we have the potential to reduce the risk of recurrence and progression and potentially also explore it in other disease settings like MIBC. With this, I would now hand over to my colleague, Dr. Joseph McQuaid, to show the data from the current phase I window of opportunity study, which was also just presented at the annual meeting of the European Association of Urology two days ago in Madrid, where the data were accepted as a late breaker.
Great. Thank you, Dr. Brookman-May. To refresh everyone's memory, the way we'd set up this first phase I study was to administer Bel-sar before scheduled biopsy and standard of care TURBT. What does that mean? All patients were injected on day one with a standard Botox needle. We had a pretreatment pathology specimen collected at that time. On day two, we proceeded with light activation. All subjects, regardless of how they did with Bel-sar or how they responded, then moved ahead with their planned standard of care TURBT. For cohort A, that was on day nine, and for cohorts B and C, that was on day 14. This really was beneficial because it allowed us to get a pathology specimen after treatment and allowed for us to have a final efficacy evaluation after treatment, regardless of how Bel-sar appeared to do visually in the bladder.
We then followed all subjects out to day 56 for final safety evaluation. Here's the construction of our cohorts. Part one was comprised of five patients. That was Bel-sar alone with no light activation based upon agency recommendation. Of course, there's no efficacy here because it was Bel-sar only without any light activation, but we got great safety data from this, which we're able to report. Part two consisted of an additional 10 patients for efficacy evaluation and was comprised of three different cohorts, A, B, and C. A and B differed very slightly with the location of the injection along the base of the tumor. They were both 100 micrograms, and cohort C was comprised of a 200 microgram injection at the base of the tumor. Next slide, please. We'll start with part one, which was drug-only. The schedule of treatment here, day one injection, again, no light activation.
Patients were then brought for their standard of care TURBT on day two. This allowed us to have that H&E specimen and path evaluation. Most importantly, we saw no treatment emergent adverse events related to the study drug. We had no SAEs. We had no dose-limiting toxicities, all very reassuring safety data, and we were able to proceed then with part two. Part two, we've discussed these cohorts, so we'll move ahead. With regard to our treatment schedule, again, day one, injection, standard Botox needle in office. Day two, light activation using another in-office procedure with a standard laser fiber, and then depending upon the cohort, TURBT on either day nine or day 14. With regard to safety, we had no SAEs. We had no DLTs.
Less than 10% of patients experienced a grade one TEAE related to the study drug, and we had no grade two or three adverse events related to the study drug. Very reassuring data. Let's look at our efficacy. We've broken down these results by AUA risk classification, which Dr. Brookman-May outlined earlier, starting with the intermediate-risk non-muscle invasive bladder cancer. Top line that you need to know is that four out of five patients demonstrated a complete response. All patients had immune response in the target tumor. Let's dig just a little bit deeper here with the data in this table. You can see all five patients here, all of them had low-grade disease, all of them had multiple tumors. I would remind everyone that only a single tumor was selected for injection and light activation.
I would also remind everyone that this was the same low ocular dose and volume, and there was no change to that. All patients were intermediate risk based upon AUA classification, and at time of TUR, that target lesion showed a complete response and absolutely no evidence of urothelial carcinoma in four out of five patients. Beyond that, we were able to see response in the non-treated, non-target tumors in three out of five patients. There was no evidence of urothelial carcinoma in those patients when they went for their TURBT. All of this was supported by what we saw in the IHC staining. We saw significant immunocyte infiltration across every single target tumor. We saw significant immunocyte infiltration across every single non-target tumor, regardless of whether or not we had a complete response. We'll move on to our next table here.
This is the high-risk non-muscle invasive bladder cancer. I would remind everyone for these subjects that these tend to be higher-grade lesions. They tend to be larger. We're using the same low ocular dose and volume, and yet we're still seeing significant changes in these tumors. We're getting immunocyte infiltration in every single target tumor, in every single non-target tumor, and we're seeing significant visual changes in the tumors, shrinkage in three out of the five subjects. We did also have a complete response in one of the five subjects who had a high-risk tumor here treated with AU-011. That's new significant data. Next slide, please. Here is a great example of one of our standard intermediate risk patients. This subject, as you can see over on the left, has a long-standing history of urothelial carcinoma dating back to 2019.
High-grade initially upon diagnosis, but subsequently was found to have recurrences of low-grade disease, multiple tumors. Again, very typical story. Has had no fewer than six TURs, prior BCG induction and maintenance, and yet it continues to come back and recur. The dome lesion there, you can see on the left, bilobed papillary tumor that was injected right in the middle with a standard Botox needle. Over on the right, this is the appearance of what remained of the tumor just seven days later on day nine, left, which is a small amount of edema, just a little bit of erythema there. I hesitate to say tumor because there's no urothelial carcinoma at time of treatment. It was a full, complete response. These images here have been shown previously. They demonstrate evidence of immune cell presence and significant infiltration here within the target lesion.
The pretreatment biopsies are on the top row. The post-treatment TUR specimens are on the bottom row, significant CD4 infiltrate. Over on the bottom left, secondary lymphoid follicles with T and B cells. Immune cell presence. We are really excited to be able to show you the next slide here. This was just discussed at the EAU meeting. Here is a multiplex immunofluorescence of that same patient that we just talked about here, a target lesion. I'm going to walk you through this. First, we have in green CD3 staining, evidence of T cell infiltration. As we move ahead to the next slide, you'll see in red CD20 plus B cells. Moving ahead to the next slide here, we have in blue, now appearing purple, follicular dendritic cells as marked by CD23.
This is a really significant finding because it means that we're having B cell follicles form, which are clear evidence of mature tertiary lymphoid structures. As you can see stained in yellow here, peripheral node addressing. These are markers of high endothelial venules, which are essentially highways for lymphocytes trafficking from the periphery. We not just have immune cell presence, but we have adaptive immune activation here. I would emphasize to everyone that there were none of these TLS demonstrated in any of the pretreatment biopsies of the target lesion. These are new. These are de novo. On the next slide here, we're getting these exact same tertiary lymphoid structures forming in non-target lesions responding to therapy. Again, not injected. This is an example of one of the non-target lesions in that subject.
We have CD3, CD20, CD23, and PNAd being stained here, early tertiary lymphoid structure forming. Next slide, please. Summarizing this, our complete clinical responses and immune responses are demonstrating several things. First, effector immunity and also development of active Immunosurveillance. In 10 out of 10 patients who had tumor cell infiltration, 100% of patients showed tumor cell infiltration with CD8 effector T cells and CD4 cells as early as seven days after laser activation. 100% of non-target lesions were showing T cell infiltration, and this is supportive of a bladder urothelial field effect. We also had focal eosinophilic infiltration that was observed in target tumors in 60% of patients. 9%, that is one out of 11 non-target tumors, also showed eosinophilic infiltration, and this is supportive of a local innate immune response.
We're not just getting these adaptive immune responses, but we're also getting innate immune responses after therapy. We saw lymphoid follicles being generated in target tumors in 80% of patients, again, as discussed with the immunofluorescence supportive of a local adaptive immune response. Next slide, please. Having discussed all those clinical findings, I do just want to rewind to what we previously discussed and shown in our preclinical models, specifically the TC1 mirroring tumor model. In this, we demonstrated tumor-free survival after just a single dose of Bel-sar, and you can see that demonstrated in the top curve. What was really encouraging in these mice was that that single dose of Bel-sar not just treated tumors, reduced a tumor-free outcome, but also protected these animals long-term from tumor re-challenge. You can see that there in the bottom graph.
If we move ahead to the next slide, you know, we have data that explains, you know, actually the immune underpinnings behind this effect that we're seeing here. In these animals, we were able to treat them with anti-CD4 and anti-CD8 to effectively knock out their CD4 and CD8 cells. In both of these cases, we didn't see those effects. We had depletion of CD4 and CD8 cells at time of treatment, and we were not getting that same long-term survival. When we were knocking out CD4 and CD8 cells, we didn't get that same protection from tumor re-challenge, which preclinically demonstrated to us how critical that immune response is with those CD4 and CD8 cells to therapy.
It really comes back full circle here with what we've discussed clinically with this immunofluorescence data here and this evidence of immune activation of adaptive immunity and urothelial field effect. We're seeing that really reflected very beautifully here with clinical data today. Dr. Brookman-May, I will hand that back over to you.
Thank you, Jill. To summarize, after seeing the data from the current phase one study, I would like to outline again the key aspects of Bel-sar's novel mechanism of action. AU-011 has a favorable safety profile with the focal treatment and with no systemic adverse events observed in the current phase one study. We had only one grade one drug-related adverse event reported in less than 10% of the patients. We see a rapid immune activation as 100% of the patients showed immune cell infiltration in target and non-target lesion.
We have to prove that there is cell-mediated immunity and a urothelial field effect in these patients. We have seen tumor shrinkage and clinical response, four of five patients with intermediate risk and one of five patients with high-risk disease at a clinical complete response. We see the effect across the field in target and in non-target tumors. We have now an accelerated development plan as we proceed with our phase one B2 study expansion to evaluate now the optimal treatment regimen in intermediate and high-risk patients. I would show now on the next slides some more details also on how we would proceed with the next steps of the study. Again, just back to the two potential treatment approaches we are exploring. Both are paradigm shifting compared to what is currently there in the treatment of bladder cancer.
We treat the tumor first to generate cell-mediated immunity. This is the basis of both concepts. The first concept again is the Immunoablative concept without TURBT. The tumor will be treated, and then we avoid the need for a surgical resection. The goal is to prevent recurrence and progression by treating the tumor and generating the cell-mediated immunity and then have less burden to the patient, also avoiding surgery, avoiding OR and general anesthesia with an office-based procedure. The patient population for this approach is intermediate risk and an NMIBC with low grade. The second approach is the neoadjuvant multimodal approach, again as a first treatment as long as the tumor is in place and then followed by TURBT. Also, with this approach, our goal is to prevent recurrence and progression by treating the tumor first and generating immunity.
The goal is also to avoid multiple cycles of adjuvant treatment to reduce the treatment burden for the patients without multiple cycles of BCG or chemotherapy, again also in an office-based procedure. The patient population for that approach could be intermediate risk as well, but it's predominantly a perfect approach for high-risk patients where you would still want to treat or resect the tumor and generate a longer-term immunity to prevent recurrence and also progression in these patients. I will now show how we will implement that in the phase one B2 study expansion in the intermediate and high-risk NMIBC patients. What you see on the top is the treatment schedule for the Immunoablative design.
Patients will be treated with two cycles of treatment, with day one and day two injection of AU-011 and light activation, two weeks later followed by the second cycle, and then followed for complete response assessment at three months and then followed for up to 12 months for durability of response. That again is the concept where we want to avoid TURBT as far as possible. What you see on the bottom is the neoadjuvant design we are approaching or we are exploring in intermediate-risk and in high-risk patients. Again, we have two cycles of treatment with two weeks in between. The patients then have a break of another two weeks after the treatment cycles before they undergo surgical resection with the TURBT, and then they will be followed also here for 12 months for recurrence or progression. With these two concepts, we also address established regulatory endpoints.
In the Immunoablative design, it will be three months complete response and durability of response, and in the neoadjuvant design, it will be recurrence-free survival and disease-free survival. Next slide, please. This is now the phase one study design with the different cohorts, and I would first like to show the study cohorts in the intermediate risk setting. We will start with 200 microgram per injection per lesion Intratumoral injection at the tumor base. Remember, in the phase one window of opportunity study, we injected one lesion, one single lesion, still with the ocular volumes, ocular low doses up to 200 microgram in the last cohort. Here we are starting now with 200 microgram, but we are injecting up to three lesions independent from the numbers of tumors at that time present in the bladder. There will be two cycles of treatment to boost the immune response in addition.
We then will escalate the dose to 400 microgram per injection per lesion. First, again in the Immunoablative approach in intermediate-risk setting without the need for TURBT, and then with the neoadjuvant approach followed by TURBT also in the intermediate-risk setting. We will also have a high-risk cohort. We need the next slide here, where we will start with the 400 microgram dose with five patients with high-risk NMIBC. Also here, we will treat three lesions, each with 400 microgram Intratumoral injection at the tumor base and two cycles. There are two optional higher dose cohorts included for intermediate-risk and high-risk disease as well. If needed, we can escalate to up to 800 microgram per lesion injection. Next slide, please. With that, I would like to summarize the main aspects again before we are then starting our panel discussion.
AU-011 seeks to redefine the treatment of bladder cancer with a novel and a disruptive approach. It's a true paradigm shift, and we are developing the treatment in a way as it is completely different to any other treatment in bladder cancer that is available or that is currently in development. We have the dual mechanism of action with AU-011, the targeted cytotoxicity plus the cell-mediated anti-tumor immunity that then initiates an active immune surveillance with the urothelial field effect. There is a transformative clinical impact possible with the treatment with AU-011. We have the frontline approach independent of the Immunoablative approach or the neoadjuvant approach. There is an immediate application possibility in the clinics. It does not preclude any downstream therapies if needed, and it reduces the total treatment burden to the patient.
Again, the cell-mediated immunity is the basis of this treatment and has the potential to generate long-term durable responses. There is overall an opportunity to apply this type of treatment in a broad patient population. We have seen the early clinical activity now demonstrated across the clinical disease spectrum in intermediate to high-risk NMIBC patients, and also the patient responding in the high-risk cohort was a BCG unresponsive patient. We also have the potential to explore it in additional indications as, for example, MIBC. With that, I would like to start now our panel discussion and invite our expert panelists to join our discussion. Welcome and thank you today for joining us, Dr. Linehan, Dr. Steinberg, Dr. Shore.
We are here now with three of the leading experts in bladder cancer to discuss the latest developments in non-muscle invasive bladder cancer and NMIBC and where Bel-sar could fit into the evolving landscape. Given the recent clinical data and the updated trial designs we have just shown, we'll cover some insights on the mechanism of action, the regulatory progress, and the potential impact for patients and physicians. Given that Dr. Linehan has an abbreviated schedule today here, I would like to start with you, Dr. Linehan, and address the first question. Dr. Linehan, you have had hands-on experience with patients in the trial. What stood out to you about Bel-sar's feasibility as an in-office procedure?
Yeah, I think for me, a lot of my patients are in the older population, and I'm trying to offer these patients treatment options that they can do in the clinic and in a sense, if you know, it's worth it for their cancer care to keep them out of the operating room. To have an Immunoablative treatment offers them a lot of care because I can still do, you know, some very minor biopsies in the office, confirm the diagnosis, and then do the injection of the Bel-sar and the light activation right after that. The patients that I did have on the trial tolerated this extremely well. In fact, I would say in some cases better than some of the intravesical therapies that we do, but it also gives me room to use intravesical therapy at a later date if I still need to do that.
Thank you. Dr. Shore, the next question goes to you. Given what we know now about Bel-sar's early patient responses we have just seen in the phase one window of opportunity study, what are your thoughts on the safety and on the efficacy profile so far?
Thanks very much, Sabine. You know, it's really nice to be able to hear the evolution of the presentations and having been part of this from the earliest. I think I might have been the first site that did the initial injection. Of course, everybody has anticipatory anxiety about that. It was, you know, it was a kind of a big nothing burger, so to speak. The injection, as Jill pointed out in this Dr. Linehan comments, it's a sort of a non-event short of a patient undergoing a cystoscopy. It's that, you know, it's that basic. I think Dr.
Steinberg, myself, Dr. Linehan, Dr. Cates, others who've done this, it's really like injecting a Botox into the bladder, which, you know, urologists do routinely. I think it's really nice to see, and I really appreciated the presentation when one can look at the preclinical work and see the Immunobiologic effect for the basis of the MOA. Now what we see, and granted, small numbers of patients, 10, 11 patients, but nonetheless, the immunobiology here is really powerfully correlative to what we saw with preclinical work. I really think it's very elegant. Seeing these patients respond not only to the direct tumor injection once it's light activated, of course, and the light activation is also pretty much of a non-event, nothing really more than just doing a cystoscopy.
Seeing the responses, which I think was really the thrust of your question, it's pretty remarkable on the intermediate risk group. Then also what some would suggest now is the field effect on other tumors. I think that's pretty exceptional. We don't have anything close right now to an FDA-approved injectable technique, technology for bladder malignancy, let alone a laser ablative technology for bladder malignancy. This is truly innovative. It is disruptive. I think as you said early, I don't know for the folks listening in, I know for myself and Dr. Linehan and Steinberg, if we can do some of these types of procedures ultimately just in the clinic and avoid the scheduling hassle, the anesthetic risk to patient, you know, the patients in the clinic, that together is very user-friendly.
Of course, ultimately the health economic outcome reporting data, you're far away from that, but one can see, and you had that in one of your early slides, is always talked about in all bladder cancer, the cost. Dr. Steinberg and I have been working on this for many, many years, and we see so many things that lead to repetitive TURBTs, recurrences, let alone progression that leads to this really dramatic cost. You know, everyone recognizes that the value proposition for innovative strategies will be very well accepted clearly by commercial payers and by government payers, regardless whether you're U.S. or non-U.S.
Thank you, Neal. Dr. Steinberg, I would like to talk with you a little bit more about especially the immune effect we have seen. Bel-sar's dual mechanism of action is a key differentiator also to other treatments.
Can you walk us through the immune staining data we have just shown and what it tells us about how AU-011 works as a treatment?
Yes, thank you for the question. You know, I think that we're still learning a tremendous amount about the immune system and how to harness the immune system to effectively treat our patients with cancer. More importantly, to try to directly target in a precise fashion, I think is critically important. We're seeing that when we look at the tremendous results we're getting with antibody drug conjugates such as Padcev, Enfortumab vedotin in multiple advanced malignancies, Sacituzumab govitecan.
This is a virus, a VDC, a viral-directed conjugate with a viral-like particle that really derived from an HPV virus that binds very actively to altered glycosaminoglycan or the surface proteins that we see in the urothelium that have been altered by the mutations of the carcinogenic effect. We're getting some really specific binding. Once that viral binding occurs, we're very effectively getting viral cell killing, creating an immune cell death from neoantigens. These are proteins and so forth specific to cancers that the immune system can identify. From what we've seen in the staining with the T cells, and let's not forget about the tertiary lymphoid structures, many of those have B cells. We're not only turning on the innate immune system from the viral killing, but we're also turning on a specific adaptive system with T cells.
We're seeing T cell infiltration and B cells. We're getting humoral cell killing, which potentially may even contribute to ADCC type of immune killing, bringing in natural killer cells. In a very elegant way, this viral-like particle and VDC is really revving up the immune system specifically to these particular urothelial cancers. It's critically important. There are multiple feedback loops that we have in the immune system to prevent damage to normal healthy tissue and creating autoimmune disease. This is a nice demonstration of what we know experimentally and clinically of how to harness the immune system to effectively treat cancer.
Thank you. I have a few follow-up questions in that regard. What does it also indicate as we are seeing similar patterns also of activation in the non-target tumors, in the target tumors?
What we call the urothelial field effect is that we see not only the effect in the injected lesions, but also in other lesions across the bladder.
Yeah, I think that this is the key, and this is why the entire world is moving towards immuno-oncology rather than standard chemotherapy, because the goal with an immunologic approach is to not only kill cancer cells at the time that you're giving the treatment, but to create an immune cell memory so that whenever there's recurrent cancer or any other cancers, urothelial cancers in the bladder, we know that in many patients, bladder cancer is affecting all of the cells of the urothelium. It can be a clonal, a monoclonal, or a polyclonal effect. By creating these antigens and by creating these B and T cell responses, we're able to survey and prevent cancers from coming back.
One of the things that we know when we treat patients with chemotherapy is that you stop the chemotherapy, many, many times the cancers come back. The whole mystery and beauty of immunotherapy is those sustained complete responses that when we look at the checkpoint inhibitors are about 20%. We realize that that's good, but certainly not good enough, and that we're looking to really, truly enhance that with additional combinations, but more precise stimulation of the immune system. I think that this is a major start as these other urothelial cells, again, many of them have the same perturbations and mutations that we see in the cancers, but potentially set at a different time clock. As their time clock ticks to where they then have a manifestation of cancer, ideally the immune system will recognize them and prevent them from becoming full-fledged tumors.
When you compare it, for example, with BCG, which is also an immunotherapy, can you compare and contrast also mechanistically how AU-011 works in contrast to BCG?
Yeah, again, I think that I think it's time to move on from BCG, but we shouldn't shortchange BCG. It does create a pretty profound nonspecific, and I put in bold, nonspecific immune response where it causes an infection of the BCG particles to the urothelium. There's almost a desquamation of the urothelium, and there's turning on the innate and adaptive immune system against BCG, not necessarily against bladder cancer. We know that it's effective, but that many patients don't tolerate multiple installations of BCG and that there are multiple escape mechanisms of bladder cancer, for example, against BCG. Some are known and unknown.
By targeting the cells more specifically and the cancer cells more specifically and creating more of a cancer-specific immune response, I mean, with CD8 T cells with specific T cell receptors for the urothelial cancers, I think is ultimately a more elegant and more advanced immunologic approach than a kind of a generalized BCG inflammation. The BCG most likely works through NK stimulation and gamma delta T cells. Gamma delta T cells are T cells that do not have MHC or do not have specific binding properties for a specific antigen or cancer. I think that a newer approach, a more targeted, more elegant approach is clearly beneficial and hopefully will move the field forward.
Thank you. One more follow-up question. When you think again about the immune activation, how does it compare also with intravesical chemotherapy?
Yeah, again, you know, intravesical chemotherapy we've been using for many, many years, and urologists like it because the side effects are very manageable. Unfortunately, the efficacies are limited. A lot of that is just because of the way we give intravesical chemotherapy and the pharmacokinetics of it. We put a drug in the bladder. It's supposed to be topically absorbed. Probably 1%-2% of that drug is actually topically absorbed. Then with a fairly short time interval, patients urinate the drug out of their bladder. For example, when we look at ADCs such as Enfortumab vedotin, it binds to Nectin- 4. The half-life of that drug given systemically is about three days. That's what you need. If you're going to have an effective chemotherapy, you need something that's going to be around more than for an hour or two when the cells are going through multiple different phases.
Just by we know that it does not really matter what chemotherapeutic agent you put in, your ultimate efficacy is going to be limited. More importantly, the chemotherapies that we are using are clearly on an empiric basis. We have no idea if that particular urothelial cancer is going to be sensitive to an alkylating agent, for example, or to some of the other agents that we are putting in the bladder. It is really empirically based. Again, I think it is time to move on.
Thank you. I have another question for Dr. Shore. What are your thoughts about the updated phase 1B2 clinical trial design? How do you think that could support a subsequent registrational pathway?
Before answering that, I really appreciated Gary's explanation. One thing just to add is, you know, BCG, like the chemotherapies, are very dose-intense, right? The dosing schedule.
Induction is once a week for six weeks, sometimes a second induction for another six weeks, followed by the maintenance, you know, three times, three months later, three intravesical installations, again at six months, and then again at 12 months. That is pretty comparable for the chemotherapeutics. Maybe it is an induction Q1 week times six and then monthly. What you saw in your outline and again in your progressing phase 1, 2B trials is at most, you know, day one, day two, injection, light activation, day 14, 15, injection, light activation, and then observation with the intermediate risk group. As we go to the more high-risk group, we do resections and then follow-up. I think your design looking at the different dosing increments is very important because we want to get the right dose. We want to FDA insists on dose optimization. I think it is very thoughtfully designed.
It was probably a little complicated for someone to follow all the nuances of it. It wasn't, you know, you went through it. I think people would want to go through it in a little bit more detail, but I think it's elegant. It's important. We need to get down the right dose and the interval between the injection. I think that will ultimately give us a lot of information to answer your question for ultimately a registrational trial.
Thank you. I have another question directly for you and then also to Dr. Linehan. I would like to ask you both, when you look at the current safety profile along with the complete responses we have seen, how would you expect that AU-011 could be used in the practice for both for intermediate-risk and for high-risk patients?
I'll take it real quickly. I know Dr.
Linehan has some time constraints. You know, it's well tolerated. I mean, that's really clear. Unfortunately, or maybe fortunately, maybe the majority of patients with BCG and the chemotherapies, whether it's docetaxel, gemcitabine combinations, or just gemcitabine or mitomycin, most patients do okay, but there is a significant minority that find it generally very intolerable from really annoying voiding symptoms afterwards. Occasionally, there's some systemic issues with BCG that can be catastrophic. It's 1%, maybe less, but I think from a patient-friendly standpoint, a clinic-friendly standpoint, and ultimately where physicians will move towards should it get approved is that if efficacy is equal, hopefully this will be better. Even if it was non-inferior and equal, I think the safety, the dosing schedule is going to be very attractive to both patients and to the physicians and the healthcare team in the clinic. I'll let Dr.
Linehan, add on to that too.
Yeah, thank you, Dr. Shore. I agree with all your comments. Thank you, Dr. Steinberg, too, as well for going through some of the immunology. I think that's one of the important points about using the Bel-sar is that when you're giving a patient BCG once a week for six weeks, first of all, if you can get BCG, and many of us can't, the patients do have some inflammation and irritation. I do have patients that not only can they not even tolerate the BCG, many of my patients are incontinent, and they can't even hold any of the intravesical therapies. Having an injection therapy for them can be incredibly helpful because they can't, whether it's gemcitabine or BCG or what it is, they literally can't hold it. Some of them will just even leak around the catheter.
I think that provides an option for a lot of my patients. I think they will tolerate it very well. I think I'm going to keep a lot of octogenarians and nonagenarians out of the operating room and exposing them to anesthesia after anesthesia, which there's very good evidence that does play a role on people's mental status. How I explain it to the patients when patients would say, "Well, why aren't you going to give me BCG? Why would we do this instead?" I basically will tell them, "Look, I'm going to direct something directly into the cancer that's going to take a little bomb into the cancer. It's going to kill the cancer, and then it's going to create this immune effect for the rest of your bladder." I might be doing two things instead of just one thing.
I think this has a lot of potential, and I'm very excited about it.
Can I just add to Dr. Linehan brought up a really important point, and it frequently never gets discussed except when you're in the actual clinic. Once that patient is incontinent, you're shutting down an entire room and a bathroom for hours. You basically have to do a clean protocol. This is a real problem with a lot of intravesical therapies that are liquid-based, obviously. We have a lot of these patients who have overactive bladders. They become incontinent. Now you have to follow a protocol. If you're short on clinic space, you've now tied up a room and a bathroom potentially for the rest of an afternoon or an entire morning. That's a real practical consideration. I really appreciate that she brought up that point.
Yeah, thank you both. Critical, critical aspects indeed. Dr. Steinberg, another question for you. You have seen the neoadjuvant study design in the high-risk patients, what we have now in the phase 1B2 study design. What will the drug effect look like in that patient population? Also, in other words, is it how which efficacy are we currently also seeing in that setting with TURBT and then BCG as an adjuvant treatment?
Yeah, I really like that approach. The thing about the neoadjuvant approach is that after you're giving your drug, you're able to do a biopsy and obtain tissue to assess how well you've done and to, excuse me, you're able to assess how you've done and to really look at a molecular level in terms of immune infiltration and what do the cells look like, any cancer and so forth.
In a perfect world, that would help you preclude needing any adjuvant therapy. Your adjuvant therapy could be rather than BCG, even though you may not see any additional tumor in the bladder. There's no reason you can't use Bel-sar in a number of different sites. Give injection, not in any visible tumor, but maybe five or six areas in the bladder to see if you can kind of create some adjuvant effect as well. Again, something you'll have to study. The neoadjuvant approach is, as you know, which is what we use in muscle-invasive bladder cancer. We're looking at it in upper tract urothelial carcinoma. Bladder cancer is an immune-responsive tumor. We do believe that if you can attack it early, there will be some benefit.
We see with the Niagara trial in muscle-invasive disease, chemotherapy plus a checkpoint inhibitor, durvalumab, improves overall survival for patients that have undergone a cystectomy afterward in muscle-invasive disease. The whole neoadjuvant concept is critically important. It gives us a lot of information. It would be wonderful to get an idea of potentially maybe you might need more neoadjuvant treatments upfront to prevent the need for adjuvant therapy down the road. Again, if we can get away from BCG, I think it would be great. As Dr. Linehan very nicely spoke about the incontinent patient, let's not forget that bladder cancer patients in the U.S. and around the world are in their 70s and 80s. Even if they're not incontinent, they have many urinary tract symptoms, irritation, frequency, urgency.
If you could eliminate that or prevent that or certainly not exacerbate that, I think you're doing something very good for the patients.
Thank you. Dr. Shore, we partially talked already about it, but when you think about the current treatments in the standard of care such as BCG or intravesical chemo, what are the shortcomings overall? Do you think that Bel-sar could ever replace these therapies also in the future?
I think the answer is yes. Look, BCG is effective. There's no doubt about it. It's very effective. It's been the gold standard for, gosh, now 40, maybe even 50 years now. That said, we're plagued by not only a BCG shortage in certain parts of the world, but some inconsistencies in the strain. There is some variability in the efficacy.
On top of that, there really are patients who are, quote, "BCG intolerant." They just can't take it for whatever various reasons, local irritative symptoms, occasionally systemic symptoms. Now, the chemotherapy, I think Dr. Steinberg did a really nice job of pointing out the difference between a chemotherapeutic MOA versus Immunobiologic. You do get durable ongoing response, the adaptive response. Now, you can see that with BCG, but the BCG regimens based upon the SWOG trials are really rather intensive. What I think if we were non-inferior in the Bel-sar developmental trials, that would be remarkably exciting and interesting as a replacement for BCG, just on the scheduling alone. Probably when we get more patients under our belt, and I'm confident of this, the tolerability and the safety is going to be better. We just have to demonstrate additional numbers where the efficacy is there.
I think everyone from the company recognizes that, and that's the importance of doing clinical trials. I think, as Gary said, in our lifetime, and he and I have talked about this before, I'd love to see BCG no longer be considered the go-to standard of care. There are probably some good economic reasons in certain countries and in certain payment processes where that could also be an issue as well, both from the payer side as well as from the healthcare provider. There are a lot of interesting things.
I think, too, as you alluded to it early in one of your first slides, the budget impact modeling or what we oftentimes call the health economic outcome reporting data from the complications, the dosing schedule, and efficacy, I think this is very interesting and exciting to me as another potential reason for replacing BCG and certainly the chemotherapeutics. It is disruptive. I think that's what Dr. Steinberg and I, who've been around a long time doing this, we find very exciting.
Yeah, thank you. When I understand you're writing also from an economics perspective, you also think there could be a benefit using AU-011. How do you think could it overall change the economics and neurologic oncology practice, also considering it from the overall health economy lens, particularly also considering that potentially the follow-up treatments, the downstream treatments could be avoided possibly?
Yeah, it's a great question.
Let's forget about physician reimbursement, which is a whole complicated source of discussion, whether if you're looking at things strictly on a reimbursement level and you're the administrator versus not. I think given the very, very attractive minimal invasiveness of the schedule of events that you outlined beautifully in your development plan, it is much less rigorous, much less intensive than traditional intravesical therapies, whether they involve a liquid-based therapy, which almost all of them do, approved now in BCG unresponsive versus those that are looking at even the BCG naive, that whole competitive landscape, maybe with the exception of intravenous pembrolizumab for BCG unresponsive CIS, but it's still every three to six weeks, including the 10-12% of serious grade 3, 4 immune-related adverse events.
I can't underemphasize the attractiveness of a clinic-based dosing schedule, which you've outlined here, that could, if demonstrated to have this impact on recurrence, field effect, progression, and then the subsequent lack of requirement for additional TURBT. That's where the real cost is. That's where that data comes up. I have looked at this in so many other ways, not just in therapeutics, but also in diagnostics and white light, blue light, etc. That never-ending cycle of cystoscopy, biopsy, fulguration, cystoscopy, TURBT, anesthetic, complications from the anesthesia, complications from perforation, complications from infection, bleeding, etc., catheterization, catheters getting clogged, dislodged, etc., not to mention the adverse impact on patient-reported outcome. All of those things really add to this cliché, but it's a true cliché that bladder cancer and MIBC, the entire field, is one of the, if not the most expensive solid tumor to treat.
I really like an innovative technology that would help not only with the efficacy, the prevention of recurrence, the prevention of progression, but at the end of the day, helping the healthcare system from an economic standpoint.
May I add also the burden of the family members and the healthcare providers and the financial toxicity? Let's not forget that every time an elderly patient comes in for BCG, many times their son or their daughter or somebody has taken off a day of work to get them to the office. Every time they go into the hospital for TURBT, there's somebody taking off a day of work or two or three days to help take care of them.
It is not just the healthcare system, but it is the overwhelming financial toxicity and healthcare burden on the family members and the patients that we also would like to decrease as much as possible.
Yeah, that is a great point.
Thank you. I have one last question, which I would like to ask both of you. Dr. Linehan has left meanwhile, but I would like to ask you if you could make a bet today, how do you see Bel-sar changing the treatment landscape in bladder cancer in the next 5-10 years?
You can ask me or Neal.
Whoever would like to start.
Again, I think that our urologists that we are training today are excellent endoscopic surgeons. They are incredibly bright and that they suffer from not enough time and energy because there are more patients than there are doctors.
I think that if you can keep a urologist at his home base in his office, not having to go to the operating room, not having to change venues to give treatments, I think that will tremendously increase the efficiency of the provider and for the patient. I think that, as Neal talked about many times, is that we need to find dose de-intensification strategies. Anything that you can decrease the number of treatments and dosing. We saw that from COVID. Patients were more than happy to not have to come in to see the doctor. I mean, anything we can do to de-intensify the treatment regimens, but more importantly, to target more specifically with novel innovative therapies, I think that's critically important.
The beautiful thing about urology right now is because of the change from the FDA guidance in 2014, 2015, we have a regulatory pathway to get many more new treatments approved. A lot of investors think, well, there's just got to be one winner and one treatment. If we can get four, five, six different treatments with different mechanisms of action, with different targeted modalities and so forth, the better off everyone's going to be. I think that if we can do more things less invasively, the better.
Thank you.
I'll take a stab at that, given for anyone who's on the phone or the call here who is US-based, it's March Madness. My gambling on my brackets have just blown up. I'm in the tank, so I'm getting killed.
I think I would do a lot better if I had to make a bet that if our regulatory pathway is successful, and based upon our 10, 11 patients, I'm optimistic. If we're successful, this will be disruptive. This will be significantly disruptive. I agree with Gary. There's never a one-size-fits-all therapy for everybody. There is a lot of really great development going on in NMIBC as well as MIBC and frontline and second and third line. It's great. I mean, Gary and I, you dedicated our entire careers here to bladder cancer. In the last seven or eight years now, we've seen this oasis now of fantastic development. It's really very, very great and rewarding to see. I think Bel-sar will be one of the top priorities for the clinic-based physicians, undoubtedly.
I would, not being much of a gambler, but I would say it would be a very, very safe bet, assuming we can get forward with our registrational studies.
Thank you both. These were two great responses to the last questions. Beyond all the other great responses as well, I really very much enjoyed the discussion and would like to thank you again for your participation today. It was very informative and very helpful for us. Thank you. With this, I would like to open the floor for Q&A for analysts.
Great. Thanks, Sabina. At this time, we'll be conducting a question-and-answer session with the audience. Please hold for a brief moment while we pull for questions. Our first question comes from Andy Barrons at Lyric. Please go ahead, Andy.
Hi, can you hear me?
Yes, we can. Great.
In the intermediate risk group, are there any concerns about committing a TURBT in regards to staging? In the high-risk group, just wondering, how long do you think you'll need to follow patients to show a decrease in recurrence risk? When do they typically recur after TURBT? How important is OS in this group?
Thanks, Andy. Appreciate the question. I might actually put that to Dr. Shore to start, if you're willing to tackle that one.
Yeah. I think two different stages, of course. What's very interesting now about the intermediate risk population is we don't really have a lot of great level one evidence for what to do best. We have still some challenges within the clinician community of understanding truly what intermediate risk disease is. There's some nuanced differences between our European definition of our European colleagues and our US colleagues.
Having said that, there is, I think, a movement now to be very comfortable with not having to resect all of these patients. I think, indeed, coming up with therapeutics that are Immunoablative. Others are looking at other forms of ablation. If we can avoid doing the resection and follow these patients in a safe way, which assuredly we can, I think that that's a real paradigm shift. I hate to use that word. It's overused. Many people think I hear this from the financial community, from some, not all, and from some payers too, that, "Oh, gosh, urologists, they use their cystoscope like a cardiologist's stethoscope. They've just got to use it. That's all they do. It's their bread and butter." I think that alluding back to what Gary was saying earlier, this is changing significantly. We want to be more efficient.
We recognize the morbidity that we put upon patients, these TURBTs, just like putting in a catheter. We technically, "Oh, it's just a catheter." People really don't like having catheters. The ability to avoid a lot of this urethral invasion with a concomitant anesthetic and having an ablative strategy, avoiding a TURBT for the intermediate risk group is extremely appealing. There are multiple studies that are looking at that approach. As it relates to, I think, your second question, I think there's a pretty good schedule of events where we look at every three months cystoscopy and urine markers. That's a little controversial, but by and large, cystoscopy with or without pre-required biopsy at a certain point in time, whether it's 6 months or 12 months in the high-risk group.
That seems to be the regimen of the protocols that most of all the studies that I'm involved with are comfortable with. It's complete response, right? We want to see a good complete response. Of course, if we have a high-risk patient who comes back from high-grade to low-grade disease, that's not a disaster either. Essentially, those high-risk patients, what we're most concerned about is the progression risk, thus the importance of the regular Q3 months cystoscopy and probably at some point in time, follow-up imaging.
For your second part of your question about the grading and staging and so forth, I'm going to say something a little controversial, and it's based on my long-term experience. I think the beautiful part about Bel-sar is to be able to treat both low-grade and high-grade papillary disease.
In the European Association of Urology Guidelines, any high-grade disease is high risk, where in the U.S. definition, smaller, less than 3-centimeter high-grade non-invasive tumors potentially may be intermediate risk. I think that what we see clinically is we see patients with a lot of smaller tumors. They may be low-grade or high-grade. They're non-invasive. I think that even in the high grade, the risk of progression is quite low. Again, we've got a time frame to figure that out. Being able to treat these patients with something like Bel-sar in either a neoadjuvant or an Immunoablative approach, we'll still have plenty of time to figure out if they truly are high-grade, what's the risk of progression. We can get urinary Cytologies. I think that more and more people are looking at urine-based circulating tumor DNA, cell-free DNA.
We've got a number of other companies that are looking at biomarkers of urinary disease, even trying to predict progression and/or recurrence of prognosis. I think that in the future, in combination with urinary markers, clinical experience, urinary cytology, we can avoid those staging TURBTs, which I think really are overkill for low-grade TA disease and even small high-grade TA disease. In the old days, if you had a TA high-grade tumor and there was no muscle in the specimen, that was thought to be a breach of standard of care. We know that if you've got a TA high-grade and there's lamina propria, it's no invasion, you don't need to go back and get muscle in those patients. They're going to behave in a fairly routine pattern, albeit their risk of recurrence is higher than a low-grade.
Their risk of progression is also higher, but still awfully low that we can manage them very effectively and cut down on the number of TURBTs. The whole beautiful thing about biomarkers is potentially to decrease the burden of frequent cystoscopy. Neal and I were at a meeting at the think tank for the Bladder Cancer Advocacy Network, and a patient advocate was talking about their experience with urology and bladder cancer and just was livid about how upset he was that he had to have frequent cystoscopies. That really struck home to me. We do need to try to instrument the patients less because that certainly is something they would like.
Thank you for adding that, Dr. Sambas. Just to add to that as well, we have also a broad biomarker program that will be implemented in the phase 1B2 study.
On the one hand, of course, again, for proof of concept of mechanism of action, but also to address exactly the points you mentioned to detect recurrence earlier, to see how response is maintained, and also to develop maybe possibilities to assess minimal residual disease going forward.
Yeah. I think, Andy, to follow on your question, I know we moved through our study design fairly quickly there, but we will be following all of our patients out to 12 months using the standard regulatory endpoints. That is in discussion with FDA that has taken place.
Thank you very much.
Thanks for the questions, Andy. Our next question comes from Phil Nadeau at Cowen. Please go ahead, Phil.
Good afternoon. Congrats on the data. Two questions for MOZ.
First, on the design of the phase 1, 2, it looks like there is a maximum dose of Bel-sar per bladder and then also the dose per lesion. Do all lesions need to be injectable in order for a patient to be enrolled in the trial, or will some patients with more than three accessible lesions be allowed in the study? That is the first question. The second question is for Dr. Shore and Steinberg. We are just curious to understand what you think in the intermediate group, in the high-risk group, what efficacy data would be necessary to see from this phase 1, 2 for you to be confident that Bel-sar should move forward in those two different disease categories. Thanks.
Great. Maybe, Phil, thank you for the questions. Joe, if you can take the first one on the study design around the dose per lesion. Yeah.
Great. Thanks, Phil. Thanks for that because it's good to clarify this. Correct. We're going to dose up to three lesions. Obviously, given the disease space, many patients may have less than three. If they have more than three, there will be untreated lesions directly with Bel-sar, which is fantastic for us because we're going to continue to see how those respond after we've treated three. I think that gets to your first point. Each lesion will receive 200 micrograms of Bel-sar in that first cohort, D. As we move ahead to the cohorts enrolled in parallel, each lesion will receive 400 micrograms of Bel-sar, again, up to three lesions. Thank you for the opportunity to clarify.
Part two, if Dr. Shore and Dr. Steinberg can weigh in on Phil's second question.
If we're looking at the complete response rate first in the intermediate and then in the high-risk group, I think it'd be probably—again, I haven't looked at the full plan, so I'm just sort of guesstimating here. After three months, certainly love to see something north of 60% would be very encouraging, probably in both stages, both for intermediate and high-risk. Gary, your thoughts?
I was going to use that 60% as well. Again, I think that we've got two endpoints that we're looking at. We're looking at a primary endpoint, which is going to be our complete response. Really, the holy grail is our durability. I think that nobody quite knows how good it can be.
We've seen in some of our BCG and responsive trials with some of the newer agents, we're seeing a durability at 12 and 24 months north of 30%, if not higher. In a BCG naive or a newly diagnosed patient or a patient who's only gotten minimal amounts of intravesical therapy, truly intermediate risk, low-high-grade papillary, non-invasive. If we could get out of the complete responders, if 70-80% of those are still complete responders at 12, 18, and 24 months and somewhere in that ballpark, that I think would be a real home run. Again, with all new therapies, we have to think about hitting singles first and then doubles and then beyond. I think that if you have a complete response, especially in the Immunoablative and you're avoiding a significant number of TURBTs, greater than 50%, 60% avoiding TURBTs, that's a really solid figure.
Icing on the cake is durability at 12 and 24 months.
Totally agree with that, except you went from—we're talking we were using the basketball analogy, and you went into baseball. I don't—
It's opening week, Neal.
Right. That's right. It's opening week. That's right. Yeah.
Great. Thank you both. Great.
Thanks for the questions, Phil. Our next question comes from Oliver McCammon at LifeSci Capital. Please go ahead, Oliver.
Hi, all. Congrats on the data, and thanks for taking my question. You tested a relatively low single dose of Bel-sar in NMIBC. Just as we think about what a higher dose could potentially achieve in the future, can you remind us on how the efficacy shifted when testing a therapeutic versus subtherapeutic dose of Bel-sar in choroidal melanoma and whether you think this has a fair read-through to bladder cancer? Thank you.
Thanks, Oliver.
I'm happy to take that. I know it's our bladder team, but as the CMO and resident ophthalmologist on the call, yeah, we saw actually—so similar to bladder, we were able to dose escalate quite significantly. We didn't have any DLTs. Side effect profile was tremendous, also less than grade 1 AEs in anyone, self-limited or topically treated with steroid for mild anterior segment inflammation. We had a similar safety profile, Oliver, in terms of really being able to up that dosing. We did see, certainly, as we got up into both increasing the dose and the number of cycles in choroidal melanoma, we had an 80% tumor control out at 12 months with upfront treatment of three cycles. Melanoma now is a little bit different, choroidal melanoma in particular, because these tumors arise from benign cells.
There is always a mix of benign and malignant cells within that tumor. We did want to make sure we had that upfront therapy with adequate cycles, but significant increase in the percentage of tumor control with both the Suprachoroidal delivery, getting the drug right where we wanted it in the choroidal space, and dose escalation over time.
You bring up a lot of very important questions. I think that there is no question that with more experience, the injections of Bel-sar in the bladder will be better. We are trying to inject the base. I think that it is going to be a little operator-dependent initially, although quite rapidly that will evolve. I think that the bladder is a much larger space than the eye. I think that we really will have the opportunity to really crank up the dose.
We'll be able to treat potentially even random spots in the bladder as well with really—I don't think there's going to be any toxicity to write home about. I think that there's an opportunity to really figure out exactly how to inject, where to inject, how much to inject. I think that the dosing that we're looking at is probably just the beginning. I suspect we can probably use a lot more dose in the bladder.
Yeah, you raise a good point, Gary. I think that's something that limits the ocular work, right? We have a closed system. We can only put in a certain volume, be it in the vitreous or a Suprachoroidal space. We have to work around that in terms of how much we can deliver at one time.
I think, again, with the small ocular dose and volume that we utilized in our data thus far, the therapeutic range we have here looks considerable. Agree, the bladder feels like a bit of a different animal, if you will.
Great. Thanks for the questions, Oliver. Our next question comes from John Wolleben at JMP Securities. Please go ahead, John.
Hey, thanks for taking the question. Two for me. Wondering just for the trial design, is this an extension to your current trial? Just wondering any gating factors to starting dosing in 4D. Also, any rationale for the two-week time period between the last cycle of Bel-sar and the TURBT? How do you think about toggling that time period and the potential effects on outcomes?
Joe, maybe you can take that for us.
Sure. John, thanks.
I think to get to your first question regarding the 200, really, we were just treating a single lesion in the current iteration of the study. As we're expanding now here, our patient numbers, we're treating up to three lesions. We wanted to keep the per lesion dose constant at 200 because really the whole bladder is going to go up to 600 now as we're treating three lesions. That's partly what factored into that decision-making. Taking your second question there, the neoadjuvant design, the two-week separation, working with our immunologist and thinking about how long we need to actually generate a prime kind of boost effect, that two-week window seemed to be in that golden spot.
Most importantly, it was enough time that it would not delay patients, particularly in a higher-risk category, from getting that TURBT that is kind of part of their standard of care. It would be appetizing to clinicians, to patients, and would still allow us to get a good immune effect.
It is an excellent question because, quite frankly, I do not think we really know that. There is so much we do not know about the immune system and how much time you need to create an immune response. It potentially is different amongst different patients. Do you measure? Potentially, we can measure urinary cytokines of interferon gamma, for example, or looking at IL-6 and IL-8, 10, 12. There are all these different things that we could potentially measure, which would be probably, if you did it all, that would be quite expensive. It may not make a difference.
Yeah, finding the sweet spot is critically important. I think two weeks, not bad. Three weeks, maybe better. Four weeks, who knows? It is an excellent question and something that we hope to figure out. Right.
Building on that, to piggyback on that, Dr. Steinberg, is it great? We are going to get a lot of biomarker data here moving ahead, right? It is going to be fantastic with the data we have coming in.
Right. Great.
Thanks for the questions, John. Our next question comes from George Farmer at Scotiabank. Please go ahead, George.
Hi. Thanks for taking my questions. When we talk to urologists, particularly those who practice in the community setting, they appear to be extremely wedged to adhering to AUA or NCCN guidelines when treating NMIBC.
All of them talk about TURBT as they're really kind of their bread and butter of their practices. As a practical matter, I was wondering how the docs on this panel really kind of feel about adoption of something like Bel-sar in the real-world setting.
Thanks, George. Gary, do you want to take that first and then Neal?
Yeah. I think our whole economic model—I mean, again, not to be overly cynical, but if you want to understand how a lot of doctors behave, follow the money. Having said that, our whole economic model is rapidly changing and being disrupted in how we deliver healthcare. I think that one model, if you think you're going to generate revenue by doing surgery, the other model is how much money you're losing by doing surgery because you're going to the operating room. You're waiting around. It's inefficient.
All that time you're spending to do—and you may get for a TURBT a few RVUs. Had you been in the office and seeing patients nonstop and doing all the things in the office? I think that for many, many, especially the intermediate risk patient population, taking them to the operating room is a real economic drain on your time. I think that the younger physicians may say, "Oh, I got to do a TURBT." I think the people that know and have been around and understand how the healthcare system works will tell you that if you can optimize office-based work and avoid these TURBTs in the operating room, even if it's in your own surgery center, you're going to be economically advantaged. Neal knows this better than anybody.
There is a lot of segmentation of the market, and it varies intra and inter-country.
I hear baked into your question, honestly, is sort of a yesteryear commentary. It is still true. There are folks who think in those terms. It is not very efficient. It is not very cost-effective. It is not very remunerative to go to the hospital or to a surgery center in most cases and try to get through a bunch of TURBTs where your turnover time between cases can be, in a wonderful way, maybe 30 minutes, oftentimes 90 minutes. It is just not a good use of your time, as Dr. Steinberg points out. You are much better served by seeing more new patients and doing things that reimburse better. In the U.S., the TURBT fee schedule—most of these patients are older, right? So they are going to be Medicare-based—is not a very sustainable model. There are many other things that the Uro-oncologic community in the community specifically will be trying to do.
I have no idea what the cost of AU-011 is going to be and how it'll be covered. Presumably, it'll find a sweet spot. I think that there's a lot of consideration for that. The commentary that I think you're hearing was much truer 10 years ago, but it's changing rapidly. I think it's also changing outside the U.S. as well.
Great. Thanks. Maybe one for the company as far as the regulatory strategy is concerned. Does it kind of make sense to go into, say, a BCG refractory disease population so you could potentially get approval with a single-arm study? Or do you think kind of going more into the lower-grade intermediate risk patient population in a randomized setting makes more sense?
Sabina, do you want to take that one?
I can take that one.
Overall, when you look at the current data we have shown, we have seen the responses in intermediate-risk, low-grade, and also in high-risk, also one finding BCG unresponsive patient. From that perspective, it makes sense to really explore the potential scenarios, the potential disease indications in both directions. Whether it will be a single-arm design or a randomized study, that's something we need to explore based on also the current phase 1B2 study design. Also, we just need more data to define the strategy. Right now, we are just excited also to get such positive feedback also from the FDA on the current phase 1B2 study design to be able to escalate the doses and develop the treatment regimen in an optimized way in both indications. Again, from a mechanism of action, BCG unresponsive is for sure an indication that could be explored.
You asked an excellent question. I think that we'll have more guidance after the ODEC meeting for Eurogen with UGN 102. They're looking at the intermediate risk patient population in a single-arm study without a randomized arm. The FDA guidance in 2024, in August of 2024, talks about randomized trials in papillary disease. As you know, randomized trials in papillary disease are expensive. I mean, that can cost a significant amount of money. Clearly, if you're going to look for an indication in intermediate risk disease and it's papillary, ultimately, you probably need to do a randomized trial. Going the BCG unresponsive route, there is a lot of competition. There are a lot of agents that are further along. It is more difficult to identify those BCG unresponsive carcinoma in situ patients. What about the BCG exposed?
Again, I think in the BCG exposed, you also need randomized trials. That was published in the European Urology. I was one of the authors on that paper a few years ago. I think that's kind of our regulatory pathway. If UGN 102 gets approved on the basis of a single-arm trial in papillary disease intermediate risk, then I think that that will change the equation.
Okay. Thank you.
Thank you for the questions, George. This concludes our Q&A session for today. I'll now turn it back over to Jill for closing remarks.
Thank you. Thank you very much. Really enjoyed the robust discussion. Huge thanks to Dr. Steinberg, Shore, and Linehan. Dr. Linehan did have to step back to her clinic on the West Coast, but we really appreciate the engagement and insights. Thank you all for your time.
We'll look forward to additional conversations.