Sam Chang: Hello everyone, my name is Sam Chang. I'm a urologist in Nashville at Vanderbilt University, and I have the great honor and privilege actually to have, as a guest, Dr. Seth Lerner. Seth is the Beth and Dave Swalm Chair of Urologic Oncology and a professor in the Scott Department of Urology at Baylor College of Medicine. But honestly, he doesn't need any introduction, the amount he's contributed, I think most recently with the work on the Cancer Genome Atlas and others, have really separated Seth as a true scientific thought leader. And importantly, he remains a clinician.

Today he's actually going to be giving his AUA presentation, looking at actually a new treatment alternative, and perhaps a game-changing alternative, for patients with upper tract urothelial carcinoma. So I'm going to turn it over to Dr. Lerner. Seth, thank you again for giving us time and for educating us today.

Seth Lerner: Thanks, Sam. Always a pleasure. Thanks again. This is really exciting to get to present these data on a Phase III trial with primary chemoablation of the treatment for low-grade upper urinary tract carcinoma that was dubbed the OLYMPUS trial. This was sponsored by UroGen, and I do have a financial conflict of interest as I've done some consulting for them and I'm the scientific PI of the trial. And quite frankly, we've been working along with several other people on the design of this, so it's exciting to see this come to fruition.

So the idea is that even though, if you look at all of cancers, low-grade urothelial carcinoma is a rare disease, and it does have sort of limited options. Despite the fact that we can get up to the urinary tract with state-of-the-art flexible ureteroscopy and see, and often times we can biopsy, and often times we can ablate, when patients have multi-focal tumors or large volume or recurrent tumors or tumors that are in difficult to reach places, such as the lower pole of the kidney, we have limited options and often times these patients end up requiring a nephroureterectomy. We can do intracavitary chemotherapy by putting a catheter up and instilling chemotherapy or immunotherapy, but the problem of course is it doesn't stay there, and therefore it's not as effective, as we know, as occurs in the bladder.

Using the product that we used in this trial, we treated about 20, 22 patients on a compassionate use protocol, and that data is published in Bladder Cancer Journal last year. And it really set the stage for the clinical trial.

So a little bit about the chemistry. Those of you who had an experience with BackStop®, which was a thermal reversible gel that kind of keeps stones from migrating up the proximal ureter while we were doing lithotripsy, this is the same principle. So it's a block co-polymer of PEO-PPO-PEO and the mitomycin is add mixed with this. And so at cold temperatures, you can see there on the figure on the top left, it's a viscous liquid that can be injected through a ureteral catheter and at body temperature, it forms a semi-solid gel with the mitomycin that sticks around for about four to six hours. So that solves the problem of drug retention and it gives the patient a much longer exposure to a chemotherapy drug that we know works in low-grade urothelial cancer.

These are just some of the tools of the trade. You'll recognize this device here, it's almost identical to the balloon dilator that we use for percutaneous procedures. And we can use actually anywhere from a 5 French to a 7 French catheter, the advantage of the 7, it goes in a little easier, but you can use smaller catheters. We have a pharmacist who mixes the gel and the mitomycin, so it comes to us in a cold box on ice and therefore it stays viscous.

And so what we do is we scope the patient in the clinic, at least what we did for my patients, put a ureteral catheter up over a wire, verify the position in the renal pelvis, check the volume, which was often done during the operative procedure, and then instill the UGN-101, or what it's now called Jelmyto™, and then pull the catheter out. And that's the end of that treatment for that week.

This is the study design. So we enrolled 74 patients. There were 71 that received at least one instillation. They were scheduled to get weekly instillations times six, mimicking exactly what we do in the bladder. The primary disease evaluation was six weeks later, following the last administration, and the primary endpoint was complete response defined by visibly no visible tumor, negative cytology, and if there was a visible abnormality, required to be biopsied and that biopsy had to be negative. And then for the patients that had a complete response, they could go on to get maintenance treatments once a month and then continuing their ureteroscopy evaluation at three-month intervals out to 12 months.

And this is just what I've just said in text form. And using the same strategy that we use with intravesical mitomycin C, we alkalinize the urine by giving them bicarbonate the night before the morning of. And then the concentration of the gel was four milligrams per cc, and up to a volume of 15 ccs for the max amount of chemotherapy of 60 milligrams. Some of the doctors did the center anesthesia, some of that was logistics that they may not have had fluoro capability within their office.

And the study was powered to show a 90% power to demonstrate that the observed complete response rate was better than 15%. Now you might look at that and go, "Well, that's not very good," but you have to keep in mind that these patients often don't have another alternative other than nephrectomy. So the FDA set the bar very low and you'll see in just a minute, we really exceeded that in spades.

Patients could have no history of high-grade disease, and they have to have at least one low-grade tumor that was left in place. So this is a different strategy. We use the term chemoablation and that tumor had to be between five millimeters and 15 millimeters in size. They could have other tumors, but this was the target lesion. And you could cytoreduce with laser in order to get down to that particular [inaudible], say if you had a tumor that was two and a half or three centimeters. And these were only renal pelvis, so we did not treat any patients with proximal renal pelvis infundibular calyceal system.

As I said, no prior BCG in the last six months, no history of high-grade disease, no current therapy, no current systemic chemotherapy, and no untreated urothelial carcinoma outside the target lesion. And obviously the mechanical aspects of access to the upper urinary tract.

This is the CONSORT diagram. We screened about 110 patients, enrolled 74. Seventy-one had at least one treatment. Ten patients did not complete the six-week induction course, leaving 61. But of those 71, 42 had a complete response at the primary disease evaluation. One patient withdrew consent from the trial and the rest of them entered into the follow-up. We have now published this in Lancet Oncology at the end of last month.

So those that achieved a complete response and were eligible to receive maintenance, 29 out of those 41 received at least one dose, and six patients are still in their maintenance therapy. So the durability is we're calling this an interim analysis, and so we'll report the full durability evaluation in all patients at 12 months in a separate publication.

An expected mix of gender. These are typically older patients. I think one of the things to remember that's really important is about half the patients had multiple tumors at baseline and about half of them had what we would call unresectable or unreachable, and that would usually be lower pole tumors.

This is the outcome data. And it's really important just to focus on the complete response, that was 59%. There were about 11% of patients who had a partial response, they may have derived some benefit. And that complete response rate is the same for resectable versus unresectable. So if you think about it, the patients that had unresectable disease, let's say you can't get to the lower pole of the kidney, this gel gets all over the kidney. So each of those areas are treated and the response rate was just as good in those patients as in the ones that were deemed resectable, but intentionally had a tumor left behind.

This is a Kaplan-Meier plot, which estimates, probably overestimates, the 12-month durability because not all the patients have been followed that long, but it does give you a sense that not only is the treatment effective, but with maintenance therapy, it can be maintained and they can retain their kidneys.

Sam asked me to talk about adverse events and this is the list here. And what I want to call your attention to is ureteric stenosis hydronephrosis. I think we did see an excess number of these events beyond what would be expected, part of it is repeated instrumentation, we know that that can injure the urothelium, but it could be too that mitomycin gets submucosal and causes some degree of edema, inflammation, potentially scarring. We're putting together a protocol to use steroids in this setting when it's appropriate because some of the PIs had success with that. I think the rest of the adverse events are pretty much what you would expect. Three patients died, none of them were treatment-related, however.

So in conclusion, this single-arm Phase III trial has demonstrated for patients with low-grade upper urinary tract urothelial cancer that initial response rate of 59%. The FDA has approved this and it will be available, we think, to practicing urologists sometime early June. It was equally effective in resectable and unresectable disease and we'll have more to say about the durability.

And I just want to thank all the patients, families, and caregivers, and especially this amazing group of investigators that were deeply committed to the success of this trial. Thanks very much.

Sam Chang: Seth, thank you so much for that presentation. This is actually something that we've attempted to do with chemotherapy agents, but in, as you know, unsuccessful ways, either retrograde instillation in the bladder or antegrade through nephrostomy tubes. But the mechanism of action makes this medication really obviously unique and the results, I think, clearly set up a treatment alternative for these patients.

So a couple of questions to ask you about, you mentioned the adverse events, I guess one of the questions regarding that is how do patients actually tolerate it? You mentioned giving it actually in the clinic, there's a listing regarding flank pain, but you're able to do that actually in the office, can they be fully active within a few hours? Are they uncomfortable for a while? Tell me about the nitty-gritty regarding that.

Seth Lerner: So one of the things that I'm really fascinated by is there's a learning curve to this. When we first started doing this with the compassionate use patients, someone from the company would come oftentimes for multiple instillations, but certainly for the first couple, to sort of help us get through the learning curve.

I have to give a shout out to Karim Chamie because Karim and many of you know at UCLA, had really sort of pushed through the idea of administering this through ureteral catheter. I think most of us when we've done intracavitary therapy it's been through a percutaneous nephrostomy tube, so to Karim's credit, a lot of us learned how to do this quite successfully and in the clinic. Now our set up, like many, is obviously we do offer cystoscopy, but we also have fluoroscopy because we do all of our urodynamics.

In terms of tolerance, obviously some patients tolerate this kind of manipulation differently, better than others. I didn't have any problem with the patients that I treated and they actually seemed to prefer the weekly cysto, put a catheter up, administer the drug, take the catheter out, come back in a week, rather than having a nephrostomy tube in. But the FDA approval allows for nephrostomy tubes and so if a patient and urologists prefer that, that's perfectly fine.

Look, when you're filling the renal pelvis, you have to be talking to the patient about flank pain. What we do during the ureteroscopy, for the most part, is we put contrast up there, kind of get an assessment of the volume, repeat that three times, take the average. If we're doing that under anesthesia and then doing it in the clinic, we might have to modify that a little bit. But I think beyond that, that initial pain really was very well tolerated.

Sam Chang: Do the treatments get more difficult to tolerate or in fact, patients get used to it and are perhaps less leery of actually the process going on? I was wondering as maintenance goes out if it becomes more difficult or about the same?

Seth Lerner: That's a good question. I don't know that I can answer that from a data-driven standpoint, but you may have noticed that some patients who had a complete response, did not go into the maintenance therapy. Question is, why didn't they do that? Because they had a drug that worked. I'm sorry, I just don't know the answer to this, but I think it's worth digging into a little deeper. Maybe they perceived the inconvenience and some pain and discomfort from the weekly instillations. It's pretty clear that in a patient who may have had a problem with ureteric stenosis, had a stint in, the doctor may have decided not to pursue that further with the monthly instillations.

You know, people get tired of repeated instrumentation, but I think in general, the patients were up for this because they were saving their kidney.

Sam Chang: Right. You said that longterm follow-up is coming. So that was one of the key questions, and I don't want you to venture guesses on the data as it accumulates, but let's take, and perhaps you know the answer to this, let's take the other side of, okay, these are low-grade tumors, these are nuisance tumors. What happened to the patients that dropped out that didn't get treatment, didn't complete the therapy, dropped out, how have they done? Are they symptomatic, have they lost their kidneys, what's been going on with those patients?

Seth Lerner: So unfortunately we did not collect subsequent treatments and subsequent outcomes. There were a number of patients, I forget the number off the top of my head, that had a nephrectomy and at least a couple of those were completely free of disease. Those nephrectomies were often due to, obviously, they could have been due to recurrence of their cancer, but at least a handful of those were due to these recalcitrant strictures, and simply couldn't be managed anymore. But I think that those are two pieces of data, which, to the extent that we have the information, should be reported. It's in the FDA submission if you want to pick through the weeds there.

Sam Chang: Right. So two more questions as we finish up, Seth, one would be, we've got an exciting FDA approval, during now who would have expected it to come out during this time period, what's going to happen next? You mentioned a learning curve, you mentioned this is new techniques, that type of thing, and I know it's impossible to predict, but what is going to happen next? How is this going to get out and available to patients?

Seth Lerner: Yeah. So the company has indicated that they'll be ready to, so to speak, sell the product and support the product in June, which is obviously not too far away. They have a lot of support around the cost of the medication, [inaudible], things like that. They don't want this to be a financial burden to the patients. I think I saw, and if I've got this wrong I apologize to UroGen, but I think it's about $1,300 a treatment, which is not really terribly outrageous, at least that's my opinion.

And they have a lot of support. So for instance, all the investigators, myself included, we're very happy to guide urologists through their first bit of this. Obviously we can't do that in person right now, but there'll be a lot of support. And actually I'm quite impressed with what they've put together to roll this out. So everything from, how do I charge for it, reimbursement, to the actual mechanics of giving it. I think there'll be a lot of support.

Sam Chang: Well that's fantastic to hear because then that leads then to the next question, with this pharmacologic now alteration of medication, what next? What's going to happen next? What are your thoughts regarding that?

Seth Lerner: Well, the company, I believe, is properly focused on the same approach to the lower urinary tract cancers. And so they've done a Phase II trial that was in Europe that showed a nice dose-response relationship up to 80 milligrams, I think, dose and they're getting ready to launch a Phase III trial. Same strategy, chemoablation, low-grade disease in the bladder. I think the opportunities and the need are for high-grade disease, right? It's the same situation and with a much higher risk to the patient, can different drugs be formulated with this gel? I think all of those things are on the table. The company, as you might expect, is focused on the rollout of this compound in the upper urinary tract, developing in the lower urinary tract. They do have some other compounds that could potentially be applied to high-grade disease, so I think stay tuned.

Sam Chang: Fantastic. Well, Seth, I want to thank you again for spending time with us today to really give us insight into a treatment alternative that has never been available for upper tract disease. A disease that really hasn't had much attention, but increasingly has become recognized as something that perhaps we can treat in a better way. And so thanks again for the review and insight, and we look forward to seeing the longterm data as well. Thanks again.

Seth Lerner: Thanks.