Mark Tyson: Thank you for having me, Dr. Chang, delighted to be here with you on UroToday. So, I think it's just great to start... And before I start, I should say, as it relates to cretostimogene and CG Oncology, I don't have any financial conflicts of interest, I'm an investigator on several of their studies, and so my institution receives funding for those trials. But I think it's always good to start with a mechanism of action, maybe there's some trainees watching. But cretostimogene is an oncolytic immunotherapy which functions through a dual mechanism of action. It's intravesical, so it goes into the bladder just like any of the other intravesical therapies that we've been using for a while in urology, but it is a conditionally replicating adenovirus. So, in RB pathway deficient tumor cells, the virus will replicate and cause direct tumor cell lysis, it also expresses a transgene for GMCSF, which augments the immunotherapeutic effect.
And so, this is why we think it's so effective, it's the RB pathway alteration. So, it doesn't have to be RB defects themselves, but anything that regulates the RB pathway, anything that silences RB can result in observed efficacy. It also is pretty well tolerated, so if you don't have any tumor in the bladder, then theoretically the virus isn't doing anything. And so, the regimen that we're using is very similar to BCG, and I think that's one of the things that we wanted to highlight, it's once a week for six weeks in a classic induction and maintenance paradigm. So, after a response, a patient will go on to three weekly instillations every three to six months for a couple of years. And that's very similar to BCG, and that was born out of the phase one data from V-0046, using cretostimogene. The weekly times six induction dosing you can see here, had a complete response rate about 78%, which is what we've seen in BOND-003.
So, it's nice to see that replicated there. And also that dose that we use in BOND-003 came out of this trial as well. After the phase one testing, this went on to phase two testing, just briefly, I'll highlight this. This wasn't a BCG failure population, not a classic BCG unresponsive, this predated the BCG unresponsive definition, but again, very similar results to what we've seen in the other studies. Complete response rate, any time point is 65%, and at six months about 47%. So, very safe profile, very favorable AE event profile, and obviously an efficacy signal. So, that leads us to BOND-003, this is the big phase three study that is registrational. So, eventually the company will submit these data to the FDA for a new drug application. But it's 110 patients in the efficacy of valuable population with BCG unresponsive CIS.
So, classic definition of BCG unresponsiveness. So, a CIS recurrence within 12 months of induction, plus at least two of three maintenance or repeat induction course. And then they can have concomitant papillary disease, high grade TA, high grade T1, but all that has to be resected. Importantly, this trial had mandatory biopsies at 12 months. And top line numbers looked great, this is not news, this has been presented a couple times in different venues, SUO, AUA. But about three out of four people have a complete response, and at any time point. So, with immunotherapies cretostimogene, you can do something like repeat induction for somebody who has persistent disease at three months, and this is something that we do for BCG quite frequently. And so, this complete response at any time point includes those patients who had a complete response at three months, as well as those who had a complete response after a repeat induction course. So, at six months.
So, that 75.5% would represent a composite of both phenotypes of complete responders. I think actually the more important number to look at here, Dr. Chang, is the landmark data, and actually the landmark data for BOND-003 look really good, 46.4% at a year. And my slides aren't updated here, there was a press release recently from CGH just a few days ago actually, for that 24 month landmark being right around 42%. So, it outperformed... Well, it performed toward the top end of the confidence interval for the KM estimate at 24 months. So, that's really, really good data, and I think that's a meaningful endpoint for patients with this disease. Just a couple more slides here on efficacy. The duration of response I think is another really compelling piece of the cretostimogene equation. So, of those 75% of patients who respond, 58% of them are in complete response at 24 months.
So, this is really important to note the denominator here is complete responders. I think just in general, the field has, I think, sown some confusion, not intentionally, but the FDA asked for complete response and duration of complete response, and that's what we're reporting. But that's different than, say, high-grade recurrence-free survival at a landmark like a year where the denominator includes all patients. So, it's easy to look at a figure like this and say 58% of patients are in complete response at two years, that's actually not what this figure is showing. Among complete responders, so among that 75%, 58% of them are in complete response at two years, and that's why that two-year number and the intention to treat population is 42%. So, a lot of numbers, but suffice it to say that in whom this works, it seems to be durable and works over the long term, which is nice to see with an immunotherapy.
And that's what I'm highlighting here in the swimmers plots. So, several of these patients have very durable responses long after the two or three-year maintenance regimens are completed, and that's nice also to see. And the other thing I just note here too is that about 50% of those that were re-induced went on to achieve a complete response, and two-thirds of those were durable. So, the reason why that's important is because you might say, well, complete responders just due to the repeat TURBT, and then the disease eventually catches up to them, and we certainly do see that in about a third of the patients, but two-thirds of them are maintaining that durability, which is good. Safety tolerability, at a high level, it's pretty well tolerated, most AEs are grade one and two, there's no grade threes that are related to treatment, no treatment-related discontinuations, and importantly, for those of us who treat a lot of patients with intravesical therapy, the median time to resolution is about a day.
So, for a day or two, they're developing frequency, urgency, pain with urination, spasms maybe at the time of instillation, but these aren't symptoms that are altering the quality of one's life for more than a day or two. This is the horizon, and with this, Sam, I'll shut up and hand you back the microphone. But I think the future is bright for cretostimogene. The executive team at CG Oncology has, I think, done a nice job of evaluating cretostimogene across the entire spectrum of non-muscle invasive bladder cancer, and they have done so in some pretty bold ways, like PIVOT-006, for example, is a randomized trial comparing cretostimogene to observation, and in patients with intermediate-risk non-muscle-invasive bladder cancer, and then you could make the argument that perhaps in high-grade histologies observation is not the standard of care, but at the end of the day, in PIVOT-006, we're going to have average treatment effects for cretostimogene, and that's going to be a really good number to confirm that efficacy that we're observing in these single-arm phase three studies.
CORE-008 is evaluating cretostimogene in a couple of different scenarios, the most exciting one for me is Cohort CX, where they're combining it with gemcitabine. I think that the potential therapeutic advantages there of combination chemotherapy with cretostimogene could be very powerful. And so, I'm really excited that cohorts accrued and I'm hoping to see some data sometime next year on that.
Sam Chang: Mark, that was a great overview of the efficacy, of the side effect profile, and of the future with cretostimogene. So, let's talk about the efficacy. To me, I think similar to you, the most promising aspect of this data is, look, not everybody's going to get a complete response. A lot do. But I think to me importantly, there is a real percentage of patients that achieve a complete response that seemed to "have a tail," that maintain this complete response disease-free state for a significant period of time. Maybe we can even conjecture maybe forever. Now, none of the trials have shown that either with creto, with other agents, but to me, the chance that with a finite number of doses, and those are stopped, that certain patients followed for a period of time really, really have that long tail. As we think about that, do you think that these patients truly will "be cure"? And do you think you'll be able to actually prevent upper tract recurrences? Don't happen often, but perhaps you've built this innate and this memory within our immune system. Tell me your thoughts about that tail.
Mark Tyson: Yeah, it's really piqued our interest with Roger Lee's CORE-001 concept with combination with pembro and cretostimogene, where I think 54% of patients in the intent to treat population were in complete response of two years. It's nice to see that replicated with cretostimogene monotherapy, that two-year number not quite, 42% is not quite at the CORE-001 number, but it's still really good, and to your point, that-
Sam Chang: Without a systemic downsides to systemic therapy, that data is very, very promising, but just with an intravesical treatment.
Mark Tyson: Yeah. And if you believe the mechanism of action, and with repeated instillation, there's a switching from that innate to adaptive immune system response, then it is I think conceivable, or it is possible that this immunotherapy has efficacy beyond the treatment duration. Now, in my experience, and I have a lot of these patients, both cohorts, that are in complete response, two, three, maybe even three and a half years later, in my experience, I don't know if it can prevent upper tract disease or extravascular recurrences like urethra recurrences. It may, I would need to look at that a little bit more closely. But I think that I would personally hesitate to say that this would have efficacy in the upper tract when used just as an intravesical therapy for bladder cancer, but certainly-
Sam Chang: Totally understand. To be honest, I was just thinking that just now, as I was thinking about, it makes me go back to some of the data that we've looked at in terms of challenging with... In animal models. But challenging with other tumors, other locations, being able to actually show a significant lack of these tumors to be able to grow in different sites because of weak conjecture, some of the therapies that we've given. Second thing that I'm struck with is, and it's the first time honestly I've seen this, is the fact that we understand, knew that there are really no grade three, et cetera, side effects. But the duration being one day, the fact that 24 hours later that, yeah, they may have had some lower urinary tract symptoms, similar to multiple intravesical therapies. Basically, everything that we do will have some, I think intravesical therapy, but that then within a day, the majority of patients actually have a resolution, that, to me, I think is very striking.
Mark Tyson: I agree, and that's a great piece. I think that's the crux of the value equation for cretostimogene, is that you can get some of these really high response rates without torpedoing the bladder, without crippling the patient's quality of life, for much longer than a day or two, and I think obviously, I'd be careful, I should be careful how I say this, because I'm not speaking about the PROs in the study specifically, just about what's been recorded by the investigator. Maybe the patients would have a different perspective on that, and we should certainly keep an open mind to the PRO data that eventually comes out as well. But from my perspective as an investigator, these are patients, yep, around the time of instillation, just like any other intravesical therapy, there's going to be some spasms, there's going to be some pain for some people, not everybody, but for some, and urinary frequency and urgency for a day or two, but then, yeah, the median duration of resolution of all of these grade one and grade twos are-
Sam Chang: One day. Yeah, that's the first I've actually seen it actually expressed in that way and captured in that way, because we see all the different medications with a side effect profile, with different lower urinary tract symptoms, but then that resolution, that's the first time I've actually seen that, I think that's actually very, very important. And then, third, in terms of we have therapeutic efficacy, we have side effect profile, and the ability to tolerate well, but then the possible multiple indications based upon the clinical pipeline, looking at different states' disease, looking at different combination therapies, et cetera. And in my opinion, I think, just as you said you were excited about combination therapies of, in particular with this cretostimogene with chemotherapy, but I think you look at all the different agents that are immunotherapeutic, that are chemotherapeutic, that could be used in combination and/or sequence, I think it is up to us as investigators to really determine, okay, what is going to be the correct recipe?
What is going to be the correct combination? How are we going to use it in that type of thing? And the fact that we have these agents, which, when we have the opportunity to work together, when you were a fellow, we didn't have these, we were just starting to study them. But the fact that now several are FDA approved, that others will be FDA approved soon, it gives us actually a lot of possible choices, but then puts the responsibility on us to help determine for our patients, and with our patients, all right, where are we going to go with this? How are we going to do it, and what are we going to do?
Mark Tyson: Yeah, exactly. It makes my head hurt thinking about it. And cost factors in too, these therapies are expensive, and so I think we have to look at it holistically. I do think there's probably going to... For us to be able to definitively say one should be used over the other in any circumstance, I think is going to require one of two things, and that'll be either a translational argument, so our TM colleagues publishing a biomarker or something to that effect, that this therapy works in this person with this mutation or this particular genomic profile on the urine, or genomic disease burden, or any number of biomarkers that we could determine this drug might work better, or comparative effectiveness. We'll have experimental data to suggest that this drug works better for these people-
Sam Chang: For this population of people now. And I think your first example of, we're getting that with many different cancers, we're going to get better and better with bladder cancer, specifically of being able to predict with your tumor, your individual tumor... Mr. X, Ms. Y, your tumor, these are the agents we think are going to be more likely to be beneficial and effective. And I agree with that. And I think also kudos to CG Oncology when it comes to the early access program, the trial that really, there are many trials that are going on, which are fantastic, but many are quite limiting in terms of patient inclusion criteria and exclusion criteria. But to have access for patients who've had different therapies, different situations, I think, honestly, having that available to patients was really beneficial to a lot of patients, and I know many patients are taking advantage of that, and hopefully gaining some benefit from that.
And we'll definitely learn with different high risk types of populations the role of cretostimogene in a very diverse population. So, no, we look forward to continued data, and we look forward to you leading various clinical trials with different agents in different situations, and I just wanted to thank you. The whole urologic community is really indebted to leaders like yourself, helping to raise awareness, not only in terms of therapeutic options, but where we should go next. So, I'll end it with thanks, Mark, really appreciate it.
Mark Tyson: Yeah, and thank you, Dr. Chang, I learned this from you, so I have you to thank.
Sam Chang: Didn't learn much from me, I learned it all from you, but no, no-
Mark Tyson: I appreciate the opportunity to talk with you about our work with cretostimogene, and like you, you said it best, I'm looking forward, I think the future is bright, we'll see what cretostimogene, what the FDA has to say about the data next year, and like you said, the pipeline of trials that we highlighted on the last slide there, how those read out over the next year or two, I think will be a very exciting time for CG Oncology and for bladder cancer patients at large.
Sam Chang: Wow. Fantastic. Thanks, Mark, we'll have to do it again, and hope to see you soon.
Mark Tyson: Thanks, Sam.