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 Elisabet de los Pinos, Chief Executive Officer at Aura Biosciences. Please go ahead, Elisabet.
Hello, everyone. It's a pleasure to be here, and we're going to start with the presentation. I'm going to make some forward disclosures. So we're very proud to have with us four of the key opinion leaders in urologic oncology: Dr. Max Kates at Johns Hopkins, Dr. Joseph Jacob, Syracuse University, Dr. Neal Shore, Carolina Urologic Research Center, and Dr. Gary Steinberg, Rush University. Thank you very much for being with us today. I'm also really pleased to have key members of our leadership team participating in today's call. Our Chief Medical Officer and President of R&D, Dr. Jill Hopkins, our SVP Therapeutic Area Head of Urologic Oncology, Dr. Sabine Brookman-May, and our Director, Clinical Development, Urologic Oncology, Dr. Joseph McQuaid. So let me start with this introduction. One of the greatest areas of progress today is the early detection of cancer.
This has translated into a large increase in the number of early-stage cancers. Patients diagnosed with early stage is good news. Unfortunately, that doesn't translate with the amount of innovation in early-stage local disease. There is a growing need for function-preserving, organ-sparing local therapies that not only can intercept the course of the disease, it can transform it and impact the quality of life of patients. We believe at Aura we can do that with our novel technology. Virus-like drug conjugates have the potential to transform early cancer treatment. So VDCs, as we call them, have unique tumor selectivity. They target a key receptor molecule that is expressed really early in the early stages of malignant tumor transformation. It has a dual mechanism of action.
With this technology, we can directly target a cytotoxic payload and at the same time have a robust immune activation to generate potential CD8 T cell immunity. Thank you. In addition, this type of technology is tumor and mutation-agnostic. We have tested this in 100 cell lines, more than 15 animal tumors, and it consistently works with high potency. And not only we have done that preclinically at NIH, we have now positive clinical data in multiple early-stage local cancers. We just very recently presented our positive phase II data in choroidal melanoma, and today we're very excited for the first time to present our early data in non-muscle invasive bladder cancer. How does AU-011 work? First of all, we have a very safe drug, and this is the reason.
When you inject bel-sar locally, it's not cytotoxic, but it's very specific to the cancer cell membrane. It will basically bind with high affinity and high avidity to the cell membrane of the cancer cell. Once you activate it with infrared light, the cytotoxic payload is able to generate reactive oxygen species that are cytotoxic to the membrane. They basically disrupt the membrane physically, and the cell goes into acute necrosis. That's mechanism number one. But this is highly pro-immunogenic. Not only we have a virus-like particle in the tumor microenvironment, but in addition, we're now exposing tumor neoantigens, releasing damage-associated molecular patterns that activate CD4 and CD8 T cells, generating durable CD8 T cell memory. That's what we call mechanism number one.
So now I am very excited because we're going to continue on how this technology can transform the field of bladder cancer, and I will have our therapeutic area head, Dr. Brookman-May, to walk us through. Thank you, Sabine.
Thank you, Ellie. Before I would like to draw your attention to our data of the phase I study, I would like to take a couple of minutes to talk about the high unmet medical need for function-preserving and organ-sparing therapies in this patient population, patients with bladder cancer. Currently, bladder cancer is the ninth most common cancer worldwide, with an increasing incidence, and it is also associated with one of the highest lifetime treatment costs in the U.S. and other regions. Most importantly, the currently available treatments, the conventional bladder cancer treatment and the treatment paradigm, they are simply suboptimal, and patients, having a high treatment burden, suffering from short- and long-term side effects with a considerably and negative impact on their quality of life.
Most of these patients are diagnosed at a local disease stage, and most of them, about 75%, are diagnosed with non-muscle invasive bladder cancer, and the treatment paradigm there consists of doing a surgery before. This means a transurethral resection of the bladder tumor, which is a surgery needing an OR, needing general anesthesia, and this treatment is then followed by repeat and multiple adjuvant instillation therapies, for example, with chemotherapy or with BCG.
BCG has been used now for almost 50 years in that setting, and while it has proven also the concept that immunotherapy can work in bladder cancer, and bladder cancer is a tumor that could be very responsive to immunotherapy, we also simply just need to acknowledge that about 80% or even more patients don't even get a full treatment course, mainly due to discontinuations because of side effects. Being a urologist myself, I can also just simply acknowledge, having seen these patients and having done so many TURBT surgeries and intravesical treatments, that these patients are really suffering, not only from the tumor burden, but really from the treatment burden.
And the patients are waiting for a treatment possibility that can intercept the disease at an early disease stage, and that is effective on the one hand, but is also safe and less burdensome on the other hand as well. And let's focus just quickly on NMIBC, on a non-muscle invasive bladder cancer disease space. As you can see here, there are different risk categories. Usually, we categorize in low risk, intermediate risk, and high risk NMIBC, depending on the grade of the disease, which is histopathologically assessed, and on the other hand, also based on additional clinical factors. And as you can see here, also, the more the patients go to the higher risk setting, the higher is the progression risk.
But in the biggest patient population here, which is the low-grade, low- and intermediate-risk patient population, these patients suffer not necessarily from progression. They suffer continuously from recurrence of their disease, and it's in most cases, not only one recurrence. When a patient has one recurrence, they will in most cases, again, get another recurrence as well. So we have the low-grade, intermediate-risk disease setting, where we see the highest unmet need with about 42%-84% of patients developing recurrence over time. And this causes, again, the need for additional treatment. Again, a surgical resection and again, adjuvant intravesical treatment. So there is a continuous cycle of recurrence and additional treatments needed. And with AU-011, we would now like to develop this drug and treatment as a potential frontline immune ablative therapy in NMIBC based on its dual mechanism of action.
We will consider the common treatment goals in this patient population, and with AU-011, we would have the chance to do a focal treatment with a direct tumor cell killing, and in addition, with a dual mechanism of action, at the same time, stimulate a broad anti-tumor T-cell response. This could provide the possibility to do a frontline early intervention for local disease with a very low treatment burden and a very favorable safety profile, with the chance to ultimately reduce the risk of recurrence and progression over time and avoid TURBT or surgery in general at the operating room. The administration of AU-011 and its activation may also be optimized for the urology clinic, and the local administration is aligned with what urologists are currently doing in their offices. The current procedure consists of two separate procedures.
We have one local cystoscopic administration of the drug with the standard, cystoscopy needle. That takes less than five minutes for injection, and then there is a separate laser light activation, also, again, less than 10 minutes, so we have overall, and with a very conservative assessment, less than 50 minutes of total procedure time, and when you look, on the cystoscopic procedure, but also the injection and the laser light activation, these are familiar procedures for urologists, because urologists use on a continuous basis the cystoscope. They do bladder injections for, various different indications, such as also overactive bladder with Botox injections. They use laser applications for benign prostatic hyperplasia or stone disease, so they are very familiar with these procedures. There is no general anesthesia needed for AU-011 treatment, and this is feasible for patients and also with contraindications for general anesthesia and surgery.
You need to consider this patient population, bladder cancer patients. It is an elderly patient population, and the majority of these patients has comorbidities. And last but not least, there is no requirement for additional safety precautions in drug handling, as there is no risk of viral replication or shedding. And with that, I would like to hand over to my colleague, Dr. Joe McQuaid, to now present the data of our phase I trial of AU-011 in bladder cancer.
Great. Thank you, Dr. Brookman-May. The first thing I'd like to emphasize here is that this study is a, you know, window of opportunity. That means that AU-011 is administered between a planned scheduled biopsy and the standard of care TURBT. Clinical response data is measured up to 21 days. I think that's a key point here, that the final clinical efficacy endpoint is obtained at time of TURBT. In Cohort A, that will be at Day 9 , and in cohorts B and C, that will be on Day 14 . We do follow all of our patients up to Day 56 for safety, but again, final clinical endpoint is at either Day 9 or fourteen. Now we're gonna provide here an overview of the two parts of the study and the various cohorts.
Part one consists of AU-011 alone, no light activation that's based upon feedback from the FDA and encompasses a total of five patients. Part two consists of injection of AU-011 with focal light activation. What differs among these various cohorts, in addition to whether or not there's light, is the dose. And in part one, all patients received 100 micrograms. 50 micrograms of that was injected at the tumor base, and 50 micrograms just a bit deeper into the lamina propria. Within the cohorts in part two, we also have slight differences in dose. Cohort A, again, drug plus light, consisted of a total of 100 micrograms, all injected, 50 micrograms, which is injected at the tumor base, and then another 50 micrograms within the lamina propria. Cohort B consists of 100 micrograms injected entirely at the tumor base. Cohort C is currently enrolling.
We have one patient evaluable at this time. In Cohort C, patients are receiving 200 micrograms, all of which is injected at the tumor base. What we demonstrate here is an overview of the AUA risk classification here on the Y-axis and the tumor grade on the X-axis. Color coding pertains to each of the various cohorts. Yellow pertains to our drug only, no light activation, and the various shades of blue correspond to our light-activated cohorts. And what you'll see here is an overall pattern. The drug-only cohort did have a higher number of low-grade risk, low risk and low grade. And then as we continued to progress through the cohorts with light activation, as our PIs became more comfortable, we began to see a higher number of both high-grade and high-risk patients.
Let's first start with part one, and that is drug only, no light activation, a total of five subjects. Again, total dose is 100 micrograms. 50 micrograms is at the tumor base, 50 micrograms just slightly deeper and just a millimeter or two away, 50 micrograms within the lamina propria itself. We injected on Day 1 . Again, there was no light activation here, so on Day 2 , proceeded to TURBT. This is primarily for safety data, again, based upon feedback from the FDA. It was a very safe cohort. We had no treatment-emergent adverse events related to the study drug. We had no serious adverse events. We had no dose-limiting toxicities. We had just a single related adverse event that was related to injection or laser procedure. That was Grade 1 .
Moving on now to our light-activated cohorts, cohorts A, B, and C. I'm gonna review these each in detail, with the results from our patients enrolled in these cohorts. Again, Cohort A consisted of 50 micrograms in the base, 50 micrograms in the lamina propria. Cohorts B and C consisted of dose injected entirely into the base of the tumor, Cohort B consisting of 100 micrograms, and Cohort C with a slight dose escalation up to 200 micrograms. The schedule: injection on Day 1 , light activation on Day 2 , and then depending upon the cohort, we either had a TURBT at Day 9 , which was Cohort A, and in cohorts B and C, we had TURBT on Day 14 . First, in regard to safety, we had no serious adverse events. We had no dose-limiting toxicities. We did have a handful of related Grade 1 AEs.
When we consider the drug-related TEAEs, we have less than 10% of patients experiencing a Grade 1 drug-related TEAE. We had no Grade 2 or Grade 3 adverse events related to study drug reported. Now, you're gonna see our results here. We've organized these by tumor grade, and this table first summarizes our efficacy data for the Ta low-grade patients. Top line, four out of five low-grade target tumors demonstrated a complete response to AU-011. And I'd like to draw attention to the fact that this is just seven to twelve days later after light activation. You'll see here patients across cohorts A, B, and C, and you'll see our screening diagnoses here. All tumors at time of treatment were low grade. At time of TURBT, every patient had multiple tumors. AUA screening risk classification is then included below.
The majority of patients were intermediate risk, low grade, and we've included the AU-011 dose and delivery just below that. We've defined complete response in this population as absence of tumor cells on histopathologic specimen. Four out of five of these patients showed complete absence of urothelial carcinoma within the injected target tumor at time of TURBT. In addition, all of the patients in this cohort had non-target tumors. For patient A1, two out of two of the non-target tumors demonstrated a complete clinical response, absence of urothelial carcinoma. Patient A3, one out of two, and in patient A4, one out of one non-target tumors demonstrated a complete clinical response.
I think what gets us really excited here is the immune response, and we're defining this as presence of immunocyte infiltration f or all patients with available IHC stain, that's patients A1 through B2 , we had an immune response in the target tumor, four out of four patients. This is where it gets to be interesting. For the non-target tumors, four out of four patients with available IHC staining at this time also demonstrated immune response, immunocyte infiltration within the non-target tumors. You can see here that three out of the four patients demonstrated necrosis within their target lesions, and we saw four out of five patients demonstrating visual changes on cystoscopy at time of TURBT after those tumors had been treated. Just to recap our immune data here, we have strong evidence of an immune-mediated mechanism of action across the light-activated cohorts, A and B.
100% of target tumors, that is seven out of seven patients and tumors, showed an infiltration of effector CD8 T cells and CD4 T cells. This is as early as seven days after laser activation. 100% of non-target tumors, seven out of seven non-target tumors in five patients available immune staining, showed T cell infiltration. This is at a distance. It's supportive of a bladder urothelial field effect, field effect. And again, I would emphasize, these non-target tumors were not treated. They were not injected. Focal eosinophilic infiltration was observed in 57%, four out of seven target tumors, and 14%, one out of seven non-target tumors, and this is supportive of a local innate immune response to tumor necrosis. This harkens back to our dual mechanism of action. What's particularly interesting is the generation of lymphoid follicles.
This was observed in 71%, five out of seven target tumors, and is supportive of a local adaptive immune response. So in summary, AU-011 shows evidence of producing pro-immunogenic changes in situ that have the potential to bridge, to activate, and to enhance adaptive immunity, and this is consistent with our mechanism of action. What we have next are two case studies on two of the subjects we'd like to share with you. The first is Patient A1 . This is a 64 year-old Caucasian male. We have his clinical history here on the left. I draw attention to the fact that he has a long-standing history of recurrent urothelial carcinoma, low-grade, dating back to 2010 . He has had multiple prior TURBTs and multiple prior adjuvant therapies, mitomycin, tamoxifen, and gemcitabine. What you'll see over here on the right are immune stains.
We have our pre-injection bladder biopsy of the target tumor that demonstrates low-grade papillary urothelial carcinoma. After injection and light activation, seven days later, we have evidence of complete clinical response. We see no urothelial carcinoma in the target lesion, and we're seeing significant evidence of necrosis, inflammatory infiltrate. This circled region here shows necrosis itself. We have our pathology results. The target lesion, again, a complete clinical response. Pre-treatment showed papillary urothelial carcinoma, non-invasive, low-grade. At time of TURBT, that target lesion showed no evidence on histopathologic evaluation of urothelial carcinoma. There were two separate non-target lesions, A and B. Neither of the non-target lesions showed any evidence of urothelial carcinoma at time of TURBT, and thus, we have a complete clinical response in the target lesion and a bladder urothelial field effect. Here we have higher-powered immune stains, H&E.
You can see infiltration of CD3, CD4, and CD8 cells within the target lesion after treatment. Patient A3 is our second case we'd like to share with you, 72 year-old Hispanic male. Now, this is a similar theme, long-standing history of urothelial carcinoma, in fact, high-grade dating back to 2019 , although at time of treatment, it was a Ta low-grade tumor. Multiple prior TURBTs. Prior adjuvant therapies included BCG induction and maintenance up until 2021 . Here we have clinical images. On the left is this bilobed tumor, small biopsy taken of the lower aspect at time of treatment, and an injection that was placed just at the base of the tumor, right in between the two lobes. On the right, TURBT.
You can see a very slight inflammatory nubbin, but the entirety of the tumor had just sloughed off, and there was no further evidence of it other than that slight erythema there, at the area of treatment. Reviewing our central pathology, target lesion demonstrated low-grade papillary urothelial carcinoma, non-invasive. Central pathology confirmed at time of TURBT, there was no evidence of urothelial carcinoma. We had acute and chronic inflammation. Of two non-target lesions, one was negative for urothelial carcinoma. The second did show low-grade papillary urothelial carcinoma. We have a complete clinical response at the target lesion, and with the inflammatory infiltration that we saw in both lesions, we have bladder urothelial field effect. Again, one of the two lesions here demonstrating no evidence of urothelial carcinoma at time of TURBT. Here we move on to the immune stains for Patient A3 .
You can see pre-treatment in the row above and post-treatment in the row below, H&E, CD3, CD4, and CD8. You can see for yourself some meaningful changes here with the degree of infiltration that we're seeing in these post-treatment specimens. We can move on to the next slide. We have some higher magnification views. On the left, the H&E pre- and post-treatment, and on the right, CD4 pre- and post-treatment. I think what's really remarkable about this patient, the H&E, are several secondary lymphoid follicles. These are visualized in the post-treatment specimen on the bottom left. You can identify these by that rim of consolidating T-cells around the periphery, with a clear germinal center that consists of activated B-cells. I would highlight that these are the first steps in generating a tissue-specific adaptive immune response with a long-standing history in the oncologic literature.
Again, just a reminder, this tissue was collected only seven days after laser light activation. Moving on to our Ta high-grade subset of patients. Three out of three high-grade tumors demonstrated immune response to AU-011. You can again see our three patients here in the screening diagnosis. Two of the patients had single lesions. Patient B1 had multiple. All had Ta high-grade pathology. AUA risk classifications are included, as well as the AU-011 dose and delivery. I would again draw highlight to the fact that while we don't have a complete clinical response in histopathology in this high-grade subset, two out of the three patients demonstrated visually smaller tumors at time of TURBT as compared to before therapy. All patients, three out of three, demonstrated significant immunocyte infiltration of the target tumors after treatment with AU-011.
Patient B2 , the only patient who had multiple tumors, showed the same immunocyte infiltration and response in IHC staining of that non-target lesion. Now, thus, in summary, we can say that after only seven to 12 days with a single low dose of AU-011, we're generating a robust immune response in three out of three of our high-grade tumor patients. In addition, we're seeing visual changes on cystoscopy at time of TURBT in two out of the three patients. This is very exciting data in this population. And Ellie, I'll hand it over to you.
Thank you very much. As a summary, this was a phase I window of opportunity for safety, with a single low dose, actually with ocular volumes, that we went into for the first time in non-muscle invasive bladder cancer. It is exciting to see this data, and it is exciting to see that it works as we believe it consistently works in our ocular programs, and we've seen consistently across many, many different types of animal models. So let me just recap four things. Favorable safety. Not just favorable, only grade 1 drug-related adverse events in less than 10% of patients. Means only one patient had grade 1 adverse events that are related. Again, very similar to what we're seeing in the eye. Rapid immune activation. That is remarkable because we all know that it takes a while to respond, especially with adaptive immunity.
The fact that we're seeing 100% of the patients with immune cell infiltration in the target and non-target lesions is very exciting. Probably one of the key differentiating aspects of this new class of drugs, if we can treat the patients frontline with something that has such powerful immune response, we should potentially see durable responses. Tumor shrinkage and clinical response. Four out of five patients with single dose in low-grade disease, 70% of the patients in NMIBC have low-grade disease. We wish we could treat them with better therapies, and now we believe we have that opportunity. So what's next? A lot of positive things and a lot of work for our team. We have obviously a key goal of expanding this phase I. We have the opportunity and momentum for these patients to keep exploring potentially higher doses.
Can we give multiple doses and explore really this immune response to its fullest potential? And we don't want to stop. In parallel, phase II design. We have fast-track designation, and with a dataset like the one we have today, we're gonna be very actively in conversations with the FDA to design that phase II, potentially with the goal of expanding it to phase III and getting the drug to patients as soon as we possibly can. So it is a great day for our patients. It is a great day for Aura. And now, obviously, we have the privilege of having, as I said, probably the top key opinion leaders in the United States with us to share their perspective on what we have and the potential of the drug. Thank you very much. And now Dr. Sabine Brookman-May will lead the moderation of this panel.
Yeah. Thank you, Ellie. I am very excited now to start with a short discussion for the next thirty minutes now with our key opinion leaders, Dr. Neal Shore, Dr. Gary Steinberg, Dr. Joseph Jacob, and Dr. Max Kates. Thank you again for joining us today and for exchanging a bit on the data that was just presented from our phase I study. Dr. Shore, I would like to start with you and just address one question to you just after looking at this data right now. We saw complete clinical response in four out of five low-grade patients, and many of the patients had multiple tumor recurrences and a lot of treatments, partially over several years. What is your initial reaction to this data?
Thanks very much, Sabine, and what a great pleasure to be here and to be with my colleagues, you know, Gary Steinberg, Joe Jacob, and Max Kates, and myself. We've all been on the trial, and so we've all had experience with the injection and the light activation. We've certainly done many other studies, whether it's intravesical or various types of applications. I have to say, it really is, as you were saying earlier, for non-muscle invasive bladder cancer patients, certainly looking forward maybe to even investigating some more advanced stages, but for this, as you point out, these low-grade patients, papillary lesions, a single low dose, which is really right in the wheelhouse for urologists.
We treated all of these patients in our clinic, did the resections in our outpatient surgery center. The fact that we're able to see, and I think really very inspiring, this effect on not only immediately an ablative effect on the target lesion, but ablative effects on the non-target lesions within a very short period of time, you know, seven days. It also gives me great confidence that, you know, this was all read centrally with central pathology, with Scott Lucia, who's one of the, you know, most world-renowned GU pathologists.
So his interpretation and also the staining quality that they did, looking, you know, at CD8, CD4, CD3, eosinophilia, all of these things, which, as you really nicely presented by yourself and Joe, really demonstrates that, yes, this dual mechanism of action, you know, so a necrotic ablative effect. And what I find very appealing, this, you know, this really interesting novel mechanism of action, it's both ablative and an immunologic effect. And so that gives for a potential for really great durability. And it goes without saying, I mean, let's face it, the safety profile on this was extremely impressive.
Yeah. Thank you, Neal, for estimating how this data could be interpreted also from your clinical opinion. Can I get in one more point a little bit more? You talked about that we were able to show an effect was not only in the target lesions, but also in non-target lesions, lesions that were not injected with AU-011, and still there was an immune response, or partially even another complete clinical response. We would say this, somehow we call it a bladder urothelial field effect. Could you explain that maybe a little bit better than I did, also in your clinical words, urological words, what we exactly mean by that and why it is so impressive?
Yeah. No, thank you. One of the challenges in cystoscopy is for some patients, you know, there are always a lot of variety of anatomy, whether it's the male or female, you're doing the cystoscopy on. And so it can sometimes be really easy to completely visualize and map out the entire bladder visually with you know your cystoscopic equipment. And there's different kinds of equipment, but there's a lot of different anatomy. And then on top of the different anatomy that patients have, which can sometimes make it hard to identify all of the lesions, despite our best attempts with traditional white light cystoscopy, we get improvement with blue light cystoscopy, undoubtedly, but we still can miss lesions.
And we may think of some as being, you know, a benign, or sometimes we just miss an actual lesion. And despite the fact that we do our best to biopsy, fulgurate, or resect the lesion, I guess really what I'm saying is, I love the potential of having a field effect, 'cause if I'm injecting right in the tumor base where I see and clearly I'm comfortable saying, "Here's a lesion," but maybe there's another lesion not too far from it, but it's tucked behind the bladder neck, or it's down in an area of thickening in the bladder wall that we call trabeculation, or I just missed it, or maybe the patient became unstable from the anesthesia, and I had to stop the procedure.
So having this early signal that not only where the tumor is directly being injected, but there are associated tumors that are showing response, not only visually and histopathologically, but also with CD4 and CD8 infiltration, that really kinda augments not only the ablative, but also the immunologic effect, and we saw that with the CD4 and CD8 infiltrates, I think is very, very appealing. You know, we want to decrease the number of times we have to do biopsies and resections, 'cause over time, patients' bladders, like, they get a little beaten up from this. And there's clearly morbidities to this, you know, not only the risk of bleeding and infection afterwards, perforations, and inclusive of the health economic impact.
And that's why, you know, your earlier slide, this is y ou know, it's often said, this is one of the most, if not the most expensive solid tumor that we treat across all solid tumor types. So I think this is, on this field effect, essentially, maybe a more simplistic way of thinking about it, it makes us better resectionists for the things that we may be missing, and it also allows for a more, potentially a more durable response.
That's a great point, Neal, especially also considering how, for example, the quality, the individual quality of resection makes an impact also on recurrence and progression rates in that setting, and could it make more reproducible also, despite even if you don't see any single tumor and still treat it despite not injecting it everywhere? Let's talk a little bit more about the immune response. Do you think that this treatment, based on the immune mechanism, could also be immune ablative and a possible replacement for TURBT?
That would be a wonderful thing. As I said, you know, we're surgeons, and we're always in the mindset of how do we kind of make our services less required, put ourselves out of business? And even though that's what we get trained to do, there, as I alluded to, there is a morbidity and there is a cost, and there are person-hours away from work that are always involved when we give anesthetics, general anesthetics in particular, and resection, resective or biopsy treatments.
So the fact that we've just seen this type of response, you know, I'll caveat it and be the first to say that it's only twelve patients, and so it's very exciting and very extremely promising, single dose, and we're still, you know, tweaking the dose, and we're tweaking the light activation, but already we're seeing these types of responses. So my answer would be absolutely yes. This would be phenomenal if we can, you know, start to cut down on the number of required transurethral resections of bladder tumors.
The fact, it was alluded to earlier, and I hope the folks listening appreciate this. This is extremely user-friendly to urology clinics, whether they're in sophisticated centers, tertiary academic centers, or out in rural America, suburbia, metropolitan, urban areas, anywhere, because everybody has a cystoscope and has a table where a patient can undergo cystoscopy. I really like this because it leads to the ubiquity of application should it get approval. Certainly, I think for doing the studies, it makes it very, very appealing.
And more and more, we, you know, have some other challenges in our healthcare system of, you know, person power shortages, and the more we can do in the clinic and avoid, you know, in-hospital required procedures, whether they're in, you know, academic or community centers or even ambulatory surgery centers. This is a clear treatment theme, you know, in healthcare, so I think this is a very, you know, potentially very interesting and exciting opportunity for both ablative with its long-term impact, and sure, if we can cut down on the number of TURBTs we do, I think that would be very welcomed by the urologic community and certainly by patients.
Thank you for this feedback, Neal. Dr. Steinberg, I would like now to talk with you about the immune-mediated mechanism of action. We recognize that this phase I study, it was a window of opportunity study, not designed to even assess any durability of response. However, what are your thoughts about the potential for longer-term antitumor immunity, similar to what we have seen in preclinical models, and particularly also given that we have seen a very rapid antitumor activity and an immune response just in a matter of few days?
Yeah. Well, certainly. Well, thank you for the question, and, and certainly, I reiterate a lot of what Dr. Shore has said. But, you know, one of the biggest challenges we have with immunotherapy is actually getting the immunotherapy into the tumor. And so the tumor microenvironment is a critically important concept, and, and many times, tumors release a number of substances that are immunosuppressive.
And so the concept of being able to inject directly into the tumor to alter the tumor microenvironment with a VDC, a virus-like drug conjugate that is gonna be readily taken up by the tumor, then releasing all of the different neoantigens and virus-like particles that will turn on and stimulate the innate immune system, the TLR receptors, as well as then ultimately the adaptive immune system, really is quite important in the overall treatment. You know, a lot of times we're using immunotherapy in the bladder, but it's in an intravesical solution, and we're hoping that it will bind to the urothelium. We know that it's critically important for BCG to bind to the urothelial cells.
We know that with all of our intravesical therapies, whether they're chemotherapy or immunotherapy, it's important to bind the cells, bind the tumors, so that you can begin to turn on the immune system. And then the critically important factor for turning on the innate and adaptive immune system is to create T cell memory, and once you've created T cell memory, you're really golden. You know, when we talk about, for example, COVID vaccinations, and a lot of the COVID vaccinations are initially through the humoral B cell immune system, but the patients that really do the greatest are the ones that also have T cell activation and T cell memory.
And so that's really our goal with all of our immunotherapies, and if you're able to inject a tumor directly and create specific neoantigens and specific T cell receptors, which create T cell memory, you really are off to the races, and that you can have prolonged immune effectiveness.
And again, I think that to look at this after a week is really short-changing the technology, because we know that the immune system and T cell infiltration and adaptive immune system and T cell memory takes quite a bit longer. It takes at least three, four weeks. We know that when we treat patients with checkpoint inhibitors, that we start seeing tumor responses, but it's not until about, you know, one and two cycles, three to six weeks, and so forth.
So there's really a golden opportunity with this novel concept to really, truly not only get a immunoablation and treatment of the tumor, as well as potentially have abscopal effects. These are tumors that are outside of the tumor that you're injecting, but to get a long-term immune surveillance to help prevent the recurrences. Because as Dr. Shore alluded to, the one thing that the patients really, really want, not only do they want the tumor to be eliminated, they don't want it to come back. And the recurrence rate is really a critical driver in the tremendous cost for treating patients with non-muscle invasive bladder cancer. It's a tremendous cost of patients and their family members losing days of work, financial toxicity, and certainly it's a psychological effect.
When you've got a patient in the clinic, and you're doing their surveillance cysto, and they've got more low-grade recurrent tumors, you know, they're-- that's enough to make them almost freak out in frustration. There really is a tremendous benefit that if we can obtain active immune surveillance to help prevent these tumors from coming back, and I think that this is a really novel way to do that.
Thank you, Dr. Steinberg. Dr. Kates, I would now like to exchange with you also a little bit more on, on that topic. So currently existing bladder immunotherapies require multiple and broad administrations, and AU-011 is finally novel due to its focal nature with the injection and application. Can you provide your thoughts also about the differences between a more global versus a focal bladder immune therapy? And having addressed that, can you also comment on the immune response we have seen in our phase I study in the distant non-target lesions in these early data?
Yeah, and thank you for having me with these phenomenal colleagues. And I couldn't agree more with much of what's been said. It's a great day for our patients, I think was previously said, and why is that? Because when I give BCG or intravesical therapies right now, I'm treating healthy tissue, and as a clinician, I'm sick of that. I know that when I treat healthy tissue, I'm delivering toxicity to part of the bladder that does not need the treatment. And so when we give intravesical therapies, we're faced quite often actually, with varying forms of cystitis, which is an inflammatory condition of the bladder that's almost expected when you give intravesical BCG, intravesical chemotherapy.
And so this notion that we can just treat the tumor without treating healthy tissue is quite appetizing to me. Because that way I can avoid treating healthy tissue that does not need that toxicity. And I think we saw that with the data presented. Then, when you put on top of that, that not only are we treating those tumors, but we're treating non-target lesions, that's even more exciting because it speaks to something that Dr. Shore said, which is this idea that there may be tumors that we can't easily see in the bladder.
So maybe you might argue, "Okay, well, the intravesical therapies treat all this healthy tissue, but they may also treat unseen tumors." So the fact that we're seeing non-target effects is this golden opportunity to both treat cancer cells and treating healthy cells. This field effect or the abscopal effect really speaks to an adaptive immune response, and which is something alluded to by Dr. Steinberg, which is this idea that, you know, how are we seeing non-target lesions respond? Well, there has to be immune cell recruitment and memory, probably in the form of T cells, we don't know exactly, but there has to be an adaptive immune response in order to see those types of effects.
Taken together, you know, clearly, a therapy like this is a better option if it were to have these non-target effects than an intravesical therapy, where we're treating tumor cells that don't need it.
Thank you, Dr. Kates. Dr. Jacob, I would now like to talk with you about what a safety profile and how we bring that into the clinical context overall. In this phase I study, we have seen only a Grade 1 drug-related adverse events, and we have just seen it in less than 10% of patients, finding one single patient. What type of patients under this consideration do you think would benefit from this type of treatments?
First of all, thank you for that question, and I don't know if I can say it better than Dr. Shore, Dr. Steinberg, Dr. Kates. I don't know if anyone in the world could say it better, but I'll just add a couple things. So with this type of safety profile, I mean, I could see this being used, of course, in the patients that, you know, you wanna avoid the OR, the patients that maybe are too sick for the OR. But with this safety profile, I could see this being applied to any or all patients. And just to sort of feed off of what Dr. Shore was talking about, you know, with the current healthcare system, you know, for me at least, it's so hard to get patients to the OR.
OR time is like more precious than gold. There's a shortage of anesthesiologists. There's a shortage of OR nurses, OR assistants, you know, and so the amount of work and the amount of time it takes to get somebody into the OR is very frustrating. And so I could see this being applied quickly in the clinics, and I could see it being applied widely to a broad group of patients because of the safety profile. Just to give you an example to the people on the call that may not be familiar with our types of workflows. So in the clinic, you know, I'll see a few patients, and then the clinic nurse will have the patient prepped, you know, basically consented.
You go into the room, you can do a cystoscopy with a quick treatment, and then you can, you can leave the room, and that whole interaction may take 10-15 minutes, and then I go on and see my next, you know, few patients. In the OR, it's totally different. Even if you're running a completely efficient surgical center, you know, let's say I have a 7:30 A.M. start, I have to go see the patient at 7:15 A.M. By the time the patient gets to the OR, asleep, under anesthesia, prepped, probably starting around 8:15 A.M., 8:30 A.M., depending on what system you're in. I may work for about 20-30 minutes doing an endoscopic resection, and then the patient wakes up, then I go talk to the family, then I go check on the patient.
That's about two hours worth of time versus a procedure that, you know, I could have done, you know, hopefully in the clinic in less than fifteen minutes.
Thank you, Dr. Jacob. Dr. Steinberg, I have another question for you, considering also the abscopal effect. When we consider a traditional immunological model with a prime and a boost to activate the immune system in an efficient way, in the light of the favorable safety profile we have seen here in the phase I study, would you also be comfortable with studying additional treatment cycles with AU-011 while seeking possible additional efficacy and long-term curability?
Thank you for the question, and absolutely. You know, I think that if you look at our present algorithms for treatment for patients with non-muscle invasive bladder cancer, we frequently are dosing patients once a week for six weeks, who are then many times following that up with maintenance therapy, you know, once a month or three weekly instillations at month three, six, and 12. Patients are used to getting multiple treatments. However, if they had their druthers, they would get fewer treatments, not more, and so there clearly is a benefit to trying to treat effectively, but treat less often.
If we can somehow design a treatment where we're getting the best ablation, we're getting the best complete response rate as well as durable response rate, I think that's the goal, and I see no reason why you can't treat patients, say, once every week, once every two to three weeks.
There are probably some immune biomarkers we can assess in the urine, various cytokines, such as IL-12, IL-6, IL-10, all these different cytokines, interferons, that kind of give us an idea of how much we're turning on the immune system, how much we're suppressing the immune system, so that we can get an idea of how often we would want to boost the patients to get the optimal immune stimulation, while not overdoing it and causing immune suppression, because there's a lot of negative feedback loops anytime we stimulate the immune system. There's also no reason why you can't retreat the patient. So if you get a good response, retreat the patient.
I think that one of the things that we do all too often in non-muscle invasive bladder cancer is we're using adjuvant therapies, so we're using surgery to remove the tumors completely, and then we're giving an adjuvant therapy to help prevent it from coming back, not knowing if we need that adjuvant therapy or not. Certainly, the adjuvant therapies do add to cost and time and so forth. So if we can figure out how we can, you know, ablate and when would be the time to potentially add a boost or a maintenance dose, I think that would be critically important. And I, you know, again, in an office-based procedure that has minimal, as we've ascertained to date, local urinary tract symptoms and side effects, certainly, we're not seeing any systemic immune-related adverse events.
But I think that there's plenty of options to really truly optimize the dosing regimen, and so that not only can you treat low-grade non-muscle invasive, but potentially there's no reason why you cannot treat high-grade non-muscle invasive. The mechanism of action would allow you to treat any non-muscle invasive bladder cancer, whether it's low-grade or high-grade, because of the uptake of the VDCs, the cytotoxic payload, and the immune cell death that we're creating, which then is stimulating the innate and adaptive immune system.
Thank you, Dr. Steinberg. Dr. Jacob, I have another question, also again related to the TURBT, and you mentioned already there are also some challenges related to it, the integration also in, in the daily, routine practice. What are your challenges you see with the TURBT right now in that setting? And also, could you also comment in general on the trend to transition bladder cancer care more from the operating room into the urological office?
Yeah, absolutely, and I think it's a great question, and I think it's important in how we treat bladder cancer in the future. You know, as I mentioned before, and as some of the advisors have mentioned, that, you know, there are economic and practical issues with our current healthcare system, and, you know, getting a patient to TURBT is not easy. There's loss of time on surgeon time, patient time, you know, loss of work. But moreover, you know, it's a more morbid procedure for patients. You know, patients sometimes have to stay the night, sometimes they have to go home with a catheter after TURBT.
As far as economics go, you know, it's not the most important thing that we're gonna talk about, but, you know, TURBT is generally a money loser for the hospitals. I mean, it's not a high-paying procedure and, you know, these procedures are really being pushed more and more to the, you know, the surgery center-type models, and, you know, the hospitals don't really want these procedures. You know, from a surgeon standpoint, as far as doing a procedure, like a local ablation or local treatment in the clinic, you really get paid very similarly to, you know, what you would get paid, taking a patient to the OR and doing some kind of resection in the, you know, in the OR.
From a urologic standpoint, I think people are more motivated to accomplish, if they can safely accomplish, you know, an efficacious treatment in the clinic. I would say there's already a push. There's already a movement of trying to take care of as much as we can in the clinic. I can tell you from my standpoint, I'm sort of stretching the limits of what we can do right now in the clinic. I mean, we have small, little biopsy forceps, and we've got, you know, electrocautery tools that we can use in the clinic. I'm trying to stretch that as much as I can and trying to take care of these patients as much as I can in the clinic because of all those reasons.
But I would say the field is starving for more tools, more opportunities, more ways that we can treat these patients, in the clinic effectively and safely.
Thank you. And do you think also AU-011 could potentially fit into that busy ambulatory clinical setting under these considerations?
Yeah, I do. I do. I think with the early data and the ease of use and the safety profile, I think it has great potential to become another tool that urologists can utilize in the clinic.
Thank you. Dr. Shore, I would like to talk with you about also one of your quotes I've heard, from you before. You frequently describe the cystoscope as the urologist's stethoscope, and I, I would agree with that as a urologist, and the audience today has also heard about various techniques utilized in AU-011 administration and activation, specifically also the bladder injection needles and the laser light activation. Would you mind commenting on the urologist comfort, also the comfort levels, not just with the cystoscopy, but also with laser application and injection techniques?
Sure, happy to. I think I need to apologize to René Laennec, the inventor of the stethoscope. You know, all kidding aside, it is the piece of equipment that every urologist. It's like really the first thing we learn in our early part of our training. You know, it's funny, I was talking to Gary Steinberg about this, you know, at an earlier point, and I think this younger generation of urologists, because of their incredible facility and expertise in with electronics and games, they are remarkably nimble and facile with all sorts of endoscopic, cystoscopic, laser, fine motor skill equipment.
Not that older urologists aren't, and I think this technology that we're talking about is it fits both, generationally, whether you're, you know, in a busy academic center or you're somewhere, anywhere in the community. We do a lot of laser work. We have laser ablative technologies well, you know, into, you know, one to two decades now for treating stones, for treating tumors in the ureter, for treating, you know, prostate, enlarged prostate. We have a tremendous experience with needles, not only in doing prostate biopsies, but inserting needles to inject directly into the bladder for neurogenic bladders and overactive bladders in the form of Botox. And this is done that injection technique is done routinely in the clinic. So, we have this really kind of very, very clear oncologic, non-oncologic experience you know, multigenerational now, regardless of where you're practicing.
You know, as Gary did a great job in outlining all the different immunotherapeutic mechanism for why it's effective, both in the innate and adaptive system. And urologists already, you know, we're proud of the fact that really BCG was one of the first immunotherapies that had an impact, not only on delaying recurrence, but also on decreasing progression in the urothelium. So the, it's not, you know, far afield, intravesical immunotherapeutic in the bladder. Of course, we see many other advances of immuno-oncologic therapy in advanced bladder and kidney cancer, and even unlimited examples in prostate cancer.
So the entire urology world, I think would be very comfortable and very, very intrigued to get a better understanding of how this could be adapted for non-muscle invasive bladder cancer.
Thank you. Dr. Kates, I will summarize the next two questions to one question, just in the interest of time, and I would like to talk with you about the patient population. On the one hand, what are your thoughts about the low-grade intermediate-risk patient population, where we have demonstrated complete responses in multiple patients? And do you think this is the patient population or the unselected patient population, independent from any biomarker selection? Do you think this is the right patient population that would benefit from a novel therapy like that?
Directly, as a follow-up question, and if yes, do you think also, is this the right patient population for a transition from the operating room into the office, or would you have any concerns with regard to not doing the TURBT or losing the TURBT as a surgical procedure?
Yeah, some great questions there. Low-grade intermediate risk is the perfect population for this drug. It's a clearly defined disease state by the FDA. These patients, it's incredibly common, and urologists are largely already managing this in the clinic. It's very common for urologists to fulgurate lesions like this, to biopsy them, you know, as was previously said, and in the clinic, and so it's very natural for urologists to do something like this in the clinic, so it's the perfect disease state to do this, and then when you think of this idea that it's unselected, and is it okay that it's unselected? I would say it almost has to be unselected.
So to do a biomarker, especially a tissue-based biomarker for low-grade non-muscle invasive bladder cancer, means that urologists are gonna start sending off genomic assays for this disease state, which nobody currently does. So one of the main problems with a biomarker-selected therapy for this disease state is you're asking clinicians to do something they currently don't do. And so the fact that this is unselected is actually preferable. And when we think about this being ablative and not adjuvant, I would argue that ablative is going to treat far more patients, if successful, than adjuvant. You know, I use the analogy that you go to a, a you're a member of a fan of a rock band, and they send out an early release for tickets, and by the time you do the early release, and by the time the tickets are available to the general public, 90% of the seats are taken.
That's what's happening with ablative therapies. They're gonna end up taking 90% of the patients, hopefully, if they're successful. The ones that aren't, the ones that it's not successful in, will be those few 10-30% of patients that end up getting adjuvant therapy. For all those reasons, this is actually the perfect disease population.
Thank you. Dr. Steinberg, one follow-up question about the patient population, low-grade intermediate-risk disease patients. How big do you think is this patient population? How many patients fall in that category?
Yes. Thank you for the question. This is a huge unmet need, but, you know, to reiterate what the other speakers have said and what Dr. Kates was saying, you know, there's a regulatory pathway that needs to be followed. So, for commercial development of new drugs, there is a regulatory pathway that needs to be followed, that the FDA has outlined, the American Urological Association, Society of Urologic Oncology, have all kinda come together and had kind of a general meeting of the minds of the regulatory pathway. And so I think the intermediate-risk patient population is an ideal regulatory pathway for this particular drug.
Having said that, once this treatment gets into the hands of the urologist, I am certain they will use it to treat all non-muscle invasive bladder cancers. So they're gonna treat the Ta high grade, especially in patients that they've treated, they may have a recurrence, so treat them again in the operating room. You know, the third time, well, you know, they've got this small recurrence. They haven't progressed. It's a relatively stable disease. Yes, they've got another Ta high-grade tumor. Let's go ahead and treat them.
So I think that when we look at, you know, the intermediate risk, low-grade disease population, that's one, probably one of the largest groups of non-muscle invasive bladder cancer patients we have. It's a highly prevalent disease. It's a highly unmet need, but to go a step further, once urologists have an FDA approval, they're gonna use this for a lot of patients. And I suspect that the insurance companies and third-party payers will be okay with that, because I think ultimately this treatment will be less expensive than bringing patients multiple times to an operating room for general anesthesia and so forth. So that's kind of the way I see this patient population.
Thank you, Dr. Steinberg. That you have also already answered my next question I would have had on the list, also the potential to develop it in other indications or other risk categories. So, to your opinion, nothing also speaks against that. I would like to sum up now, because in the interest of time, we need to get to the Q&A finally, but maybe one final question, just really very quickly. We have two minutes left, and I would like to address that question to Dr. Shore. Also, as you know, we have the phase I trial ongoing, and with this positive early data in mind, how might we optimize development also in the phase II study?
And I would just really need to get a quick assessment and a fast response from you, thank you. Oh, you are on mute.
No, no, I'm sorry, sorry, sorry. Yeah, super quick, now that I'm unmuted. Just quickly recapping, we see small numbers, but remarkably well-tolerated. So that's great, that's why we do early-phase studies. That's been accomplished. We need to further get a better understanding of the dose, number of treatments. We need to better understand the time between when we dose and when we light activate. I think that having some flexibility in that development plan is gonna be very important to the clinician community.
Thank you. So in the interest of time, I will skip the last questions we had on the list, but I would like to thank everybody again, all our four great experts in this round, to participate here, to provide their expert opinion and bring the data into context. So thank you again for this very valuable insights and discussion.
Thank you. So now we're gonna open to the Q&A from our participants in the call, analysts, investors. Thank you so much.
Thank you, Ellie. Yes, we'll begin our question and answer session, so please hold for a brief moment. Our first question comes from Andy Berens at Leerink. Please go ahead, Andy. Andy, you may be on mute.
Next question, I think we can't hear.
Yes, we will go to the next analyst while Andy figures out his mute. So our next question comes from Phil Nadeau at Cowen. Please go ahead, Phil.
Hi, congrats on the data, and thanks for taking our questions. Just two from us. First, in terms of defining the dose, can you discuss, in the current data, was there any signal as to which of the doses that were tested were better? And then, more broadly for the company, how will you determine what is the right dose through the phase I trial? Can you give us some sense of how you'd frame that? And then a follow-up question, to the one that was asked to Dr. Shore, just in terms of the phase II design for the physicians, for the other physicians, what do you want to learn from phase II? How would you design that phase II trial? Thanks.
Thank you, Phil. So the first question on how we determine the best dose, Sabine?
I would like to comment on that, so thank you for that question. And based on the current data we have just presented today, we will now work immediately on an expansion on the phase I study to also test different dose regimens and finding multiple doses in the patient population. So this will also determine how we are going forward and to determine also which is the dose that gives us the highest efficacy. But this still needs to be determined and also gets into our further development plan.
Thank you. And I think there was a second question addressed to Dr. Shore on, how do we learn from what we have now implementing that into phase II? Or Steinberg? Was it Shore or Steinberg? I can't remember to what, physician was asked.
Yeah. No, I think it's already sort of been alluded to. It has already been said, there's a huge unmet need in the patients in the intermediate risk category. There's a lot of interest in that space. It's a huge population of patients. These are patients who really could benefit from AU-011's unique mechanism of action, both ablative and immuno-oncologic. And I think ultimately, we certainly are gonna look at response rates. I think that, you know, already having some biomarker in terms of CD4, CD8, eosinophilia, eosinophilic granulomas are really very positive in terms of things that we can further evaluate.
And the, you know, I think the, as has been already said, I think FDA, particularly in the bladder cancer space, has been very amenable to new endpoints and new trial designs. So I think there's, you know, that's sort of the phase II. Obviously, it's a big question that was asked, and it's gonna take a lot of very careful thought. I think the early appreciation of getting the dosing right, the timing for laser application, is gonna be very important in that phase II development plan.
You know, when we talk about dosing, we're not talking necessarily about the concentration of the VDCs. We're talking about, can we do multiple injections? So, you know, depending on the size of the tumor, can we inject multiple sites? Can we also potentially inject kind of in a random, you know, each part of the bladder randomly to, again, improve our abscopal effects or our smaller tumors that we don't visibly see? So when we talk about dosing, it's not just the concentration of the VDC in the solution. It's the amount of VDC injections that we can use and the total volume of drug that we can use throughout the bladder.
And so those are questions that we still need to think about.
Yeah, it's such a good point you're bringing up, Gary, because as Ellie said, they started off with the approved ocular dose.
Yeah.
And so there may be, you know, an incredible opportunity to multidose and go much higher up in the potency.
Next question.
Thanks for the questions, Phil. Our next question comes from Andy Berens at Leerink. Please go ahead, Andy.
Hi. Can you guys hear me now?
Yes.
Yes, we can.
Okay, sorry about that. I was clicking the button, but it wasn't letting me unmute. Congrats on the data, and appreciate you guys hosting this event. Two questions from us, and apologies if you presented this already, but I was juggling between two webcasts. Did you guys tell us which of the patients in the low-grade and high-grade buckets were BCG refractory? And then another one for the doctors. Since TURBT is both an excisional biopsy treatment, but it's also it allows you to stage the disease to determine risk of systemic disease. Just wondering if you would still want to do a TURBT in patients that are treated with bel-sar, even if they get a CR? I guess what I'm trying to understand is if there's a way to do histological.
We have to do histological staging, or is there another way to determine the need for systemic therapy? Thanks.
Thank you. So the first question will be addressed by Dr. McQuaid.
Sure. It's a great question. We did two case studies into two of the patients who had complete responses. One of them certainly had BCG in the past, in the distant past. Across the board, several of the patients treated had multiple prior courses of BCG. We didn't present all of that data in full today, just in the, you know, time available to us, but yes, absolutely, multiple patients with CRs had that.
Great. And, the second question, perhaps Dr. Max Kates, is what is, the risk that we have in, low-grade, IR patients, moving them away from a TURBT and missing the proper staging? Is that a risk, or, you feel comfortable that these patients can potentially be treated in the office?
Yeah. So one of the reasons why low-grade intermediate risk is very appropriate for this is that visual resolution of a papillary tumor is going to be good enough for urologists. A TURBT is certainly not necessary. And I think even I would go a step further and say we're all becoming a little bit sensitive to this idea particularly because we're doing less cystectomies for non-muscle invasive bladder cancer. More and more patients are getting TURBTs, and so we're trying to avoid TURBTs in general because patients like this oftentimes have had three, four, five TURBTs. So actually, the goal is to not do any more TURBTs, because the more TURBTs you do, the more toxicity those patients will have over their lifetime in terms of bladder symptoms.
No, typically, you would just do visual documentation of response.
I think that your point is a good one, and that at some point, we do need to make sure, as urologists, that we have the accurate grade stage, and we can do that with urinary cytology. We can do that with a biopsy in the clinic, a cold cup biopsy in the clinic. Certainly, we can have, you know, a visual opinion of what we think is non-invasive versus invasive, low grade versus high grade, but I think that you can fairly readily get accurate staging and grading in the clinic, in the office, without the overriding concern for systemic disease and/or progression to muscle invasion.
Again, we're doing a lot of surveillance cystoscopy and cytology on these patients, and I think that is very, very safe and certainly within the standard of care.
Okay, thank you. Can I ask one more as a follow-up, Ellie?
Absolutely. Absolutely.
Yeah, just, and maybe you went into this, too, and I'm sorry if I missed it, but would you expect, you know, in the registrational trial, and I know it's obviously early days, but would you expect to have to follow patients to have some sort of risk for survival longer term? Or do you think that just getting a CR after the procedure would be enough as a registrational strategy?
Yeah. So I will ask, Dr. Sabine Brookman-May, to answer.
Thank you. So you're mainly asking about also survival analysis as a follow-up, in addition to early efficacy endpoints, but I understand your question correct.
Correct.
So in that setting, also what we know from prior regulatory interactions, is that in that regard, in this patient population, it would not be needed. You would always need an overall survival assessment, at least to show that there is no detriment, no negative impact on overall survival, but not as one of the primary or secondary endpoints. So this can be also provided by additional data, but the efficacy endpoints in this patient population, they are really focusing on early response rates, maybe at around three months timeframe, and then also on longer term duration, after nine or twelve months, for the durability of response.
Okay, thanks, and congrats on the progress.
Thank you.
Thank you, Andy. Next question.
Yes, so our next question comes from Liisa Bayko at Evercore. Please go ahead, Lisa.
Hi there. First question, just I know you didn't really discuss, you just talked about safety, but, can you discuss, if you looked for any responses in just the drug only? I was curious.
Absolutely. Dr. McQuaid?
Yeah. Thanks. That's a great question. Certainly at the time of TURBT, we had the pathologic specimen there on Day 2 after drug only. And there was urothelial carcinoma remaining in all of the subjects who had drug only, no light activation. That's to be expected, given the mechanism of action, that we didn't actually activate those cytotoxic particles.
Okay, great. You've talked about a pretty remarkable early response here. How long do you want to follow up, just to test for durability? Are you comfortable with that this is the kind of response you're gonna get?
Thank you. I will ask Dr. Brookman-May. Thank you.
Yeah, thank you for that question. So as already outlined, also for a study design in a phase II study, where we would like to look for durability of response and complete response, usually in that setting, you could have an early, look, for example, at three months. This is what is currently used also in other studies in that field. And you look at the complete response rate at this relatively early time point. And then, of course, you would need to follow the patients for a longer time, a few more months, nine to twelve months, to show also that these responses are really durable. And this would also be the concept we are considering for development plan of AU-011.
But we also need to consider we have fast track designation, and this is something we will also continue to use for continuous communications with the FDA to really set up the ideal study design to prove the efficacy and also the durability.
I think the FDA wants to see a minimum of 12 months durability, and anything more than that is the goal. I mean, I think that for the urologic community and the patients, we'd like to see 18, 24, 36 months durability. But the milestone, I think that the FDA wants is a minimum of 12 months durability.
Yes, and to that point, I just would like to make the note that we are lucky because we are on the heels of an ongoing phase III, and we have phase II data with phenomenal durability of response at 12 months on the ocular program. While we don't have it in this first phase I, it is the exact same drug, and we're very excited to see the durability in that other program. Next question.
Yes, our next question comes from Anshul Dhankher at LifeSci Capital. Please go ahead, Anshul.
Hey, everyone. Congrats again on the progress today. Great to see this data so far. You know, we touched on this a little bit. I think maybe Dr. Steinberg was commenting on maybe the likelihood of a broader immune response that's more systemic beyond just the bladder. I was wondering if is there any plan on assessing that in future studies with maybe peripheral blood samples? And then at what timeframe would you want to take those samples following the treatment and TURBT? Thank you.
Yes, Dr. Brookman-May.
Thank you for that question. So based on the mechanism of action in the focal administration right now, we would not expect that there is a broader systemic response from a safety profile. But nonetheless, also for the upcoming phase II study, we are considering to do a broader biomarker assessment. On the one hand, of course, also to see if there is also to prove or confirm again the safety profile, but also to develop potential prognostic or predictive biomarkers that show us which patients benefit most from the treatment. But these details will be clarified also as we are going forward with our phase II study.
Excellent. Thank you.
Next question.
Yes, thanks for the questions, Anshul. So our next question comes from George Farmer at Scotiabank. Please go ahead, George.
Hi, good afternoon, and thanks for taking my questions, and, great data to see, that you have so far. I was wondering if the physicians here could comment on the durability that they typically see with standards of care, TURBT and/or adjuvant therapy. How variable is that, from patient to patient? And, kind of getting to this concept of 12 months in a clinical trial, I mean, while the FDA might find that acceptable, would you, as a physician, find that acceptable, depending upon the results of a phase III?
Good question. Dr. Max Kates, would you like to address durability with TURBT?
Yeah, sure. So, durability with TURBT is variable, but one of the reasons why FDA defined this intermediate risk group as the way it did, is because recurrent low-grade tumors are slightly more predictable, and that they're more common to recur after TURBT alone. I usually would quote patients somewhere in the 30%-40% chance of recurrence once they've had one recurrence. And honestly, maybe more, but that's what I typically quote. To your question of what type of durability would be necessary? I view this disease slightly different, which is, how many TURBTs can I avoid over a patient's lifetime or disease journey? So if they're recurring in less than a year, I'm not really helping that patient because they're gonna have eight or nine TURBTs in their lifetime. That's not helpful.
But beyond a year, if I'm reducing their global TURBT burden, right? 'Cause they're getting recurrences a lot, from eight to three, that's clinically meaningful and significant, and that's gonna help that patient quite a bit. So I think to try to be a little more firm on your question, somewhere in the 12-24 months range is gonna be meaningful to me because that's how I'm gonna reduce their TURBT burden.
Mm-hmm. Okay
The way a lot of these patients are currently managed with TURBT and then intravesical chemotherapy. There was a recent study looking at heated mitomycin C at two different time intervals, and then just standard mitomycin C in the intermediate-risk patient population. You know, the chemotherapy is given in an adjuvant setting. At twelve months, about 35% of the patients have recurred. That's kind of a ballpark figure of the standard of care, which is TURBT, followed by intravesical chemotherapy. Having said that, you know, that's a fairly high burden of treatment. There is you know, a lot of local urinary symptoms. Mitomycin C, a lot of the intravesical chemotherapy agents are vesicants, and they cause a lot of sort of toxicity of normal cells as well.
So, but that's kind of a benchmark that you wanna at least meet, potentially, if not, do better. And then, to reiterate what Dr. Kates was saying, is that if you've got a patient that has gone from multiple tumors, and now they've got a recurrence, but it's one- to two-millimeter tumors, and you can just zap them in the clinic, that's a significant clinical benefit for the patient and for the healthcare system. And so while it's not, you know, yes or no, it is still a clinical benefit. So this concept that, you know, it's either all or none, is not clinically relevant all the time in this patient population.
Mm-hmm. All right, great. Thanks very much.
Thanks for this question. Yeah, thanks for the question, George. So our next question comes from Julian Harrison at BTIG. Please go ahead, Julian.
Hi. Congrats on these data, and thank you for hosting this. Ellie, you mentioned earlier on the potential to dose higher. Just wondering if you could talk more about how wide that window is, relative to the regimens you've studied so far in bladder cancer. Also curious if there are any specific segments within NMIBC that make the most sense to explore higher doses in?
Yes, well, thank you. I think that with the safety that we have and the efficacy that we're seeing, again, with a very low single dose, we have a lot of opportunity to explore higher doses, and I think, as Dr. Steinberg mentioned, potentially even injecting a few times, right? Can we boost the prime boost effect of the immune system to have that optimal adaptive immunity, so all of those are gonna be explored in our ongoing phase I? With the momentum that we have, it's an excellent setting to explore these higher doses, and look, potentially high-risk patients are more bulky. They may need more than the low grade, and that's usually in development.
You especially focus on one population where you can optimize from a regulatory perspective, get everything as homogeneous as possible and then expand. So I think there's a lot of opportunity. There's, as I usually say, cancer drugs that have high efficacy but absolute good safety are something that patients should be looking forward. So thank you for the question.
Excellent. Thank you. That, that's very helpful. And then last question from me on the topic of abscopal effect, potentially translating to durable clinical responses. At this stage, I mean, is it sufficient just to see adequate CD four and eight T-cell infiltrate? Is everything else a nice to have, or do you actually need to see more than that, too?
So I would just say one comment, because especially as we have such a great relationship with NIH, and we were sharing this data, and they said, like, "It's fantastic to see the generation of lymphoid follicles." And that is a reason. Usually, for an adaptive immune response, you would expect a little bit more time. And we were designing this with the opportunity. We were worried that one to two weeks maybe is too short. But when we see the generation of lymphoid follicles, that is the key that an immune adaptive response is taking place. And we were all so excited. It's not just one patient that we're seeing, it's in multiple, so it is real.
That's why we think that, again, it is a very robust proimmunogenic cell death, very focal, very safe, but hopefully the immune system will treat what we cannot see.
Excellent. Thank you, very helpful, and congrats again.
Thank you.
Thanks for the questions, Julian. So our final question comes from Ed White at H.C. Wainwright. Please go ahead, Ed. Ed, you might be on mute.
Can you hear me now?
Yes.
Okay, great. The question I have is on timing. Congratulations on the data, but the timing to the next approval here. There's a lot of different avenues you can take right now. As you said, you have to look at different doses. We're looking at the patient population, there could be different durability timelines to look at. I'm just curious as to how you're viewing timeline to approval. Then also, the field effect was great, but does that throw out another variable for you that gives you an perhaps another avenue of treatment to be studied that could slow down the process, but yet improve the efficacy?
Yeah. So, obviously, you know, we are not slowing down at Aura. And there's the opportunity of an open study and momentum, and patients. I think that it would be, you know, not the right thing to have patients waiting for the perfect design of the perfect phase two, and, you know, spend two years in phase one. That's not what we're gonna do. So we have the momentum. We will explore a few things, and we have fast track designation in parallel. I can guarantee that our team is gonna be exploring the design of that phase two to make it as streamlined as possible. There's a lot of learnings. As I said, the FDA is highly collaborative. They want new drugs for these patients. They want these patients to avoid ten years of recurrences and surgeries.
So I feel like we have a great opportunity to keep exploring in phase one, keep in parallel talking to the FDA, and launch a phase two that potentially can be expanded for registration, right? This, the possibility of adaptive designs and, you know, especially when we have good drugs that work and are safe, I think that we'll certainly not be slow here.
Okay, thanks for taking my question.
Great. Thanks for the questions, Ed. So, Ellie, it looks like that was the final question. I'll turn it back to you for closing remarks.
Thank you, everyone. This was, as I said, it's a great day for patients, it's a great day for urologic oncology, and it's a great day for our company. We look forward to staying in touch.