Trinity Bivalacqua: Yeah, absolutely. Thanks, Ashish. This is another arm of the CORE-008 trial where we're investigating the cretostimogene. And in this trial, it's in the BCG-naive space, high-risk BCG-naive. These are my disclosures. As everybody is probably aware, we know that cretostimogene is an oncolytic adenoviral gene transfer, which replicates in RB-altered tumors. And with lysis of any cancer cells or dysplastic cells, you also get activation of the immune system and increase in GM-CSF, which is also what I believe is probably the true mechanism of action of the efficacy of creto, where you get activation of the immune system with T-cell engagement and cytokine production. We do know that this is highly effective in the BCG-unresponsive space, BCG-unresponsive CIS, plus or minus papillary disease from the BOND-003 clinical trial. The question is, can it be moved a lot earlier into the BCG-naive space? So this is one of the arms of the CORE-008 trial, multi-cohort trial. You can see here that this included patients with high-grade T1 or TA or plus or minus CIS so it was 125 patient trial. Patients could not have had prior BCG exposure, but if they did have BCG exposure, it had to be greater than two years prior.
Maximum one or two BCG doses within the past 24 months were allowed. So essentially, you might think of them as BCG-intolerant, never really got an induction course, but the investigator thought they'd be able to give it, they were allowed. The other part of this trial, which I think is important to discuss, and you alluded to it, is that it also investigated the utilization of the five-step versus two-step optimized intravesical administration. We know that the five-step involves washing of the bladder with detergent, and then with a wash after, and then administration of creto, the optimized administration is actually a two-step where you place the detergent then creto or the adenovirus. And what we found in this trial, and once again, this is extremely early data. Median follow-up of this trial thus far is only 4.6 months, so five months. The majority of patients have had the three-month evaluation, but very few have had upwards of six to nine months. What we see here is the first report, which I actually presented at the SUO, this is overall complete response at any time, which was 83%, showing that in the BCG-naive space, there's actually true activity, which I think is probably no surprise to most people that have worked with creto in the past.
And as you can see here that the CR rate was really no different between the two-step and the five-step protocol. As we have seen in previous trials, extremely good side-effect profile, very few side effects. If they are, they're always local, no treatment-related discontinuations, and 98% completed all protocol-defined treatments in both of the arms. Here's the data that we presented where you can see that you see an increase in accrued imaging levels. This is cretostimogene replication in the urine. So what this first data point is. You can see a nice peak after one to two intravesical instillations, which then comes down after the sixth instillation. You can see that it also increases with the maintenance treatments. This is very similar to data that we saw in the BOND-003 cohort. And I think what this essentially tells us is that no matter if you have the five-step versus two-step, we're seeing similar transgene expression. And this also would suggest that effective viral clearance supports less of the close contact precautions that some of us were using prior to this. This is GM-CSF. Unlike creto, we saw the same peak, excuse me, after one to two doses, which came down after six, but then didn't necessarily see that same peak with the maintenance treatments. I don't know the explanation for that, but maybe the immune system or maybe there was no tumor there. There was nothing going on in the bladder, so maybe that's why it wasn't increased, but this also aligns with previous work that we did in the BOND-003 trial. What this suggests is that the five versus two-step is safe.
We see early efficacy in the BCG-naive space. So moving this very effective intravesical adenoviral gene transfer, oncolytic adenovirus and BCG-unresponsive, we're now moving it into first-line BCG-naive with very good efficacy, good safety, and the optimized approach works. One caveat, early days, still don't have long follow-up, so it remains to be seen how effective this is in durability, but I suspect that we're going to see nice durable response. Thank you very much.
Ashish Kamat: Thank you so much for presenting that. Tell me a little bit about the WASH process and how it evolved over time, because that was one of the criticisms that many people have or had about the whole administration, and the fact that it's now optimized will potentially make it easier if and when it's available, we all think it's going to be approved. Tell us a little bit about the actual flow.
Trinity Bivalacqua: Yeah, so I think what I've learned from the team at Penn that's doing this is that honestly, the patient's just not there as long. It's an easier process for the nurses. So at Penn, we have nurses that are doing the intravesical instillation. Actually, I have a nurse practitioner that does all the trial instillations, and she says that it's frankly just easier. And when you talk to the patients, they're still tolerating it well. They're not seeing any local side effects or increased side effects, and it just shortens the timeframe for which patients are in the clinic, and it's less of the in and out, the washing and whatnot, which patients like. So I think that the big take-home from this trial, which is in the BCG-naive patients, it's really the two-step versus the five-step and demonstrating efficacy. And now we're seeing biomarker activity, which is similar in both approaches. So I think this really supports its utilization moving forward if the FDA ultimately approves this. I'll have to wait and see.
Ashish Kamat: Yeah, no, I mean, again, anything we can do to make it easier for our patients, because you have efficacy, you have low side effects, all that's great, and you also want to reduce the burden of time and financial toxicity so hopefully this will be a step in the right direction. Any insight into whether this is also going to be applied to the other disease states that creto is being studied in?
Trinity Bivalacqua: Yeah, great question. I don't know the answer to that. Honestly, I don't know the answer to that, but I've got to believe that if the data continues to mature and demonstrate similar safety and efficacy, I see no reason why it wouldn't be able to be brought into some of the other arms of CORE-008, and I think that that's something that I would love to see, but I don't know what the plans are there.
Ashish Kamat: Yeah, no, sometimes it's a difficult practical situation because you've done the trial using it one way and it's not yet approved and you tweak it and you change it. Now, is it going to be approved based on the old way of doing it or the new way? Do you want to tweak it after it's approved? All of these questions that I'm sure everybody at the company is really thinking long and hard about, it's going from IV to sub-Q when it comes to systemic IO.
Trinity Bivalacqua: Right, exactly. Good point.
Ashish Kamat: Which one do we use and how do we use it? But this is all great. I love the fact that this is headed in the right direction to make it more patient-friendly, which is ultimately the goal of anything that we do. So again, Trinity, thank you so much for taking the time. Always a pleasure having you.
Trinity Bivalacqua: Thanks. Appreciate your time.