Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee. We are incredibly fortunate to have John Gore speak to us today about a multi-institutional trial looking at MitoGel. John is a Professor of Urology at the University of Washington. He doesn't really require any introduction, you all are all aware of him. He's also the program director of the, probably to me, one of the finest urological oncology fellowship programs in the country and he's done a wonderful job leading that. John, thanks so much for spending some time with us. I think you've got a few slides to kind of go over some of these important findings.

John Gore: Yeah. Thank you so much for having me, Sam, it's always great to talk with you and great to catch up. I have a couple slides I'll share just to go over some of the data that shows some of the updated effectiveness of UGN-101 MitoGel or Jelmyto in treating low grade upper urinary tract urothelial carcinoma. Just a quick reminder on the inclusions for this study. This was a multi-center study that involved numerous sites. These were for small, low grade tumors of the renal pelvis. They could be treated but there had to be a residual tumor of five millimeters or more so five to 15 millimeters of residual tumor in the renal pelvis. Going back to the original data, which was published in Lancet Oncology a couple years ago, of the 71 evaluable patients, 42 or 59% had a complete response at the three month evaluation.

Really the objective of this updated analysis was looking at the durability or 12 month effectiveness of patients that had a complete response to MitoGel. What did we find? Well, we found that of those 71 patients 56% still had a complete response after 12 months, which is a durability of about 82%. This is a small trial because this is a rare cancer but it's a pretty impressive durability. One of the adverse events that's generated some buzz, looking at both the original article and the follow-up article, is the 44% rate of ureteral stenosis, which was the most frequently reported adverse event in the study. This is a Kaplan Meier curve that I love just because it shows a really nice flat line, indicative of the pretty impressive durability of response among those who did have a complete response at the three month evaluation.

But again, just putting some numbers on all the various adverse events that were outlined in this study, the most notable one is this ureteric stenosis. What's notable about this is this table stratifies patients who basically only got induction UGN-101 compared with those patients that got induction plus at least one maintenance treatment. There appears to be a fairly substantial difference in the risk of ureteric stenosis, with a much higher risk among those that got at least one maintenance dose, so it does appear that the more doses you get the higher that risk of a ureteral stenosis.

What are we learning as we accrue more experience with using Jelmyto or UGN-101? Katie Murray and her team demonstrated in a small sample size study that it's possible by going away from the retrograde installation that most of us used for the majority of patients in the study, to antegrade installation, that maybe, just maybe, that's associated with a lower rate of ureteric stenosis. Among the eight patients she treated, the CR rate was 50%, which is pretty evocative of the trial results, but she only found ureteral strictures in one out of eight and it was a very manageable ureteral stricture, so encouraging that maybe a different installation technique might be associated with lower rates of ureteral stenosis.

Sam Chang: That is fantastic. A couple things to kind of touch base on. I am impressed with that tale, with that durability that you pointed out that basically greater than 50% responded a year and then the vast majority really maintained that. Obviously, I'm concerned about the stenosis rate with maintenance. Do you know the breakdown in terms of induction versus maintenance in terms of how they did with that tale? Did you have to have maintenance to maintain that length of durability or no?

John Gore: No, It appears that actually the patients that only got induction had a fairly similar CR and durable CR rate as the patients that got maintenance. One of the conclusions of our paper, the Journal of Urology paper, is that we're really in this position where we're kind of following bladder based treatments for induction and maintenance but maybe, just maybe, maintenance is not as necessary for these low grade upper urinary tract tumors.

Sam Chang: Especially with the rationale behind increasing the length of time and exposure and getting that effect, have you put the nail in the coffin then for maintenance? John, what do you think? I don't want to put you on the spot here but ...

John Gore: You can put me on the spot anytime. I do think that ... This is something that's being studied. I think that as we accrue more experience with this novel way to get chemo into the upper urinary tract, dose optimization is going to be really important. Part of me wonders, from my own experience with the patients that I put on the study, if even a post-ureteroscopic ablation installation of a single dose of Jelmyto might have similar benefits as serial induction treatments and might have a better safety profile in terms of limiting the occurrence of ureteric stenosis. That might be a more extreme under-dosing but I think, at minimum, in my own patients I advocate induction and a deferral of maintenance if they're complete responders.

Sam Chang: I think the idea that you just brought up is an incredibly, to me, kind of an exciting idea for study, for sure, in terms of obviating the need for obviously the outpatient either the ureteral catheterization treatments or even the antegrade installations. Avoiding the need for a percutaneous tube for that antegrade installation and then treating, where do you see then ... You talked about optimization, dose optimization. For you, based upon Dr. Murray's small study, small, understood, but appears promising. To be honest, I'm slanted a little bit because our institution, that's how we're doing it. Dr. Luckenbaugh and Dr. Scarpato are treating in an antegrade fashion. Patients are loving it, tolerating it. Our small numbers, great early responses. It's done in the clinic. It's gone great. As you start doing more of these clinically, what is your go to or what will be your go to, what do you think?

John Gore: In our practice, our team of providers ... You mentioned the different providers you work with. Our team of providers has bias toward antegrade installation in part, frankly, because of the ergonomics. On the study, I did all of these in our back urodynamic suite using a C arm, a flexible cystoscope, a glide wire, and then the installation ureteral catheter that comes in the kit. It worked fine. I had zero failures to instill so we were able to get everyone their doses, but that's a lot of rigamarole. If you think about the democratization of access to new technologies and new things, not everyone has a C arm in their clinic and you don't want to put these patients to sleep just to instill Jelmyto in their upper urinary tract. I think it's possible, if the safety profile is better, clearly the administration technicalities is better with nephrostomy based installation and that has also become our default.

Sam Chang: John, where next? Where do you think Jelmyto needs to be either evaluated or improved upon for patients with uro .... Obviously, I think they're looking at lower tract within the bladder but where do you find the next step in terms of research endeavors are most exciting for you?

John Gore: I think two big areas. One is as we discussed, dose optimization. We think about induction and maintenance extrapolating lower urinary tract data, but in the lower urinary tract we don't typically give induction and maintenance for low grade tumors. We typically give post DURBT installation and that's it so I think dose optimization is one key area. Then, clearly a huge need is high grade tumors, small high grade tumors. I, unfortunately, have not found as many Jelmyto candidates in my practice because it turns out small, low grade tumors in the upper urinary tract, gosh, that's this sort of unicorn patient that's lucky enough to be a candidate for these ablative and installational combination therapies. And so, I think trying to figure out how well this might work in high grade patients would be really fantastic and of huge benefit to our patients.

Sam Chang: Well, John, I do not know or understand why this is the first time we've had a chance to get together and talk in this way. I promise you that we'll have more conversations like this because I think your insight and your honesty is absolutely refreshing and I think everyone really appreciates it. I thank you personally for the time that you were able to put and spend together with us and thank you again for everything, John, appreciate all that you do.

John Gore: Anytime you ask, I'll come running, Dr. Chang.

Sam Chang: Great. All right, thanks, John.