Christopher Chapple: Thank you, Alan. I can't thank you for the kind introduction enough. I really hope I can live up to those expectations. You're too kind, and I'm very honored to be invited. So basically the question is, have we reached the end of the road with pharmacological intervention? I think the first thing to do is to actually identify what we're trying to treat. At the end of the day, overactive bladder is a term that's been widely used, a condition which is understood, and an area where therapy has been developed over the last 30 to 40 years. Now, the problem with the term is, what do we mean by it? Well, it's a symptom complex, and with any symptom complex, one has to bear in mind that the bladder is an unreliable witness, as Turner Warwick first defined. In other words, that symptoms are not disease or condition specific. Now, we all recognize that urgency is a pivotal symptom, which leads on to increased frequency, reduced volumes voided, incontinence in a third of women, and nighttime voiding. And of course, urgency is a cerebral sensation. The next problem, which often causes confusion, is that overactive bladder is often considered also to be merged indistinguishably with urodynamics. But of course, urodynamic detrusor overactivity only occurs in around 44% to 66% of women. In men, it's 58 to 90%. The blue bars are those with incontinence.
So of course, if you've got incontinence with overactive bladder symptom complex, you're more than likely to have urodynamic detrusor overactivity. And one of the problems is that it's been recognized that urodynamics doesn't really define outcome or response to treatment. Now, another issue, of course, is that we mustn't forget that the majority of men that present with lower urinary tract symptoms due to benign prostatic obstruction, so-called BPH, which of course is a bit of a misnomer because BPH is a histological problem, we mustn't forget that they usually present with OAB symptoms. And there's this old publication from the States, going back to 1982 in J Urol, where Chalfin and Bradley looked at injecting lidocaine into the prostate after carrying out urodynamics or whilst the urodynamic test was ongoing, and then assessing urodynamics again. And they showed it abolished the detrusor overactivity, which of course occurs in around two-thirds of men with benign prostatic obstruction. So the question is, how does lidocaine work? Of course, it's going to be inhibiting neural traffic. And is it because of that, that we find a TURP by cutting out the urothelium reduces overactivity in so many men who undergo TURPs?
So you can see that first of all, we're dealing with urgency, which is a cerebral sensation. Secondly, there's good evidence that even in men, we're dealing with some other aspect rather than just the motor obstruction. Now, if one looks at the bladder itself, we mustn't forget the urothelium has a metabolic rate four times that of the detrusor muscle. And if you actually look on here, you can see the detrusor muscle at the bottom, the urothelium at the top, and you've got these tram lines going across from the suburothelial area down to the detrusor and in the suburothelial space. These are the so-called interstitial cells, and they're responsive to acetylcholine. This is a slide from Karl-Erik Andersson, a well-known pharmacologist from Lund in Sweden. And this just is important because it shows this box on the left, you can see, it shows that there's release of neurotransmitters from the urothelium, both acetylcholine, ATP, nitric oxide. And what you've got is non-neuronal release. When you stretch the bladder, you get release of these neurotransmitters. Of course, the detrusor is a workhorse. It's from the Latin detrudere, to drive out. It drives the urine out. If you've got a non-functioning detrusor, the bladder won't work. But of course, you've got the suburothelial space where you've got all of these nerves with acetylcholine on sensory nerves. And don't forget you've got release of acetylcholine when you stretch the bladder. So, let's just think about the bladder. Sensation as you're sitting there from your bladder, however full it is, is going up the periaqueductal gray matter to be analyzed by the cortex. And we know this from work such as this from Griffiths, you can show that areas of the cortex light up when you've got a full bladder. Now, we all know key-in-the-door syndrome. I'm finding that as I get older.
You've had a fullish bladder, you get home, you put a key at the door, and you've got to make a run for it to the bathroom. So what's happening is that you're getting unconscious sensations of symptoms going up to the cortex from the bladder as the bladder fills. The pontine micturition center is a bit that controls the bladder. But what's happening is that the cortex is inhibiting that. And that occurs until permission is given to void when that negative inhibition of the pontine micturition center is released, and then of course the bladder empties. So, what are the targets? Obviously the CNS, the detrusor muscle itself, or the urothelium. The CNS, of course, drugs have too many side effects, so really not a target. The detrusor muscle, what everybody seems to think the detrusor muscle is probably the target. They say for PDE-5, they say for beta-3, and of course it's a no-brainer for the antimuscarinics. But is it the target or is that a bystander effect? What about the urothelium? Now, a number of different areas have been looked at over the years, and of course we know the muscarinics work, the beta-3 agonists work. I'll give you an example. If one's looking at the urothelium, the TRP receptors are inhibited by hot spices. And you can see here down at the bottom, resiniferatoxin, which is very potent as compared to, for instance, jalapeno or sweet bell pepper and capsaicin a little less potent.
Now, we know that if you put capsaicin in the human bladder and resiniferatoxin, you actually inhibit the detrusor contraction. Now that's not acting on motor mechanisms, it acting purely on the sensory nerves. It causes explosive degranulation of sensory nerves. So at the end of the day, we know that if you inhibit the sensation and the sensory mechanisms of bladder, you stop the bladder working. It's a no-brainer, as you know from UCSF, Tanagho, and his coworkers, Rick Schmidt, actually produced sacral neuromodulation. And we know that that, of course, acts not on the detrusor, but on sensory nerves, as well as motor nerves, but predominantly on the sensory nerves. And it's a third-line therapy for overactive bladder. Botulinum toxin the same. Rich Schmidt was also involved in developing that. And this is some work from our group where in a [inaudible 00:08:57] animal model, if you actually then apply botulinum toxin, on the left here in this slide, you can see you reduce the sensory neural traffic in the spinal cord, as compared with before on the right. So again, it's supporting the view that you're targeting the sensory nerve component with botulinum toxin. So what about intravesical pharmacology? There've been a number of studies with oxybutynin intravesically and also tolterodine, although tolterodine not really, to be honest, come to very much. But I think what's really interesting is that intravesical oxybutynin at a dose of 0.1 milligram per kilogram reduces episodes of urgency incontinence by 85%, the same as actually antimuscarinic oral therapy.
So the real key thing about this is that there's work from Kim and Yoshimura, they actually instilled oxybutynin into animals, rat bladders, and they found that if you measure the blood level, you barely find any oxybutynin in the blood. And the point is that if you actually look at the detrusor muscle itself, you also don't find much intramuscular oxybutynin. The vast majority of it is actually in the urothelium and the suburothelial area. And that suggests, again, that that is the area that you're targeting with an antimuscarinic. You're not acting predominantly on the motor mechanism, otherwise you'd have higher levels in the detrusor muscle. Botulinum toxin again, early work by Rapp and coworkers in Munich, if you actually take muscle biopsies before and after botulinum toxin, you actually see that there's only a 5% reduction in the amount of neurotransmitter released into muscle. I mean, this is the stuff that's working on cholinesterase receptor. And there's only 5%. And yet the treatment works. So again, that points towards the fact that this is a sensory mechanism rather than a motor mechanism. Beta-3 agonists, it always gets quoted as motor. But when you actually look at the data and the pharmacology by Igawa, Takeda, and Yamaguchi, they show actually the vast majority of the beta-3 receptors are actually in the urothelium. And the work from Victor Nesium and his coworkers in Buenos Aires, if you actually give a beta-3 agonist to a patient before you carry out urodynamics, then even before the urodynamic detrusor overactivity occurs, once the bladder starts filling, you have reduced sensation. Now, if you're hitting the detrusor muscle, that's a motor mechanism, you shouldn't have a sensory effect until you hit the actual detrusor overactivity and stop that from occurring. So, the fact you've got a sensory effect early on prior to the detrusor overactivity, once again, suggests the effect of beta-3 is on the urothelium, not the detrusor. PDE-5 inhibitors.
The key question mark with these is their pharmacology. What I mean is, are they acting on smooth muscle relaxation, and therefore a motor component? Or are they inhibiting sensory neural traffic? We know that tadalafil intramuscular injections into the detrusor only cause minimal changes in amplitude of contraction. Again, which suggests it's not the motor mechanism. Intravesical, I'm unaware of any studies. There's good animal data to support this is actually a sensory target, but as I say, the pharmacology from my perspective, from a mechanistic point of view, is not very clear. So, what about the future? And I think we know that there'll always be new drugs coming along. With regard to a new oral antimuscarinic, I think very unlikely for economic reasons. I think the same to some extent would stand with beta-3 agonists, although there's some evidence there are a few more in the pipeline. Again, I think as with the muscarinics, the clinical development probably won't occur if we're honest. And I think that's probably the case with PDE-5, which is of course used off-label for both men and women. And again, I don't think will achieve clinical development. However, I do think the focus now is very much on gene therapy, and there's a number of companies working in this area. Is this going to be the future? Intravesical administration of agents have fallen by the wayside.
Early studies with capsaicin looked promising and resiniferatoxin. Indeed, resiniferatoxin had a huge study carried out, although never published, was actually negative. And obviously, as I say, I think there are companies working on gene therapy with the aim of targeting sensory mechanisms, but of course, getting it into the sensory nerves without hitting the motor nerves and damaging the detrusor is very tricky. So, I suppose, I think the future is that we will have therapies that are going to hopefully target sensory mechanisms. And we have a whole plethora of drugs already with different mechanisms that almost certainly will turn out to be acting predominantly on sensory mechanisms rather than the motor. So I'll leave it at that. Thank you, Alan.
Alan Wein: That was a terrific summary. Karl-Erik Andersson, who you mentioned, used to talk and still does about what he thinks as the ceiling effect for all these medicines, which is, it depends on what marker you use, let's say reduction in urge urinary incontinence episodes. And it seems to be like 60 to 70%. And even if you combine pharmacologic therapies with different mechanisms of action, it seems to stick sort of right there. I mean, do you think that that's really the ceiling? Because it certainly seems to be with all the stuff that we use.
Christopher Chapple: Yeah. I mean, it's a very good point. It's difficult to know. I think part of his reasoning for that is that there's about a 30% placebo response.
Alan Wein: Yeah, I was going to ask-
Christopher Chapple: And I think one of the major problems with the fact you get a placebo response in these trials is not that the drug's not working, it's just it's usually the first time that the patient has actually used a bladder diary.
Alan Wein: Right.
Christopher Chapple: At the end of the day... I mean, a few years ago with Sender Herschorn, we'd carried out a secondary analysis of a study with an anticholinergic. And we actually looked at the placebo and the active treatment group. And we found that in the active treatment group, they actually increased their fluid intake a little. And in the placebo group, they'd reduced it by a significant amount. And that may be one of the explanations for the placebo response, because of course, carrying out a bladder diary gives you biofeedback, the patient biofeedback. They realize that if you reduce your fluid intake, it improves matters. Secondly, I suppose if one's looking at a ceiling effect, there will be other mechanisms at play, not just the cerebral cortex, which you may be influencing by affecting the afferent traffic back to it. And there may be other mechanisms at play which you're not targeting with that specific drug. So, those would be my thoughts on the subject, for what it's worth.
Alan Wein: I mean, do you think that the placebo effect in pharmacologic trials... I mean, characteristically, the company pays for a three-month trial. And very rarely do they go back and look and see how many people are on the medication at the end of the year, and whether the medication is still effective or not. Do you think the placebo effect lasts a long time in these people, if they're followed properly and encouraged to, let's say, take a look at a bladder diary every so often?
Christopher Chapple: Yeah, I agree with you. I think most people don't carry on using the bladder diary from my experience of talking to patients who've been in trials. And I agree with you, the placebo effect doesn't last in the long-term. Indeed, evidence in support of that, as you appreciate and know, you've been involved in this work, is looking at the long-term data from big real-life clinical practice databases. And we know that only around 20% of patients stay on an anticholinergic for more than a year in those large studies. And the same beta-3, it's around 40%. So, I agree with you. I suspect if people did use the bladder diary more often, it may improve the response to some extent. Although another reason patients stop, of course, is adverse events.
Alan Wein: So it sounds like the ideal drug would be one that abolished all sensation from the bladder, but preserved the ability to voluntarily initiate micturition in an unobstructed fashion, assuming there wasn't an anatomic obstruction.
Christopher Chapple: Yeah. Yeah. But I think not all sensation because at the end of the day, the patient needs to know when they're reaching anatomical capacity. So in that sense, otherwise, if we both realized it could cause some other problems down the line with back pressure, et cetera. So I think it's got to be, to deal with what I presume is an abnormal sensation. I mean, let's face it, 15% of the population probably have a degree of overactive bladder congenitally, if you like, to some extent. So, there must be some other nuances there that are actually affecting the system and making it more sensitive. So if one could actually target that, I think that's the key.
Alan Wein: Yeah. So, the companies that are developing the gene therapies in particular. There was one that they stopped the development of. And I'm assuming that the reason that they stopped the development of, it wasn't that the drug didn't work, but I think maybe they realized that, "Hey, what are we comparing this to?" And actually what we're comparing it to, because you had to inject it in the bladder wall, we're comparing it to botulinum toxin and that works pretty well. So unless this magical gene therapy is better than that, then what are we doing? I mean, so is anything going to come along that's better than botulinum toxin? I mean, admittedly, yep, there's an increased incidence of infection, occasionally somebody goes into retention. But the results for overactive bladder are pretty good.
Christopher Chapple: Alan, you always ask the right questions as ever. And I've always found that your insight into things is so amazing. I mean, the bottom line is that what we're trying to do is hit the sweet spot where you're targeting the sensory disturbance, in other words, what's causing urgency, versus the motor component, which I think is secondary to the sensory bit. I did a study, phase-two study with Roger Dmochowski, which we wrote up in patients with overactive bladder. And we found that with onabotulinumtoxinA, once you got to 150 mouse units, what you actually had was the maximum effect on the OAB symptoms. And then beyond that, you just got more retention because you started hitting the detrusor. And the problem with the gene therapy is you'll be hitting the detrusor muscle, stopping the detrusor working, putting them towards a retention situation. Which is not what you want, of course, with an OAB type scenario. So, that would be ideal for a patient with a neurogenic detrusor overactivity where of course the worry is you've got high pressures in the bladder with secondary effects on the kidneys. And in those patients, the ideal thing, as we all know, after all, that's what we've used Botox for, and before that, clam cystoplasties, is to actually produce an acontractile bladder with ISC. So, that would be my take on it. I think it really emphasizes that the target is not the detrusor muscle primarily. That is, if you like, is the servant of what's going on, although of course you need a functioning detrusor.
Alan Wein: So last question, do you think these drugs act any differently in a patient with neurogenic lower urinary tract dysfunction than non-neurogenic? Or is it the same mechanism of action?
Christopher Chapple: I think there may well be differences because obviously in the neurogenic, for instance, it depends on the neurogenic, the cause of the neurogenic problem. If it's a spinal cord injury where you've got no impulses going up to the brain, then obviously there, you're wanting to stop the detrusor muscle contracting. And an antimuscarinic would be ideal. I don't think that there's any decent trials with beta-3 in that subgroup. With MS, of course, where you've got patchy defects, then of course you could get a combination of both effects from my perception. The trouble is, as you and I know from having discussed this over the years, the data with neurogenic patients is very limited because the market is much smaller. But we do know that these drugs are effective in a number of patients. Although I have to say the antimuscarinics are probably the most effective in the patients with a spinal type injury.
Alan Wein: Well, as usual, I've learned a lot. And I thank you for taking your time to do this, and I hope to see you at one of the meetings soon.
Christopher Chapple: I look forward to that very much. And thank you for giving me the honor of speaking.
Alan Wein: Listen, thanks so much, Chris.