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E. David Crawford: Hi, everyone. My name is E. David Crawford. I'm a professor of urology in the Department of Urology at the University of California in San Diego. Several weeks ago in my clinic, I evaluated two men who had a diagnosis of BPH but really weren't doing well. They continued to have urgency, frequency, and nocturia. I upped the dose of Tamsulosin from 0.4 to 0.8, even tried Cialis in one of the patients. I thought about anticholinergics, but I grew up in the era of side effects from anticholinergics. I know when I've tried it in a few patients, they mentioned to me the neurocognitive effects and so forth.

Just that evening, I went home and read the Journal of Urology, and the lead article in the August journal was on the COURAGE trial. It was authored by the person joining us today, Dr. David Staskin, who is an associate professor at Tufts University and was the first author on that large randomized clinical trial of over a thousand men evaluating the efficacy of a beta-3 adrenergic receptor agonist.

I invited David to share his publication with us. I know that UroToday has already previewed it, and let's talk a little bit about it. David, welcome. We share a little bit of ancestry in a way. You were at the University of California, San Diego as an intern and then a fellow at UCLA. I was a fellow at UCLA a long time ago, and I'm at UCSD now. Welcome.

David Staskin: Thank you very much.

E. David Crawford: Let's get started with you describing the trial. I think you have some slides that we can show, and we'll go through those briefly and then have some interaction.

David Staskin: It would be my pleasure, David. Thank you for inviting me today.

This is an interesting study in the 2021 BPH guidelines. It was specifically mentioned at the end of the combination pharmacologic section that with an alpha-blocker, an antimuscarinic could be used. That data was there, and you spoke about that for a moment. There's always been somewhat of a question when using antimuscarinics about dry mouth, blurry vision, constipation, some of the neurocognitive effects, et cetera. And then it also spoke about using a beta-3, and the specific statement was, "More data is necessary."

In a way, it's a "You asked for it, you got it." Here is the data. This is a very extensive study, a phase three trial called the COURAGE trial. Obviously, as urologists and as primary care physicians who may be joining also, people know that BPH certainly has both obstructive and irritative symptoms, storage symptoms. They may be alleviated, some of the obstructive symptoms, with alpha-blockers with or without a 5-ARI, which seems to also improve some of the storage symptoms. Vibegron is a selective beta-3 agonist that's been approved for overactive bladder.

What this study looked at was men greater than 45 who were receiving treatment, okay, treatment, pharmacologic treatment, for their BPH, either an alpha-blocker with or without an ARI. They had the normal OAB symptoms of frequency and urgency. We looked at an IPSS total score but specifically analyzed the storage score. It's interesting that for urologists that use the IPSS or the AUA symptom score in their office and are looking at the total score, if you're seeing irritative storage symptoms rather than obstructive symptoms, it would make sense, not just intuitively but medically, to go ahead and treat the storage symptoms. They had more than two nightly nocturia episodes. In fact, the group together in the data had an average of about 2.7.

Let's look at the disposition and the baseline characteristics. You can see the screened randomized flowchart there, which is pretty consistent with most lower urinary tract studies. You can look at the demographic characteristics. All men were treated, again with an alpha-blocker with or without an ARI. About 20% did have ARI use. If you look at the placebo and the active treatment group, they are very similar. Again, IPSS storage average of nine, which is the baseline for the analysis of response to storage symptoms. Volume voided about 166.

This is the data, and it really did show a robust... actually an early separation. The drug has a half-life, which would cause a pretty good onset of action, certainly by a week, and good separation early and by 12 weeks. A very good response both for micturitions, for urgency episodes, for nocturia episodes, IPSS storage scores, UUI episodes, and for volume voided per micturition. The first two that I showed you were the primary dual primary outcome variables, and these were the secondary outcome variables. Again, a good separation and a robust one compared to placebo for response.

People are always interested in adverse events. I think the beta-3 class, specifically Vibegron, when you look at the fact that there's no hypertension in the label, the AEs are what you might expect. Specifically, in a study like this, you look at hypertension with the beta-3 agonists. We don't expect to see it, and we didn't. The study happened during COVID, and there was no COVID effect, beneficial or not, with the Vibegron. Also, TAE is a special interest. If you really look at it, urinary retention is the one that you're keyed on here. The five is a 0.9%. The placebo had three patients with urinary retention, and as far as the other things, we're not seeing them. Urinary retention, not an issue. Elevated PVR, which I believe was five in the placebo group and seven in the active treatment group, is not a big concern.

So the patients really did well, and they experienced persistent improvement. The study watched patients for 24 weeks, even though 12 weeks was the ending, so we saw a good and persistent response in all outcome variables, including the IPSS storage score. The difference actually made a difference for the patients.

The Vibegron was well tolerated with a good safety profile, which we saw in the phase three study that had been published previously in female and male patients in 2020. And that study actually included 15% of males. But I think it was important, again, the guidelines asked for it. People are specifically interested in seeing patients so that if they come in that real-life situation where you saw them in the office, they've been treated pharmacologically for their outlet obstruction, that if they're given Vibegron, you expect to see a response for their persistent OAB symptoms.

Thank you.

E. David Crawford: Well, congratulations on that publication in that study. It's a high bar to get studies in the Journal of Urology, and this is... I must say, I've been doing randomized phase three trials for a long time. When you see Kaplan-Meier curves separate like that, you see that there's a nice distribution in both arms. The treatment arm, the placebo, and then the side effect profile being very parallel to the placebo is unbelievable.

There certainly fits an unmet need, but let's make sure we understand it. It's in men who are being treated for, in quotes, BPH and persistently have OAB-type symptoms. Is that correct?

David Staskin: Yeah, that's the way the protocol was set up to answer that specific question about pharmacologically treated because that's really the group that you see where men are receiving some type of treatment. Again, alpha-blocker alone, or in this case, 20% of the patients were also treated with an ARI.

E. David Crawford: Okay, let's just back up a little bit. I know this wasn't in a study, but we see men right out of the starting gate that have more OAB symptoms than obstructive symptoms. What's your thought about utilization there of this group of therapeutic agents?

David Staskin: Well, just to go in general, which would include antimuscarinic studies that go way back, Steve Kaplan did some of the original studies with an alpha-blocker and an antimuscarinic. When you start to look at the data, it really says that men do best, obviously, for their obstructive symptoms with treatment for their outlet. Men do very well with treatment for their OAB symptoms in combination with that.

The antimuscarinic group, a lot of the data that came out of that said if your prostate's less than 40 grams, if your flow's greater than 12, and you don't have a significant PVR... I don't think a number was taken, but let's just say 50... then these men really have a low risk of urinary retention. There is data from this study to be presented, which analyzed flow and PVR and peak detrusor pressures in a subgroup of these patients. I'm not going to go into the details of that, but the findings are not surprising that the safety and effectiveness are there, especially in this beta-3 class, and especially the other side effects that you'd like to not see with an OAB drug are not present with this drug.

Again, I think it really changes the way we do this. You may want to approach a man with no obstructive symptoms, a small prostate, and treat him for his OAB. Again, not studied here, but really intuitive and logical. Post-op patients who've actually had a procedure whose obstructive symptoms are better and have persistent irritative symptoms. The idea of using something for OAB, it opens up that horizon. In this specific trial, however, this really does answer the question, at least to a significant degree, about treating these men, again about 500 patients in each group, and getting very robust data showing an improvement.

E. David Crawford: Well, if the safety is reflected in this group also, it's a pretty well-tolerated regimen or drug to try.

Two more quick things here before we go, David. This study would add to a new indication to the FDA approval that already exists for the drug, correct?

David Staskin: The form of the trial was a phase three. I believe there have been things submitted to recognize the data in the study, but I'm not aware of any of the specific details of that.

E. David Crawford: I guess the last thing I want to ask you is, we all know that the bulk of men with BPH-like symptoms and OAB-like symptoms see their family practice doctor. How do we get this message to them?

David Staskin: I think that, again, the demographics of this group are helpful for primary care physicians who may be treating these men, and they're using alpha-blockers with or without an ARI in their practice. If they're comfortable with that and they see persistence, we won't see the elevation of the alpha-blocker doubling the dose to treat the irritative symptoms. We'll see the storage symptoms start to be treated.

I think that this can be done in the primary care office. Obviously, if there's a question and a residual urine measurement is necessary, and a flow measurement is helpful, and understanding prostate size, I think this is a good patient to see in the middle of a busy day for a urologist.

E. David Crawford: Yeah, yeah. Well, I think the safety profile of this also will be reflected in family practice about utilization without a lot of worry about retention.

David, thanks for your time. We appreciate it.

David Staskin: Thank you for inviting me.

Let me, before we close, it was a very flattering statement you made, but there are a lot of excellent co-authors on this paper. They deserve credit. A lot of really great investigative sites—50% of the patients in the United States, 50% outside of the US, and the patients themselves, who put up with these protocols and come in and do a good job of getting data for us.

E. David Crawford: Great. Thanks very much.

David Staskin: Thank you.