Diane Newman: Welcome to UroToday's Bladder Health Center of Excellence. I'm Diane Newman, a nurse practitioner, and I'm the center's editor. I'm very pleased today to introduce you to a colleague of mine, Dr. Ken Peters, who's a Professor and Chair of Urology at the Oakland University William Beaumont School of Medicine. He's also Chief of Urology at Beaumont Royal Oak, which is in Michigan.

So, I heard Ken speak at the AUA and at the ICS on this really exciting new kind of therapy for overactive bladder, so I asked him to come today and talk to us a little bit about this novel gene therapy. So he's going to give his presentation on efficacy and safety of a novel gene therapy in female patients with overactive bladder and urge urinary incontinence, and these are actually results from a Phase 2A trial. So thank you so much, Ken, for presenting this to us.

Ken Peters: Thanks, Diane. It's great seeing you and I'm looking forward to talking about this topic. I think it's very exciting potential technology here for the future of management of these tough patients. So thank you very much for allowing me to talk about the efficacy and safety of this novel gene therapy in female patients with overactive bladder. I'm presenting this on behalf of my co-investigators that you can see here. This study is supported by Urovant, and it is a 12-week outcome of this study analysis. Just for disclosure's sake, you can see the disclosures listed here.

URO-902 is an investigational gene therapy for overactive bladder, and it's a very unique and interesting gene therapy. It is in a plasmid vector, so it's not a viral gene therapy. And this vector expresses the alpha subunit of the human BK channel, which is a large conductance calcium-activated potassium channel, and these potassium channels reduce bladder overactivity and basically lead to detrusor relaxation.

This compound is injected into the detrusor similar to botulinum toxin. It's done directly into the detrusor under some local anesthetic in the office, and the intent of it is or the hope is that it increases these large potassium channels as its mechanism of action.

As far as background, there was a small study completed. It was a Phase 1 trial, and it was in women using this compound and it showed a significant reduction in urgency episodes and daily voids, and there was no serious side effects, but again, it was a very small study with only a few patients in it. So the concept behind this and the mechanism of action behind this and the little bit of data that there were in humans is what really led to this placebo-controlled trial that I'm going to talk about here.

And what I am presenting, again, is what I stated. This is a pre-specified 12-week analysis of a 48-week multicenter, randomized double-blind placebo-controlled trial. Patients got a single treatment or a single dose of URO-902, and it was done in two different phases. The beginning of the study, we used a 24 milligram dose, and then after six weeks of the initial enrollment, a data safety monitoring board evaluated this and gave us the okay to then increase this to a 48 milligram dose in the active-treated group compared to just a placebo, which was saline that was injected in a similar fashion.

The study participants, they had to be women between 40 and 70. Your typical OAB population. These are women who have urgency frequency, but they had to have urgency incontinence to be part of this study too, and they were not adequately managed on oral OAB drugs. This is an exploratory study. It was more around safety and less about efficacy, so safety was our primary, looking at adverse events, post void residuals. And then we were doing an exploratory analysis from change from baseline and changes in daily micturitions, urgency episodes, incontinent episodes and quality of life. Again, this study was not powered to have the efficacy data being appropriate. This is more of a early study to say should we move forward into a bigger randomized controlled trial?

The other thing I just wanted to show in this slide is this is the Cohort 1, the top, which was the 24 milligram, and then at week six you could see Cohort 2 came aboard. Patients were stratified to either if they had less than or equal to three incontinent episodes per day or greater than three between active treatment and placebo, and then they were stratified in that second cohort of whether they had previously received Botox or not.

This is the patient population. It's kind of what you would expect in OAB. You can see the average age was around 65 or so. You could see it broken down between less than 65 and greater than 65, and it's what you would expect in an OAB population. It's people more in their 50s and 60s who are involved in these clinical trials. Urge incontinent episodes, you can see that the majority of patients in the study had more than greater than three episodes per day, and you can also see that the majority of patients in the study were not exposed to Botox in the past, and this is broken down between each of the doses and the placebo on the slide you're looking at. There was urodynamics done and whether they had detrusor overactivity or not, and you can see that the presence of detrusor overactivity, it was around 50% in the 48 milligram arm. For some reason that one happened to be 73%, but it was just one more data point to look at as we looked at outcomes of this trial.

In the end, this injection was done and then patients were followed now at 12 weeks. This is looking at the 12-week data, and this change of micturitions from baseline to the 12 weeks. You can see that this was a dose-dependent change and that the dark blue line at the bottom was the higher dose, the 48 milligram dose, and you can see that it had the most significant reduction in mitruitions per day. Next to that was the 24 milligram dose and then you could see placebo. We were excited to see this because it seems to be aligning with what we were hoping we would find in this trial. The dose is a relatively arbitrary dose. We may have not found the maximum efficacy dose for this clinical trial.

Looking at urgency episodes per day, so this is basically voids that are associated with significant urgency. This you can see in a very similar fashion that you had a greater reduction in urgency episodes per day in the higher dose, and then you can see compared to placebo up top. But you do also see with the 24 milligram dose that there is a greater reduction of urgency episodes compared to placebo. So it's nice seeing a dose-dependent change. It's nice seeing that this change seems to be consistent over time, and I think the one thing that I take away from this a little bit is it doesn't look like we've peaked. In other words, the slope is still downward, and so longer follow up is going to be important to see what happens then from that 12 weeks onward.

The next slide, this is just is looking at urgency incontinent episodes per day. This was less impressive for sure. You see an overall reduction in urgency incontinence, but you don't necessarily see a big separation between the placebo and the active-treated group. You could argue there's a lot of reasons for this and this is only 12 weeks and where this efficacy really started, it isn't clear, and you can see that we still have a downward slope, so this could change over time. But I think everything is at least going in the right direction even though they're not as separated in this as we saw in the micturitions and the urgency episodes.

This is ... for people who are bar graph people, which I kind of like this a little better. It's just putting it there on paper here. Micturitions, you can see the dark blue is the higher 48 milligram dose. Urgency episodes, again, you see this nice downward trend. Urge incontinent episodes, you see the trend, but nothing reached statistical significance at 12 weeks.

The next slide is looking at OAB-q and the symptom bother score, and in this, a reduction in the score is an improvement. You can see that we saw a significant reduction in both the 24 and the 48 milligram dose on the OAB-q symptom bother score where the reduction was not as profound in the placebo group. And then as a clinician for me, the PGI-C, which is Patient Global Improvement of Change, and what we looked at as being meaningful was somebody who said that they were moderately or much better.

So we took out the people who just said slightly better, and what we found is that the patients who said they were moderately or much better, again, it's a dose dependent where you could see placebo was about 30%. You have the 24 milligram around 41% and then 48 milligrams around 58%. So again, from a clinician standpoint, this is what we care about. It isn't like, "Well, how many less voids do you have a day?" It's like, "Is the patient happy?" And I think that's what this reflects. And again, in a bar graph form, you can just see percent of patients who said they were moderately better or much better on this questionnaire.

So everything is tracking in the way we would like it to track from an efficacy standpoint, and I think we'll learn more as the data matures and ultimately, hopefully future studies are done, but the important part of this study was looking at adverse events since this is a very novel therapy to be used in humans, and really we have very few adverse events. A couple things I just want to point out. One is we always worry about urinary retention when we use things like botulinum toxin. We had one patient develop urinary retention that was residual volume greater than 350 CCs. This resolved spontaneously by week six. They did not need to catheterize. They really weren't bothered by it. It was just picked up on their routine evaluation.

And then urinary tract infections I guess would be the other thing I would point out because we know with botulinum toxin those are more common, and you can see that there was none in the 24 milligram dose and there were four in the 48 milligrams and one in the placebo. So overall there was no serious adverse events. There was really nothing else from a AE standpoint that really rose to any level of concern, and actually I felt overall it seemed to be a very safe treatment.

So just to conclude, this is a pre-specified 12-week analysis of a Phase 2a trial for OAB using URO-902 at the 24 and 48 milligram dose compared to placebo, and I think what we can say at least is that it seems to be associated with clinically relevant improvement in efficacy and that it was a very well-tolerated treatment for this patient population. This study continues in long-term follow up. The 48-week study, hopefully it'll be out soon and presented in the future. So, I guess I'll stop there and we can chat about it further.

Diane Newman: Yeah, thanks so much, Ken. That was really, really a nice overview of this. Let me ask you though, so it's injected in the detrusor muscle. Do you mix it with something and how much of an injection is it?

Ken Peters: So it's mixed in a vehicle, so it is very reminiscent of botulinum toxin. So it's the same volume and it's the half CC injection in 20 different sites for a volume 10 CCs.

Diane Newman: I see. And I see you did include individuals who had gotten Botox initially before this. You didn't see any difference. I know these numbers are small though.

Ken Peters: So that really hasn't been looked at yet. There was nothing at least in the cohort that was grouped together in the final database. As we sort through this, we'll separate out, see if it was different in those who had been exposed to it or not. But we thought it was important to include both subsets of patients because certainly if someone's had botulinum toxin, if they were doing great with it, they probably wouldn't be looking for a clinical trial to be part of, and so I think it would give us some real world experience of what we would expect clinically as we manage our patients.

Diane Newman: Well, I think it was nice to see your retention was really low. And again, I'm sure we have to see larger numbers. Now, are you going to go into Phase 3 now? Is that going to be the next step for this?

Ken Peters: So this is all in the hands of the company still. The 48-week study data has not been made public yet. I would anticipate that if the data tracks similar to this and over time it remains safe and efficacious, even if it starts to wear off over time like we see with botulinum toxin, I would suspect that they would be looking at doing a Phase 3 study. But I think this first quarter of this year, hopefully we'll have all that and we'll know more and see what the direction is.

Diane Newman: I agree with you because it does have a lot of positives. If this is effective, it doesn't have the toxin issue as we see with Botox, and then also hopefully that you're going to have less issues with retention and complete bladder emptying with this kind of agent as opposed to what we have with Botox.

Ken Peters: I think that would be the great thing, if it could be safer and as efficacious or more. And what I still wonder, since it is a gene therapy, will it last longer because of the integration and the change in the potassium channels. And again, you and I can sit here and speculate it, but at the end, the data's going to tell us that. It's like, stay tuned.

Diane Newman: I know, and you and I have been in other studies where we really thought those initial Phase 2 really showed us something and it didn't pan out, so you're right; we need more research on this, but I think it's exciting that what they have here is another possibility with overactive bladder, a different way to deliver it, which again, if it's maybe once a year or whatever, I think is going to be fine. This seems like it's a fairly safe procedure for injection. So thanks so much, Ken.

Ken Peters: Thank you.

Diane Newman: I really appreciate you sharing this. I think this is really going to be helpful and informative.