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Sam Chang: Hi, my name is Sam Chang. I am at GU ASCO 2024, and we have the pleasure and honor of having Dr. Sia Daneshmand here from USC. He really requires no introduction. But we're going to talk about the ABLE-41 trial, which has actually been selected by the GU selection committee to focus on actually a trial in progress which looks at the real-world usage of nadofaragene firadenovec. Close enough? All right. So tell us about that, Sia, and thank you for being here with us.

Siamak Daneshmand: Yeah, absolutely. Sam, pleasure always speaking to you. Exciting times, first of all, for bladder cancer.

Sam Chang: Oh, absolutely.

Siamak Daneshmand: I'm super excited about this meeting and tomorrow, especially, with all the abstracts being presented. As you mentioned, this is a trial in progress. And so what this is, is basically a real-world, multi-center registry of the use of nadofaragene firadenovec in the real world. Now, basically, it'll be multi-institutions. We're looking at around 50 institutions with about 200 patients that'll be enrolled, and it's basically physician discretion of the use of nadofaragene firadenovec. And basically, we're going to track obviously outcomes, complete response rates at any time, at one year. That's the primary objective of the trial. There'll be physician surveys. There'll be patient and caregiver surveys given before the trial starts and during the follow-up periods, and then also physician surveys about a month in and at one year. So really getting a better experience of what's going to be happening in the real world now that it's been approved and in our hands.

Sam Chang: Right, right.

Siamak Daneshmand: Yeah.

Sam Chang: And so looking at patient characteristics, disease characteristics, the number of doses they receive, all those types of things.

Siamak Daneshmand: Exactly. All of that. CR rates at any time up to one year and both patient and physician experience, which is important, right, when we have a multitude of drugs that are going to be approved in the future. What is the ease of use of this? As you well know, and you were a part of the trial and you're using it now, this is easy. It's once every three months, so-

Sam Chang: I think that's obviously the attraction. And I think right now, there had been some concerns regarding access, approval, and then a period of time where it wasn't available and then a period of time where it was available for certain centers. But then more recently, there's a change in access. Is that right?

Siamak Daneshmand: Yeah, absolutely. So we had the early access program, select sites around the country. That was around November. But pretty soon, actually January 17th, I think, it became widely available. So it is now commercially available anywhere. And you and I have had experiences already within the early access program and it's been great.

Sam Chang: So currently, then, no limitations in terms of access.

Siamak Daneshmand: Right.

Sam Chang: So anyone can... And when we look at its indications, it's basically for those patients who are BCG-unresponsive with evidence of CIS at the time. And the treatment cycle, to remind folks, it's once a quarter.

Siamak Daneshmand: Exactly.

Sam Chang: I mean, it's-

Siamak Daneshmand: This is one of the first drugs, right, we've had that we do once a quarter. We're so used to doing intravesical therapies once a week for six weeks. That's our standard. This is truly once a quarter. And we're going to be looking in the future at repeat dosing. It's an immunological drug, right, so we do BCG and we repeat BCG, whether it's persistent disease.

Sam Chang: Correct.

Siamak Daneshmand: And the best thing about this study is, again, physician discretion. There are very few exclusionary criteria. So we're going to be looking at real-world data, what's happening out there with patients. Obviously, not everybody falls into the slots in-

Sam Chang: Exact criteria. Exactly.

Siamak Daneshmand: ... trial criteria, right?

Sam Chang: Exactly.

Siamak Daneshmand: So once it's approved, then we can play around with the drug and see where it fits best for patients.

Sam Chang: And to be able, then, to offer to patients... I've had conversations at different meetings and different conversations offline and cystectomy, for many of these patients, it's hard to swallow that as being the next step. You examine a bladder. You see a bladder. And there are patients that you really think should go to cystectomy, but then there are many that the disease, at least volume-wise or at least appearance-wise or at least action-wise, hasn't shown that propensity of being much worse. And so to have this alternative, I think, is an exciting time.

Siamak Daneshmand: Yeah, absolutely. You're so right. And you and I are quick to go to cystectomy if a patient requires it. Many patients have small-volume disease. They just have carcinoma in situ. It's non-muscle invasive. It's a hard pill to swallow to go from intravesical therapy to suddenly oh, you need your bladder out because you've got a small, high-grade Ta or CIS recurrence, so this is great that we have options now. And we'll take any success rate, right, for-

Sam Chang: Right. Oh, absolutely.

Siamak Daneshmand: ... these drugs because if we can save the patients from a cystectomy, then it's a real win for those patients. There are plenty of them out there.

Sam Chang: Right. And thus far... Obviously, you're involved in the trial setting. In those patients so far in the real world, as you are starting to collect the data, any signals regarding concerns about tolerability or any signals of anything at all that you've seen so far?

Siamak Daneshmand: No. So it's limited. We haven't started accruing to this registry yet. But we have had patients on nadofaragene firadenovec, and it's extremely well tolerated. Obviously, we had experience with it-

Sam Chang: Sure. Oh, during the-

Siamak Daneshmand: ... during the trial.

Sam Chang: ... during the accrual of the trial. Sure.

Siamak Daneshmand: Yeah, many, many years ago. And so it's a similar experience. It's been very easy to use, very user-friendly, and the patients so far have been doing great.

Sam Chang: Well, I think from our patients' perspective, they're definitely interested in an intravesical option because they've all had intravesical therapy. So they're familiar with that as opposed to bladder removal for sure. And then the icing on the cake is we'll give one treatment and your next treatment is three months later. And they'll be three weeks later, now three months later, and they have this feeling of really, it's going to work and it's going to keep working. And we talk a little bit about its mechanism of action and those types of things and our hope that we get longevity, like you said, with repeated treatments. I think with now increased access, we'll be able to further garner to see actually what happens real world as well.

Siamak Daneshmand: Right, right. Yeah, this is the first FDA-approved gene therapy. This is different than cytotoxic therapy that we're used to. Of course, BCG is an immune type of therapy, but this makes the urothelium a factory of interferon-producing cells. So it makes sense that-

Sam Chang: So the hope is as tumors may or may not develop, that that field effect, just like we're worried about the field effect of CIS, but if we can get the bladder basically having this response maybe for continued long periods of time... And that's why I think the registry will be important in terms of evaluating repeated doses, seeing what happens long term. I think it's really, really important.

Siamak Daneshmand: You mentioned field effect. I'm going to turn this over. I'm going to ask you a question.

Sam Chang: Yes, yes, yes. I'm looking forward to it. Bring it, bring it.

Siamak Daneshmand: Yeah, bring it. So, okay, CIS in the prostatic urethra. We always think this is an ominous finding. We do a TUR. It's limited. What do you think about using something like this in someone who has limited disease in the prostatic urethra?

Sam Chang: Already put a patient on.

Siamak Daneshmand: Yeah?

Sam Chang: Exact same scenario.

Siamak Daneshmand: I love it.

Sam Chang: Patient number two has received nadofaragene. Now, we'll see what happens, but my go-to now is... I have partners who perform HoLEP, very, very extensive dissection and you get pathologic tissue. So we do a HoLEP. In those patients that have stromal disease, something worse, we proceed. They're out of that loop. But for those that only have mucosal involvement, slight ductal involvement, that type of thing but have cored that all out, my attempt is not on any trials because they're excluded, but these patients actually, we have tried intravesical, sequential gemcitabine-docetaxel, and now I've got a patient with nadofaragene. And I do think that it's going to act... To me, this is more likely to be successful than chemotherapy exposure. You're going to need... To me, it's less likely, perhaps. But with immunotherapy, having that kind of contact and then the response within the bladder, it only makes sense to me that there'd be-

Siamak Daneshmand: Right. You're constantly voiding it out.

Sam Chang: Exactly.

Siamak Daneshmand: Absolutely. I love what you're proposing, and I like the fact that you're doing a HoLEP before to get pathological confirmation that we don't have stromal invasion.

Sam Chang: Exactly.

Siamak Daneshmand: Because our worry is always that, right?

Sam Chang: Exactly, exactly.

Siamak Daneshmand: We have intraductal.

Sam Chang: Exactly. And it's gone both ways. We found patients where we didn't think it was stromal involvement, whatever, and we found it. Then we're switching gears to neoadjuvant treatment, then bladder removal, that type of thing. So these are discussions that will happen real-world as this agent now is available.

Siamak Daneshmand: Exactly.

Sam Chang: How are we going to use it? How effective it's going to be. The jury's still out on it, totally, but at least we have that possibility. So.

Siamak Daneshmand: Exactly. No, these are the things that are limitations within trials because they have to keep it within a box. But now, you and I and people get more comfortable with expanding the use of the drug in various settings, then we can actually put them in the registry, be able to look back, and see what happened to these patients. Yeah.

Sam Chang: And that's why your ABLE-41 trial is just... You've been involved and led so many different types of evaluations of different therapeutic interventions. This is just another example of how you've led our field. And so I want to thank you not only for this time but for everything that you've contributed to the field.

Siamak Daneshmand: Thanks, Sam.

Sam Chang: Thanks for spending some time with us.

Siamak Daneshmand: Thank you so much.