Robert Svatek: Thanks, Ashish. And I appreciate all your mentorship. I trained under you, and it's great to be sitting here to share this with you. So this trial was conceived in the early part of my career, and the goal initially was to test the priming aspect. And that's where this originated because of a paper that came out of the Pasteur Institute showing that when you prime mice, that you could improve T-cell recruitment to the bladder, and that resulted in improvement in antitumor immunity. And so that was the initial impetus that started this. And the original concept was going to be a prime component in the US and boost in Europe. And so it was a large collaboration. I just say this because there are many people that helped to put this together.
Ashish Kamat: And since you mentioned that, I also want to tip my hat to you because I still remember Matt Albers, you contacted him and Molly, and it was through the IBCG. And they were like, "Oh wow, he reached out to us." And you didn't just reach out. You reached out, you got the idea, and now you have this phenomenal trial. So kudos to you.
Robert Svatek: And we even went to ... Seth Lerner and I went to France and spent time with them, went to the institute. And so I think a lot of people worked to get this. And the problem that we had was that we couldn't get a strain to do the priming. And so we were forced to look at comparing strains. And that's how we got to the point of looking for a strain that would be able to test priming. And then in the same context, well, it would be great to test the two strains against each other. And so a small company in Japan agreed to provide the product and they were using a priming version for preventing TB. And so that's where the strain came from. And so the three-arm trial comparing two different strains and also a priming arm. And so the results are two different sets of results. One is the Tokyo versus TICE. And what we see there is that Tokyo was not inferior to TICE. Officially, we have to show that it comes within a certain range. And as you'll see in the Kaplan-Meier curve, it's clearly non-inferior. And so we also looked at a subgroup of patients with CIS and in that subgroup as well, Tokyo was not inferior to TICE. So that was co-aim one.
Ashish Kamat: Sure. And just for our audience, was there anything about the curves, the separation, the absolute landmark numbers that surprised you? Anything you were not expecting?
Robert Svatek: Yeah. We didn't know what to expect. We thought it could go anyway. We really didn't know. There was some preliminary data that maybe Tokyo was a little stronger and we just didn't know. The Kaplan-Meier curves are separate actually. Tokyo is above TICE and it almost looks like it could be superior, although it does not make statistical significance. And I want to point out that we were not powered to test that. We only were powered to test non-inferiority, which we showed. But it does strike me that there appears to be a separation between the curve. So that's of interest. The adverse events were slightly higher in the Tokyo strain. I see you shaking your head. Did you have experience with that? Some people anecdotally thought that maybe ...
Ashish Kamat: So it was anecdotal, Rob, but also I've done a good amount of work in Japan through the IBCG. And when you hear about the side effects that patients in Japan experience with the Tokyo strain, or for example, in India with the Moscow strain, it is a lot more. And whether it's the preexisting priming that the patients have in Japan or in India that might have been vaccinated, nobody knows, but I wasn't surprised. And then anecdotally, yes. You could tell who was on what just based on the side effects they had.
Robert Svatek: I heard some of the same comments. One regret I have is that it was not a blinded trial. And I do ... Part of me feels that those that were on Tokyo may have been systematically more tuned to report the adverse events. At any rate, there was a slightly higher adverse event rate in the Tokyo group, but the patient-reported quality of life was not ... It was slightly better in the TICE, but not clinically significant. So it'd be interesting to see how it would be adopted into practice.
Ashish Kamat: And then the priming.
Robert Svatek: And the priming. Yeah. So the priming was unfortunate because we did not see an improvement in survival with priming, not at all. And if you look in the CIS population, no difference. And what's interesting to me, it's fascinating, is that we checked PPD at baseline. And then after, we gave them ... We checked it again at three months and six months. And we looked at PPD conversion, meaning you go from negative to positive, because everybody on this trial was PPD negative in the beginning. So we looked at PPD conversion, and it was higher in Tokyo strain compared to TICE. And what was remarkable was that if you got primed, it wasn't increased above regular intravesical. So for example, I think the PPD conversion for TICE was about 23%, and for Tokyo, 33, 32%. So it was higher than TICE, but it didn't matter that you got primed. And we found that the PPD conversion did not predict response. It was not associated with high-grade RFS. So it's interesting to me that a relatively low number of people converted, even though you're priming them and you're giving them a ton of BCG. So maybe their immune system is weaker, that it's not able to convert. Maybe it has something to do with their cancer. Maybe it has something to do with their age. But I think it's interesting to me that we had such a low number of converters. And despite the fact that Tokyo had higher rates of conversion, it did not translate into an improvement in outcome.
Ashish Kamat: Yeah. If you put all this together, it just brings back what we all know about BCGs, that we understand a lot, but we still don't understand exactly how it works. Which is great because again, James Allison, who got the Nobel Prize in this is often said that BCG is probably the best immunotherapy out there, which you and I agree on. It really works well. Again, this trial took a lot of effort. And I know you've got a lot of correlative studies and assays and tests that are going to be analyzed and presented. But before we get there, because I know you haven't done that to where you can publicly do it, but what is your sense if you now look at the CREST data, the POTOMAC data, the ALBAN data. Now you look at your study, the prime data. What is your sense as to today in 2026? How are you using this data, including your trial, to consider patients and how you counsel them on treatment for their non-muscle-invasive high-risk disease?
Robert Svatek: I think tomorrow there will be a pro-con of utilizing immune checkpoint inhibitors with BCG and I'm looking forward to seeing the thoughts there. My personal bias is that it's a very small population that would benefit from combination with immune checkpoint inhibitors just because of the side effect profile. What I think this trial does though is provides us with a pathway to get another strain into the US. One of the challenges that we have is that we're not giving adequate BCG. And you and I both know that it's clear that maintenance results in better outcomes with randomized controlled data. And so we have a lot of patients out there that are getting suboptimal BCG, incomplete regimens, or they're getting lower doses. So I think this at least provides an opportunity for another strain to come into the US. And that changes the landscape subsequently, so that we can at least give patients adequate BCG instead of having a situation where we have this BCG exposed, but they're not quite unresponsive. So that's number one. I think number two, we took a risk, right? We tested a relatively ... It wasn't completely novel in its sense because this idea had been around before, but it's cheap, right? If this would've worked, the goal was to improve RFS by 30%. And I think we do want to think about other ways to repurpose or look at drugs like that, that could stimulate the immune system at a relatively inexpensive cost. I think thinking along those lines is something that cooperative groups can do well.
Ashish Kamat: Yeah. No, I think that's critical. That's a point that you raised because some of the stuff, as you know, I grew up and did my medical school in India, and I always like to give back to the global community. Many parts of the world can't afford these million dollar drugs right now. And if you could take something such as BCG, repurpose it, prime it, who knows? Maybe your subgroup analysis will show that, okay, maybe in this select group of patients, older ... I don't know. I don't want to put words in your mouth. Maybe you should still prime them, even though the oral core, it didn't help. Obviously, Merck has promised us by the end of this year, 2026, the plant will be up and running, meeting all the requirements. With that in mind, are you planning on taking this to government to say, "Hey, allow us to bring Tokyo?" What's ...
Robert Svatek: Yeah, I would love to see it finish the marathon that we started by getting it approved. That said, this is a small Japanese company and honestly, the challenges to getting it approved are several. It's a manufacturing issue. They currently ... It's a relatively smaller factory there. And for them to meet the demand of the US would take building another factory. Now, they could provide some right now that would help, and we're hoping that that will move forward, but we still have to submit for the BLA, submit for FDA registration. And so there's still some hurdles to go, but my hope would be to see this through to get it into the US. And you're right. I hope Merck can get this factory up and going, but I still think that even if it's great to have two companies and to have an alternative. And even if Merck can successfully complete this, I still think it would benefit us to have another option and there's another strain in the US.
Ashish Kamat: Absolutely. No, I mean, we still remember the days before Sanofi went out of business, right? There was enough BCG, you could even do between strain comparisons here in the US. Rob, as always, keep up the good work. Thank you for taking the time. Pleasure having you.
Robert Svatek: Thank you. Great to be here. Thank you.