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Sam Chang: Hi, I am Sam Chang. I'm a urologist in Nashville, Tennessee. We have Professor Trinity Bivalacqua from the University of Pennsylvania who will enlighten us about the CG Oncology drug. Trinity, I'm going to turn that over to you and welcome and thanks so much for spending some time with us.

Trinity Bivalacqua: Thanks, Sam. I appreciate it. I'm going to go ahead and start sharing my screen so I can tell you about Cretostimogene. I'm going to call it Creto from here on out to make it easy for everyone. This is CG0070, as formerly known. I'm going to talk to you a little bit about some of the trials that have been going on as it relates to the use of this oncolytic adenovirus for the management of BCG-unresponsive CIS, plus or minus papillary disease.

I just want to make the point that these trials have all been done through the SUO CTC, which has been really a wonderful platform for us to get these trials done.

I'll start a little bit now talking about how this oncolytic adenovirus works. I think probably at this point, everybody's very familiar with this. If you guys remember back, going on probably close to 10 years ago, this was the co-genesis oncolytic adenovirus, which is now showing true efficacy in non-muscle invasive bladder cancer.

Now CG Oncology, it is a replication-deficient adenovirus, which is driven primarily in Rb mutated cancer cells, but it really has a dual mechanism, which I'll point out in a second. It is a replication-deficient adenovirus. It's highly immunogenic and has been shown to have good efficacy in the bladder. It is combined with a form of detergent to allow this to get uptake into the bladder urothelium and lining to induce its effect.

It does encode for GM-CSF, which is part of the dual mechanism. It is primarily uptake into Rb mutated cells and causes direct tumor lysis. But there is some data to show that it probably works in Rb intact cells.

As I pointed out earlier, this is a replication-deficient adenovirus, which has a dual mechanism. It truly has significant anti-tumor immune responses because when it's uptake into the cells, you see a direct stimulation of cytokines and antigens from the dying cancer cells, which activates T-cells, and you see the same activation of T-cells and tumor lysis and cell death that you see with other immunotherapies. This is the proposed mechanism by which you see the effect of this therapeutic agent, which is given intravesically.

As everybody has become aware, here in the United States, there are multiple agents that are approved for BCG-unresponsive CIS, plus or minus papillary disease. As we know, pembrolizumab and now nadoferagene or interferon are FDA approved. Multiple companies are looking at their various agents either given intravesically alone or combined with a systemic agent.

What CG Oncology has done is designed multiple trials to look at the efficacy of Creto as monotherapy as well as combined with a systemic agent.

The first trial that I'd like to share with you and tell you about the results is the BOND-003 trial. This is a Phase 3 trial which looks at Creto alone given intravesically in BCG-unresponsive CIS. It's a single-arm open-label trial, given to patients who have BCG-unresponsive CIS, plus or minus papillary disease. Of note, if you have high-grade T1 or Ta, it does require a re-resection prior to treatment. And there is a mandatory biopsy at 12 months.

I think one of the novelties of this trial, which is honestly different than other intravesical agents that have been studied in BCG-unresponsive CIS, is that it allows for a second induction course of the therapeutic agent. Just like when we give BCG as a second induction course in patients that are BCG-naive, if they're unresponsive or have refractory disease after one single induction course, that's what this trial allows for. That's one of the novelties of this. And it also allows us to be able to extrapolate the efficacy and response rates in patients who are initially unresponsive to the agent and then given a second induction course.

Here are the results of the BOND-003 trial, and once again, this is a Phase 3 trial. There are 66 patients enrolled, and what I'm presenting right now is the six-month time interval. We do not have the 12-month time interval, at least right now. That will be forthcoming. But what it showed was that at any time point, there was a 75% complete response when Creto was given to BCG-unresponsive CIS patients. At six months, that response rate was 63%, and at three months, the response rate was 68%, as you can see here, and the table on the right-hand side. The duration of response was durable, which you can see in this next slide in the waterfall plot.

I'd like to point your attention to this middle portion of the waterfall where you can see that patients who initially were refractory to Creto were given a second induction course of Creto to see if they had a response afterward. And actually, 31% of patients had a complete response after reinduction, which I think is one of the things that are important for us as we consider utilizing this in our patients if it ever gets FDA approval. It's currently on fast track for FDA approval and it's forthcoming.

This is early data at six months, but hopefully, as you can see here, it's very durable. Hopefully, the durability continues at 12 months. The fact that you can see a 74% complete response at any time point and a 68% complete response at six months points to the high efficacy rate in this disease.

It's very well-tolerated. As you can imagine, if anybody has treated any patients with intravesical therapy, the main effects are related to bladder spasms, pain with urination, urinary tract infections, and the like. I can tell you from treating lots of patients with Creto, the main, at least in my hands, the main problems as it relates to local symptoms are bladder spasms, and I oftentimes treat these patients with anticholinergics to help reduce this.

Now, we're going to present, shifting gears a little bit, to talk about the other trial, which has also been conducted in BCG-unresponsive CIS, plus or minus papillary disease, where it is combined with a systemic agent, pembrolizumab. This is the CORE1 trial.

Now, this is a trial that combined Creto intravesically with Keytruda, or pembrolizumab. What you can see here from the waterfall plots as well as the complete response rates at any time point was 85%. This is, once again, a Phase 2 trial. This was only in 34 patients. At six months, the CR rate was 82%. And at nine months, the durability was 81%, and at 12 months, 68%.

If you compare this to any other agent that is either FDA approved or in trials that are being conducted, you can see that there's a very high response rate with the combination therapy. If you talk to anybody who's very active in this field, and when you think about how we are going to treat this in the future, I think we all acknowledge that combination therapy, either combination therapy; intravesically or intravesical combined with a systemic agent, is probably the way that we're going to treat this disease process in the future. Once again, this trial also allowed for reinduction if a patient was refractory at its first time point.

The side effects were very similar to the BOND-003 trial. There were some Grade 3 side effects, which I think is likely related to the pembrolizumab or PD-1 checkpoint inhibitor, but overall, very well tolerated in this disease state.

This is my last slide, which just points towards the potential use of Creto either as monotherapy or combined with a systemic agent. In this case, the Phase 2 trial combined it with pembrolizumab. CG Oncology is looking to move this into the intermediate risk, BCG-naive non-muscle invasive bladder cancer, that's the PIVOT-006 trial. And also looking at trials, looking at high risk in the BCG-exposed. The intermediate risk PIVOT-006 trial is actually going to be conducted through the SUO CTC, and we'll see if an oncolytic adenovirus like Creto has some efficacy in patients with intermediate risk used as an adjuvant therapy.

I'll stop there and answer any questions.

Sam Chang: Trinity, great presentations about the ongoing trials and the future trials looking at this adenovirus.

A couple of questions that people always ask: How close are we to FDA approval? Do you have any idea?

Trinity Bivalacqua: No.

Sam Chang: I know it's fast-tracked. Are we looking at calendar year 2024 or early 2025? I know this is all guesswork, but any idea regarding the FDA approval process?

Trinity Bivalacqua: Yeah, I mean, as you know and others, this is a process. It takes time. My understanding is that it's targeted for 2024. What quarter, I don't know, but it is, I guess, possible that we could see this as the newest agent on the block for the management of BCG-unresponsive CIS this year.

I think if that does occur, it's going to be a very crowded field, and it's going to become very hard for us as practitioners to decide what we're going to utilize in this disease space.

Sam Chang: And I guess that leads to the second question regarding how do you sequence, how do you balance. I'm intrigued by the combination of mechanisms of action, so the immunogenic stimulation with the GM-CSF, the killing of the cancer cells to increase that.

The adenovirus, once it's taken up by the cancer cells, it also by itself has a cytotoxic effect? Is that right?

Trinity Bivalacqua: That's right, yeah, that's right. You have a cytokine release, which is antitumoral, and tumor lysis. I think the combination therapy, if that's sort of where you're going as to what is the mechanism. In the bladder, when you have cytokine release and you have activation of T-cells, you get an upregulation of interferon signaling, right? So when you have interferon signaling, you're going to have an increase in PD-L1, PD-1 in either tumor cells or the tumor microenvironment, right?

I actually think probably the mechanism of action where you're seeing this enhanced efficacy in patients that are treated with the combination is likely related to that. I mean, we know that pembrolizumab alone or other PD-1 inhibitors that have been studied in this disease space, the efficacy is actually there, but I think we all acknowledge that it's not what we would like and we need to do better.

I think it's synergistic, to your point, not additive. Clearly, that data, the data that we see here in the Phase 2 trial, would suggest that there's a synergistic effect via the mechanism I've just spoken about.

Sam Chang: Right, and it has to add to the longevity of that response as you've shown in the waterfall plots. When you logistically ... We were involved in the early BOND trials, BOND-001 and BOND-002, years ago.

Trinity Bivalacqua: Yeah. Right.

Sam Chang: Tell me about the actual logistics regarding... We used to have to put in a separate detergent, separate detergent... Is it now kind of a single process where the detergent and the agent are placed at once in terms of the overall process and logistics?

Trinity Bivalacqua: Yeah, that's exactly what it is now.

I do remember the early trials that were done years ago where the process was a bit more laborious.

Sam Chang: Yes.

Trinity Bivalacqua: I think now it's a single instillation. You're able to give it very efficiently in the clinic. We actually, our nurses and myself, have utilized this now for a year, two years, and frankly, the only problems we're having right now, a little bit, are related to bladder spasms.

That's kind of the issue.

If you look at other agents, obviously nadoferagene or adstiladrin, it's a very similar effect that you see there. But we use anticholinergics and it seems to help patients. We've never had a patient have to withdraw due to local side effects though.

Sam Chang: Wow. Well, it is definitely a very exciting time. When you look at the agents out there, the different mechanisms of action, the possible, just like you said, synergism between multiple possible interventions compared to even five years ago, Trinity, it's a significant, significant change, so very exciting times.

I'll leave you with this last question. How are we going to be treating non-muscle invasive bladder cancer, high risk, two years from now, three years from now? Are we going to use many of these agents before BCG? Are we going to still use BCG? Or is it yet to be determined?

Trinity Bivalacqua: This is the million-dollar question, right? When we sit down and we talk about where the future goes, I think you pointed to this a little earlier. It's about sequencing, right? How do we sequence these agents? I think we're still going to be using BCG in the BCG-naive state. I don't believe that we're going to be using a different agent. However, that being said, due to the BCG shortage and the bridge trial that's in the cooperative groups, which is comparing BCG to GemDoce, I mean, listen, if that shows it's amazing, that it's not inferior to BCG, maybe we'll be using that. But I do think that BCG is going to still be our gold standard. When BCG fails patients and we see that they're unresponsive, I think it's all going to be about sequencing.

What I would love to see in the future, which I think we need to start designing trials that point towards this, is a biomarker that then directs us to one agent or the other. I think we're really far away from that. I think we're probably 10 years away from that if we're lucky.

I think it's going to be about us designing trials that say, "Listen, patients that have been exposed to agent X or Y or Z, how do we sequence it to see what effect it has?"

That being said, I think we, as urologists who are taking care of these patients and also performing cystectomies, have to acknowledge that people with CIS and high-grade T1 disease, it's a dangerous, potentially lethal cancer, and we have to be careful by pushing it too far. I think that's a balance that we all have to ultimately acknowledge.

The good news is, in these trials, we're not seeing that we're losing a lot of patients due to relapse, systemically. I think if we do things right, ultimately we're going to have to learn what the sequencing protocols are to benefit patients.

Sam Chang: Yeah, I think you bring up some key points: the initial risk stratification, the early biomarker prediction, as well as prognosis, but prediction of what agents may work, being able to then switch early or maybe avoid certain treatments that are less likely to be effective, and then finally, that difficult determination always regarding the timely early cystectomy versus being able to spare patients the morbidity of the cystectomy.

I think we are going to be transitioning from the guidelines saying the next best step for this patient is radical cystectomy. I think we're going to have many more options, and that only serves, I think, all our patients well.

Trinity, thanks so much for the update, and we're excited to see the trials come to fruition and see the long-term results and hopefully FDA approval in the near future. So, thanks again.

Trinity Bivalacqua: Thanks, Sam. Appreciate it. Have a great day.