Shane Pearce: Thank you. Thank you, Dr. Chang for having me in. So I'll be presenting the first results from CORE-008 Cohort A, which was a phase two study, so early data from intravesical cretostimogene in patients with high-risk BCG-naive non-muscle-invasive bladder cancer, which was recently presented at the SUO. Disclosures. J&J as a speaker and Fortec. And no relevant disclosures with CG Oncology. So there's some huge unmet needs, as we all know, in high-risk non-muscle-invasive bladder cancer. BCG failures can occur in up to 40% of patients when we use broad definitions. And BCG-unresponsive rates vary in the data, probably lower in some of the modern series, but up to 30 to 50% of patients and have persistent or recurrent high-grade disease despite adequate BCG. We've got major issues that I know I struggle with in my practice in terms of the BCG shortage.
And recent survey data from the FDA indicated that 92% of respondents reported that the BCG shortage was affecting their ability to treat patients with high-risk bladder cancer and also had an impact on trial enrollment in about a quarter of respondents. Tolerability of BCG is another issue with 26% of patients experiencing grade three to four toxicity and only 16% of patients in the SWOG trial actually completed all of the recommended maintenance treatments. So we know BCG can be difficult for patients to tolerate and complete a full course of induction and maintenance therapy. There's also real-world data indicating that up to about 24 to 28% of patients will discontinue BCG due to toxicity. And lastly, when we're looking at the NCCN guidelines for high-risk non-muscle-invasive bladder cancer, we should also be considering cystectomy in some of these very high-risk patients.
But as we all know, that comes with its own list of issues, including complication rates, morbidity and long-term quality of life. So cretostimogene is a unique tool for us as a dual mechanism of action. So it's an adenoviral vector that will selectively replicate and within and enlist bladder cancer cells while amplifying an anti-tumor immune response. So it sort of has this unique dual mechanism of action for direct cytotoxicity and then recruiting the immune system through T and B cell activity, inducing immunologic memory. The mechanism is interesting where cretostimogene and normal cells where we have Rb that can bind to the E2F promoter region and prevent actual expression of the GM-CSF gene on this engineered genetic material in the viral vector. Within the cancer cells, Rb is unable to bind to the promoter region and get expression of GM-CSF and selective cancer cell lysis and death, as well as recruitment of the immune system.
And so the CORE-008 study that we're talking about here, Cohort A, is specifically focused on patients that are BCG naive, who have CIS plus or minus papillary disease, and looking at complete response rates. So the treatment schedule and assessment schedule on the trial, this shows that patients were induced with kind of that familiar regimen, six weekly treatments, just like we would do with BCG. There was an allowance for reinduction in this trial for patients who had residual high-grade TA or CIS at the initial assessment at three months. And there was a within study randomization between two different administration techniques, kind of the traditional cretostimogene five step protocol for administration, and then a optimized streamlined two step administration protocol. So this allowed us to kind of look at maybe a shorter administration technique and how that would affect results. Cystoscopy cytology every three months with mandatory biopsies at 12 months, CTU or MRU at six months, and an optional maintenance in year three. Just looking over the patient demographics here, not really anything major jumps out at you.
I would say the trial is pretty typical for bladder cancer trial where we're seeing over-representation in terms of male and Caucasian patients, but age group is appropriate for a bladder cancer study. You can see that the vast majority of the patients did not receive any prior adjuvant chemotherapy, 87%. And there was a handful of patients, seven patients on the trial that did see BCG, but it was after prior to a two year washout period. And the demographics baseline characteristics were similar between the two original versus the optimized administration protocol, so no major differences between those two groups. And the big result from this trial was that there was a 83.7% complete response rate. And really similar results, maybe you could see a higher CR rate in the optimized administration protocol of 88% versus 79% in the original administration protocol, but study wasn't really powered to detect a difference between these two groups, but we can see that they're similar. Median follow up in these early results is 4.6 months. No patients progressed to cystectomy and there was no treatment-related progression of muscle invasive or metastatic disease.
There were three patients that were reclassified and really a consistent treatment effect across all of the subgroups. And I think importantly, very well tolerated patients reported kind of the classic intravesical side effects that we see that we're all used to dealing with as urologists and in terms of bladder spasms, dysuria, urinary frequency, hematuria. In conclusion, cretostimogene monotherapy in this phase two trial demonstrates consistent efficacy, safety, tolerability, and a high-risk BCG-naive group of patients with carcinoma in situ and allows for really another option that may promote our ability to allow patients to avoid cystectomy and some of the other systemic toxicities of other treatments. And the trial also importantly shows that we can optimize and reduce the time that the patients are sort of on the table, so to speak, for the intravesical treatment by shortening the protocol for administration. And I think these results really support the activity of cretostimogene in non-muscle-invasive bladder cancer, which we've seen previously in other disease states for NMIBC and really supports continued research in this area and additional treatment arms are planned for high-risk BCG-naive NMIBC.
Sam Chang: Great. Dr. Pearce, exciting results from a treatment that obviously has had significant results from a BCG-unresponsive group of patients, both CIS and papillary. So it's actually reassuring to see that in the BCG-naive population, there seems to be such a robust response with that CR rate in the high 80s. Tell me a little bit about this optimized administration versus the original administration. Those who are not familiar with cretostimogene and its administration may not know much about that. So can you give physicians a little bit of a background and the rationale behind the different treatment regimens?
Shane Pearce: Yeah, that's a great question. And the original protocol was a five step administration that started with a saline wash. There was a DDM dwell time after a saline rinse in the bladder, followed by another saline rinse. And so the DDM is given as kind of a surfactant to facilitate the viral vector absorption into the mucosal surface. So saline, DDM, another saline rinse, and then the cretostimogene, well, and I believe there was another saline rinse, so sort of a five step protocol. So it was a bit time consuming. The new protocol eliminates the saline rinses. So the patients essentially will have a catheter placed the bladder drained, DDM, 15 minute dwell, drain the bladder, and then instill the drug. So it's a much more really feasible workflow, I think for a busy urology office if this rolls out in the future.
Sam Chang: And then once the medication then is instilled following the optimization, the 15 minute dwell of the initial kind of agent that increases the bind and absorption, then there's no wash afterwards, correct?
Shane Pearce: Correct. Yeah. There's no wash after the intravesical agent.
Sam Chang: I mean, so if you look at the combination of efficacy, if it continues to hold out, obviously the durability response will be very important and this will just take time as we accomplish that. But if you have durability response matching as well the significant complete response rate, but then you throw in the side effect profile, this medication seems very, very well tolerated.
Shane Pearce: I agree. I think it is well tolerated. I've had a lot of experience just managing patients on the trial and it's really fairly straightforward because it's right in our wheelhouse in terms of the symptoms we're all really used to managing with patients on BCG, patients that have bladder spasms related to other instrumentation or even stents and things of that nature. So the toolbox that we all have for managing these patients applies very well. And I think it's hard to really make, can't really make any direct comparisons to other intravesical therapies that we have in this trial because of the study design.
But I think if you look at the numbers and it was well tolerated and that's what I've seen is that it's very well tolerated. And obviously, in this population, we just have a huge unmet need for new therapies and all those challenges that we talked about with the BCG shortage seems to wax and wane. And we're in my practice right now in a tough time with BCG. And so I think the more options we can have in the future, the better for our patients.
Sam Chang: I think essential points that you raised regarding the fact that we have so many promising studies, we have agents recently approved in the BCG-unresponsive space that are being looked at in the naive space. We have immediate risk medications now. I mean, it's a very exciting time and these results will only actually increase the interest in further studies with this agent, looking at the impact on patients that have not received BCG. And so Dr. Pearce, thank you so much for the presentation. I think it was one of those that really brought a lot of excitement at the SUO because of the two things you mentioned, the complete response rate and that safety profile, very well tolerated with an optimized scheduling and administration protocol, which to be honest, that original protocol, we've been involved in the early, early bond trials more than a decade ago.
I mean, before I had gray hair, we've had trials with this medication and that the saponification and different things that were required and the treatment protocol did make it difficult. But, clearly well tolerated and really does seem to have a significant signal of efficacy. So we look forward to long-term outcomes and hopefully you'll be able to update us as time goes on.
Shane Pearce: Thank you so much for the opportunity to speak with you and share the data.