Trinity Bivalacqua: Awesome. Thank you so much, I appreciate it, Ashish. So, this is actually a presentation that was presented at the EAU last week for which we were in the trials in progress. So, understand this is a presentation where we're discussing a trial that's currently enrolling, and we'll go into that more. These are my disclosures. So, as probably everybody that's watching this would know that cretostimogene is an oncolytic adenoviral gene transfer, which does replicate in RB-altered tumors, and during this replication and lysis, it also releases GM-CSF, which is part of the adenoviral gene transfer. This, in my opinion, is probably the most important aspect of this and what is how we see the efficacy that has been shown in BCG-unresponsive disease. And I think that this is probably the GM-CSF and activation of the immune system, which leads to cytokine production and activation of T-cells is probably what is causing the effect. So, this has been shown to be effective in the BCG-unresponsive space of BCG-unresponsive CIS plus or minus papillary disease, and that was the BOND-003 trial.
However, there is the question, can this be utilized in other disease spaces? At the current time, CORE-008 is a multi-cohort trial, where cretostimogene can be tested, either alone or in combination in different disease spaces. And what we're showing or presenting today is the trial in the BCG-exposed space. Now, BCG-exposed is a relatively new disease space which has been described, particularly by the IBCG, with its description, where you have persistent or recurrent high-grade TA or CIS at the first cystoscopic evaluation after induction BCG, where you get adequate BCG of five or six, as well as anybody who had a delayed relapse after adequate BCG induction, this is greater than 24 months, or a delayed relapse in patients that had inadequate BCG. So, it's kind of a catch-all disease space, where we in the field would oftentimes potentially use BCG, also chemo, but the question is, can we use an alternative approach? And that's where this trial is focusing on cretostimogene's effect or efficacy in the adjuvant setting in this disease space. You're very familiar with this schema, this is the exact same trial design as the BOND-003 trial, where patients are allowed to get reinduction. So, this is super important to understand, if the patient has evidence of high-grade TA or CIS at the time of their three-month evaluation after induction treatment, which is weekly for six weeks of creto, they're allowed to get reinduction. There are mandatory biopsies at 12 months to evaluate the bladder, and we could obviously talk about this more later, and how this may impact ultimate results. CT scans, MRIs are required, and treatment is optional up to three years, but required for the first two. There's a maintenance phase which is identical to the maintenance of the SWOG protocol, as well as the BOND-003 trial. So, what this represents is a trial where we're trying to evaluate creto's effect in the BCG-exposed non-muscle-invasive bladder cancer.
I think importantly, this is another partnership with SUO-CTC to bring forward this in BCG-exposed patients, and we look forward to the results. I'm happy to field any questions. These are the key collaborators that are involved in this trial. Obviously, we want to thank all of the investigators, SUO-CTC, and obviously our patients and families who have contributed their time to this trial. So, Ashish, happy to answer any questions if you'd like.
Ashish Kamat: Thanks so much, Trinity, for presenting that. You've done a lot of work, and we've done work together in refining this space and understanding it, and discussions through the IBCG and AUA with the FDA. So, tell me a little bit about your thought process behind going into this space without a comparator arm. What's your thought process there?
Trinity Bivalacqua: Yeah, I think what we would find in... What I believe we'll find in this trial is that there is going to be an effect here, that this is going to be effective. But the real question is, how much more effective is it compared to a comparative, which in my opinion, should probably be BCG because in clinical practice, we're using BCG in this disease space, especially in those patients that have BCG resistance, where they have high-grade TA or CIS at that three-month, we're giving them a second induction course of BCG. And as you know, because you've shown as well as others, and I think we've even done work together on this, that you still have at least a third of patients, if not more, are probably going to get a good durable response with a second induction course of BCG. So, I personally think that this is a great trial to randomize to BCG versus out of creto. I don't think it needs to be a superiority trial, I think it needs to be a non-inferiority trial, and I think that that would provide us with a lot of information about two things. One, in a rigorous trial, what is the effect of a second induction course of BCG? That's the first question. And as well as, hey, how does creto compare to that? I'd love to see that trial.
Ashish Kamat: Yeah, no, absolutely agree. Because otherwise, as you know, and you alluded to this, close to 60, 65% of patients with CIS will respond to that reinduction. And for TA, like you said, it's about one-third. So, overall, they're going to have at least 50% patients respond. And I just wonder, patients, investigators, the company's going to invest a lot of money in this single-arm study, you're going to get a positive result, but how is it going to be used by the clinicians? What are the patients going to think? All of these are going to be unanswered questions. But again, kudos to everybody that's taking part in the study. We need studies like this, but sometimes we need to make sure that we have the right control arm. So, really appreciate your perspective there.
Trinity Bivalacqua: Yeah, absolutely. I would agree with those sentiments completely. But as you said, this is a trial that I think will provide us with information about this oncolytic adenovirus in another disease space. And the reason why I think it's important that we do this is because it's so well tolerated. The side effects, what we've learned from previous trial is so good, it begs the question, can we use it earlier, as well as in additional disease patients like BCG-exposed?
Ashish Kamat: So, let me put you on the spot a little bit, Trinity, because I think you are the perfect person to answer a question such as this. Say the results of the KEYNOTE-676 comes out, where they actually have BCG plus pembrolizumab, and it's randomized to more BCG. And that shows a number that's similar to CG, but it was randomized against BCG. How would you factor that in your discussion with patients as to which option you would use? Would you go by the side-effect profile that you just mentioned is so mild with CG? Would you go with the trial that actually had a comparator arm? How would you factor that in?
Trinity Bivalacqua: Yeah, it's exactly how I would present it to patients, is that we've got a positive result where we see the addition of immune checkpoint inhibitor, systemic therapy that adds some benefit. Now, that we will find out, right? I think we both believe that it probably is going to benefit patients, but the question is, who is it going to benefit, how much is it going to benefit, and at what risk or at what cost? And that's how I choose something for a patient. Whereas, if you've got an intravesical agent, for example, like creto, which we know has so few side effects and also effective, I'm frankly going to be reaching for that first before I went to the combination. One thing we haven't talked about, and what about cost? That's the other thing that we all have to consider is what about the cost to the patient, to our healthcare system? And I think at some point we need to also consider that.
Ashish Kamat: It's always good to have more choices, and Trinity, always great to have you on.
Trinity Bivalacqua: Thank you. Thanks, Ashish.