Tom Keane: Good afternoon, everybody. This is Tom Keane coming to you from UroToday. In these COVID times, it's been a while since I've had an opportunity to address you, and today we have a real treat. Eric Rovner has been a member of the faculty at the Medical University of South Carolina for over 15 years. He is a great personal friend. He is a professor of urology who works with me on a daily basis. I'm a cancer guy, as you know. Eric is probably one of the preeminent people in female urology, overactive bladder, diverticulectomy in females, et cetera. And I've asked him if he wouldn't mind actually giving a short talk on what is new in overactive bladder treatment. I think you're going to really enjoy this and, Eric, you are very welcome and thank you for doing this talk.

Eric Rovner:  Well, thank you, Tom. I appreciate the opportunity. What I'd like to do is talk a little bit about what's new in overactive bladder. It has been an interesting few years, as you know. For a long time, we didn't have very much in the way of developments after some pharmaceutical changes and the development of beta 3 agonists a few years ago, but now we've got all sorts of new drugs and technologies that are either in the pipeline or have just completed the pipeline. And what I'd like to do is talk to you about some of the more interesting interventions that are either present or will be coming shortly.

As you know, there are multiple treatments for overactive bladder. Currently, we use behavioral therapies, pharmacological therapies, and office-based therapies such as percutaneous tibial nerve stimulation and a variety of surgeries such as Botox or chemodenervation and even sacral neuromodulation. There have been some advances, really, in both office-based treatments, pharmacologic treatments, and surgery and that is really what I want to concentrate on over the next few minutes.

So what's new? Well, we've had several new drugs come out, especially in the space of beta 3 agonists, but there are some other interesting compounds as well, and some of these are pretty close. And then there is a whole host of new technology, some emerging new technologies specific to sacral neuromodulation. There is some new competition there with respect to tibial nerve stimulation that not only do we have new implantable tibial nerve stimulators that are near approval from a regulatory perspective, but we also have some really interesting developments in the world of chemodenervation specific to Botox, which is a different delivery mechanism for Botox, and then a host of other things that are somewhat interesting technology.

What I'd like to talk about first is actually some developments in the world of pharmacotherapy, drug therapy for overactive bladder. As you know, antimuscarinics really ruled the world for decades until beta 3 agonists came along. Although it appears that the efficacy for both beta 3s and antimuscarinics are pretty similar, there are obviously problems with both of these compounds, not the least of which is the limited efficacy. Although the efficacy is okay, it's certainly not optimal, the cure rates are not especially high, and of course, the well-documented claims of adverse events from antimuscarinics such as dry mouth and constipation still dog this class of drugs.

And finally, most recently over the last few years, claims of ongoing dementia related to the chronic use of antimuscarinics have really rocked some people's practices and our patients are now coming and talking about the risks of dementia with chronic antimuscarinics.

With respect to beta 3s, there are risks of hypertension and drug/drug interactions in collective patients, although generally they're tolerated very well. There have been some new papers come out over the last few years about combination therapy with respect to the efficacy of combining antimuscarinics and beta 3s, but we are still limited to some degree in efficacy there, as well as individual side effects from that combination. Nevertheless, efficacy does improve when you combine drugs.

With respect to beta 3 agonists, there are a couple of new drugs in the pipeline. Most notably vibegron. Vibegron is a drug that has completed phase three trials. It's the closest to getting approval and probably will be through the FDA in December or January of this year. Solabegron is a drug that is a little bit further behind. They've completed phase two studies, but have not been published. And then there is a drug called ritobegron, which is a drug that was developed in Japan which did not make its initial phase three primary endpoint of frequency but it is still in development. And then finally, there's an interesting drug called THVD-210, which is a combination of pilocarpine and tolterodine as a combination pill, which at first glance seems rather attractive because tolterodine is an antimuscarinic better known as Detrol. It does still have a side effect of some dry mouth, and pilocarpine is a sialogogue, which is a drug that improves salvation. So if you combine a drug that may have a side effect of dry mouth with a drug that produces saliva, you may have a solution for that dry mouth problem. And that drug is still in phase two.

I just want to talk about vibegron for a moment. It was a drug originally developed by Merck and then sold or acquired by Urovant. It is a once-daily beta 3 agonist and it is being investigated at a single 75 mg dose. The drug is purported to have a faster onset than mirabegron, although they have never been compared head to head. And again, phase 3 studies have been completed showing a promising 41% dry rate in a 52-week extension study. That's a 41% dry rate, it is pretty impressive. And decreases in urgency, urgent continence frequency, and increase in volume voided. All very promising for this drug.

Even more promising is that the drug/drug interactions in their studies are minimal. It does not inhibit the CYP2D6 pathway. There are obviously no unwanted antimuscarinics side effects. And so far there does not appear to be a hypertension warning as opposed to mirabegron, but we will have to see once the FDA gets through all of the phase three studies.

So that's sort of what is new on the pharmacology front. As many of us who practice in this field know, there have been some exciting refinements to sacral neuromodulation over the last six to 12 months. Medtronics, who produces the Interstim device, after 20 plus years finally came out with an MRI compatible implant. This is really a boon for those patients who are reluctant to pursue this therapy because of the possibility of needing an MRI in the future. This allows such individuals to get implanted. And also Medtronics' Interstim has a rechargeable implant, IPG, implantable pulse generator now, and this would perhaps improve the overall lifespan of the IPG, requiring fewer re-implants for battery issues over the lifetime of the device. And Interstim has also spent some time coming up with very standard ways of doing their therapy in terms of implant technique including some best practices, looking at the optimal location within the foramen to place the needle and the lead as well as some optimal therapy standardizations with respect to programming and follow up.

In the same vein with sacral neuromodulation, there's finally a competitor on the market. After 20 years, Medtronics has a competitor. This is really exciting in the field. Axonics has come out with a sacral neuromodulation implant, which is placed very similarly surgically to the Interstim device. The initial data at two years looks excellent. It looks even superior to the initial Interstim data. However, there has been no head to head studies between the Axonics device and the Medtronics device, but nevertheless, their programming platform appears very simple to understand from a patient perspective and from a practitioner perspective. They also have an MRI compatible device and they also have a rechargeable IPG.

These are very exciting developments in this field. I think this allows this technology to be expanded to a much broader audience going forward.  So we look forward to more studies from the Axonics folks, as well as studies on the newer Interstim implantables. And again, all of these devices are currently commercially available for implant in the United States.

PTNS, percutaneous tibial nerve stimulation, has been around in the U.S. for a decade or more. The new player on the market is the NURO device by Medtronics, but essentially it's the same technology as the precursor device, which is the Urgent PC from Cogentix. These devices have demonstrated superior efficacy to drug therapy with a reduction of OAB symptoms. However, there are significant limitations to PTNS, and this is most notably that the patients need to come to our office every week for 12 weeks for the initial course of therapy, and then they need maintenance therapy going forward every few months to maintain the effect. And finally, it does involve a needle in the leg in order to properly deliver the energy for the percutaneous tibial nerve stimulation.

So there has been a lot of refinements in this area that are coming to the marketplace, and there are four companies, actually, that are developing an implantable PTNS device, a device that can be implanted in the vicinity of the lower extremity to stimulate the tibial nerve.

There are a variety of different platforms amongst these four different devices. The Protect PNS device has been developed by Micron. They were formerly the Stimguard company, and this is an implanted electrode with an external stimulator, and they are currently undergoing a trial, enrolling patients for comparing their device efficacy versus a neuromodulation device, the Medtronics neuromodulation device.

Another company is Stimrouter. I'm sorry, the device is Stimrouter, the company is Bioness, and they also are an implanted electrode with an external stimulator and they have an interventional OAB trial ongoing.

There's an Israeli company called Blue Wind Medical that has a device called the Renova, which is a rechargeable implant. That is to say, the device is placed into the lower extremity by the tibial nerve and then there is a recharge that is required every two or three weeks. And their U.S. interventional trial started basically in August of 2020, so we will get some data in a year or two regarding this device. European trials have already been completed and show, at least in single-arm trials, some really good efficacy with the Renova device.

However, the device that is furthest along in development is the eCoin device from Valencia. This is actually an implanted intrinsic device that is a battery that's implanted that has at least a three-year lifespan. Again, it's implanted in the lower extremity. Their pivotal trial has been completed with more than 71% of patients with more than a 50% improvement in urge incontinence episodes. This shows some real efficacy and some real promise. Their PMA was filed with the FDA in August of 2020, so we look forward to approval with this device in the coming months.

Also, some developments with PTNS are home-based or wearable PTNS devices. These are devices that do not require surgery or needles to, I should say, promulgate the same type of stimulation of the tibial nerve that both the implanted devices need and the needle delivery devices need. These are home-based wearable tibial nerve stimulating devices. None of these are approved currently, but there are three companies that are in various levels of regulatory approval in the U.S. and Europe.

The neat thing about these wearable devices is you can take them home. They're really easy and convenient. They are completely safe, at least in the initial studies, and they are completely noninvasive. So the patient can wear the device and then take it off as they need. And they can use the device for as long as they need on an as-needed basis. The exact frequency stimulation and the need for either daily stimulation, weekly stimulation, three times a week stimulation is still unclear as with all of these devices, including the device from Theranova, from Avation and geko, are all very early in phase one and phase two trials.

I just want to talk a little bit about some other technologies that are interesting spins on what we currently do. Botox or botulinum toxin is a very, very, very efficacious treatment for overactive bladder. It's delivered, I should say, via a needle into the bladder. The holy grail of intravesical Botox delivery would be, Tom, if we could deliver Botox without a needle, without sticking the patient 15 or 20 times in the bladder. And there have been several studies looking at ways of developing or delivering Botox without having to deliver it via a needle with an injection into the bladder wall. Some studies have looked at urothelial disruption with protamine sulfate or DMSO. Other studies have looked at increasing the permeability of the urothelium with electromotive drug delivery or low energy shock waves or even ultrasound.

And then, finally, there are several investigations looking into nanocarriers, using liposomes to deliver a botulinum toxin and even a company that has developed a thermosensitive hydrogel, where it's a liquid outside of the body mixed with Botox, and then it is delivered into the bladder where it forms a solid, and then it elutes the Botox over time due to degradation from a urine environment. It elutes the Botox over eight to 12 hours. And there is a phase two study that's been completed in August and we await a readout of that study to see how efficacious this particular Botox delivery system is.

On a completely different vein, there is a radiofrequency ablative technology developed and now in trials from Hologic. It's an endoscopic device that is placed transurethrally, and in essence, delivers radiofrequency ablation of subtrigonal nerves in females with preservation of the overlying epithelium. That is, it delivers the energy below the urothelium, destroying the nerves but preserving the urothelium to minimize urgency and dysuria. Preliminary trials have been completed and a very large sham-controlled U.S. trial will begin enrolling patients shortly, so we look forward to this very different spin on technology for refractory overactive bladder.

So in summary, there are lots of new developments in overactive bladder. It's a very exciting time to be in this field. There are new drugs coming. There are several new refinements in sacral neuromodulation which are already available. There is a new competitor on the market for Medtronics, called Axonics with some new technology. We are still looking for the perfect way to develop and deliver Botox in the bladder, but there are multiple studies ongoing looking at this. Multiple different types of delivery for tibial nerve stimulation, including implantable devices as well as wearable devices. So we look forward to furthering developments and further studies in all of these fields. So that's all I have to say today, Tom. Happy to answer any questions you might have.

Tom Keane:  Yeah, that was a fabulous update and extremely well put together. Just a couple of questions. It's really interesting that you are not talking about bladder ablation and it's following on the cardiac ablation. It's really interesting to see how these fields are crossing and how we are doing separate things.

One of the big questions I have to ask is that, with sacral modulation, when do you decide, or do you start out when you see somebody with overactive bladder, presumably they start out on medicine. And then when do you make that decision? I know you said a 40% effect was a good result. So when do you make a decision to switch to sacral nerve stimulation or how is that decision taken? What needs to happen?

Eric Rovner:  Yeah, that's a very good question, Tom, and the AUA and SUFU have come up with some guidelines previously that were almost a step-therapy approach to treating overactive bladder. That is, we sort of start with behavioral therapy and pharmacologic therapy, and then move on to so-called third-line therapy, such as Botox or sacral neuromodulation.

The latest OAB guidelines suggest that in a well-counseled patient, you can actually move on to third-line therapies without having to go through behavioral therapy and drug therapy in a well-counseled patient who chooses to undergo third-line therapy. And that by and large, at least in my practice, is a decision made by the patient. When they want to move on from medications and behavioral therapy, that is when we start talking about a third-line therapy such as Botox or neuromodulation, and by and large, patients really know what they want once they understand both of those two modalities. They really understand what is involved in each of those. They are very intelligent decision-makers and patients choose smartly between Botox and neuromodulation

Tom Keane:  And then my last question, because I know we are running out of time, there has been reports of neurologic long-term consequences on patients who are on antimuscarinics. What is your opinion about that? Is this a genuine potential problem or is it something that we needn't worry about?

Eric Rovner:  Yeah, it's interesting, Tom. Over the last few years increasing reports, including in JAMA, suggest at least in retrospective studies and large databases that there isn't, there seems to be a relationship between chronic use of antimuscarinics and worsening of cognitive function and worsening and potential progression to dementia. We argue about these things in our meetings, whether or not these are true or not, whether these are artifacts of the way the studies were done. What I think is fair and what is honest, is to counsel your patients that it is possible and have the patients make the decision for themselves, especially if the drug is efficacious for them. If they are willing to accept the possibility that these drugs could lead to some cognitive dysfunction, then I think as long as you've counseled your patient appropriately and the drug is working for them, then it's reasonable to receive it.

Tom Keane:  Eric, it's been a pleasure having you on Uro Today. He's one of my best friends, but it has been great, and it's great talking to the public again. Don't forget UroToday. It is one of the best possible sites you could go for any information on urologic problems. Look forward to talking to you again. This is Tom Keane signing off. Thank you very much.