CNS may be path to future voiding dysfunction therapies

December 1, 2015

In this interview, Karl-Erik Andersson, MD, PhD, discusses current treatments for common voiding dysfunctions and future directions, including central nervous system agents and combination therapies.

While a number of medical and non-medical therapies are available to treat overactive bladder, underactive bladder, bladder outlet obstruction, and bladder pain syndrome, the search continues for therapeutic options that raise the bar of efficacy and safety. In this interview, Karl-Erik Andersson, MD, PhD, discusses current treatments for these common voiding dysfunctions and future directions, including central nervous system agents and combination therapies. Dr. Andersson is professor of urology at Wake Forest School of Medicine, Winston-Salem, NC. He is also a Jens Christian Skou fellow at Aarhus University, Aarhus, Denmark. Dr. Andersson was interviewed by Urology Times Editorial Consultant Philip M. Hanno, MD, MPH, professor of urology at the University of Pennsylvania, Philadelphia. 

 

I’d like to discuss the management of several common voiding dysfunctions, starting with overactive bladder. What is the current state of therapy using oral medications, and how can we expect our oral therapy options to change in the future?   

The current first-line therapies are various antimuscarinic drugs and the beta-3 receptor agonist mirabegron (Myrbetriq). There may be changes in the proportion of people treated first with antimuscarinic drugs or the beta-3 agonist, but for the next 5 years at least, these two drug classes will be first-line pharmacologic therapy. There are possibilities to treat those who do not respond to these two types of treatment with botulinum toxin (Botox).

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If we look at what’s in the pipeline, there are very few new drug principles. There are a couple of new antimuscarinic drugs in development, but they don’t appear to have any specific properties that would make them better than the ones we have. Since we have such a low number of established and accepted drugs, I think we have to use combinations. One of the combinations in the pipeline is the antimuscarinic solifenacin succinate (VESIcare) plus mirabegron, which is currently in phase III trials. We will likely see that drug combination on the market within the next few years.

Next: "Looking outside what is recommended by the regulatory authorities, a lot of drugs are used to treat OAB."

 

Looking outside what is recommended by the regulatory authorities, a lot of drugs are used to treat OAB. I know some clinicians use imipramine (Tofranil), and I don’t think this is a good way to treat patients because of the risk of cardiac arrhythmias. Other drugs, particularly those working on the central nervous system, have shown efficacy, but the efficacy has not been better than that obtained with antimuscarinics and mirabegron. In the near term at least, I don’t think we will have any drug acting on the central nervous system that can be developed into useful therapy. Unless a drug shows better efficacy and better tolerability than what’s currently available, drug developers are unlikely to back it financially.

 

Do you see new ways to deliver botulinum toxin, other than intradetrusor injection?

We have the liposome-coated botulinum toxin that can be instilled into the bladder, and this was examined in a small phase II study of 24 patients. In this controlled study, 12 of the patients were treated with botulinum toxin, and 50% of them responded quite well in terms of urgency and frequency. If you look at this as a proof-of-principle study, it might work.

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There are other developments that involve modifying the botulinum toxin molecule. The active ingredient in botulinum toxin is an enzyme that inactivates the mechanism that releases nerve transmitters. You can attach to the enzyme a component that directs the molecule to a specific site and another component that enhances penetration. This is not only an interesting principle for overactive bladder, but we may be able to use it in pain treatment as well. It would be interesting to see if this actually works in interstitial cystitis patients, for example.

I think this is a novelty that has potential to develop into something new. If you can document botulinum toxin as an instillation as an effective form of treatment with a lasting effect of 6 to 9 months similar to that observed with injection therapy, it may be an agent we can start in patients earlier, rather than first trying another antimuscarinic, then two antimuscarinics or mirabegron.

 

You’re saying there might be a way to change the molecule itself to make it usable as an intravesical instillation.

That’s correct.

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Percutaneous tibial nerve stimulation has had surprising efficacy as a less-expensive, noninvasive way to deliver neuromodulation. Do you see these units being applied percutaneously in shoes or boots?

I think there is a very good preclinical rationale for that. It has been worked out at the University of Pittsburgh that this type of stimulation in combination with drugs may be very promising. Percutaneous nerve stimulation by itself has efficacy comparable to that of the best antimuscarinics.

If you could combine an established drug with transcutaneous nerve stimulation, you may actually increase efficacy because the treatments are based on two different principles. For example, opioids such as tramadol (Ultram) used in low doses have been shown to work very well in cats. Tramadol is as efficacious as any antimuscarinic. There is a controlled clinical study showing that, but we can’t recommend tramadol because of the side effects. The principle of using a low-dose opioid is intriguing, however, because there is no more effective way of stopping bladder contractions than with opioids.

Next: Realistically, can a drug be designed to effectively treat underactive bladder?

 

Let’s turn to underactive bladder. There’s no really effective pharmacotherapy for underactive bladder, although muscarinic receptor agonists, anticholinesterase inhibitors, and alpha-adrenergic receptor antagonists have been used with limited success. Realistically, can a drug be designed to effectively treat underactive bladder?

If you mean that one drug could solve the problem, I would say no because underactive bladder has so many different etiologies. However, if we could define the underlying causes, there are many potential targets for drugs that might offer improvement.

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I don’t think the drugs you mentioned can be applied with any success. For example, the mechanism of a muscarinic receptor agonist is to cause a contracture of the muscle. It contracts the bladder if the bladder is able to contract. I don’t think it’s useful, and it’s painful. If you inject patients with carbachol, which we did many years ago, the result is a painful bladder contraction. We could increase intravesical pressure, but patients couldn’t void better.

A new agent that is in phase I trials, meaning it has passed the tolerability level, is a prostanoid EP2 and EP3 receptor agonist. In presentations at the 2015 AUA annual meeting, this agent was observed to have a very nice effect in a monkey model of underactivity. It was shown to contract the bladder and relax the urethra, which is theoretically what we would like to see. I seriously doubt that it works in all cases of underactive bladder, but at least it is a step in the right direction.

Next: "A presentation at the 2015 AUA annual meeting showed that there can be a progression from overactivity to underactivity."

 

Dr. Mike Chancellor has hypothesized that underactive bladder and overactive bladder may not be entirely separate disease entities. Instead, chronic untreated or treatment-refractory overactive bladder due to neurologic diseases such as diabetes or bladder outlet obstruction, or aging, sarcopenia, and frailty may progress to detrusor hyperactivity with impaired contractility and finally underactive bladder. Do you think there’s a continuum there?

A presentation at the 2015 AUA annual meeting showed that there can be a progression from overactivity to underactivity. This has been shown in an animal model of ischemia. Many of the disorders you mentioned may have bladder ischemia contributing to the lower urinary tract dysfunction. Ischemia initially causes overactivity and if the ischemia continues, the result is bladder underactivity. Chronic bladder ischemia most probably hits not only the detrusor muscle with the deposition of collagen, increased stiffness, and reduced compliance, but also causes reduced sensation because you lose nerves. Thus, progressive bladder ischemia may lead to a combination of detrusor hyperactivity with impaired contractility (DHIC), which was the original term for this condition.

 

Expression of vitamin D3 receptors (VDRs) is present in the human urethra, prostate, and bladder. Decreased cell proliferation and induction of apoptosis in the prostate have been achieved with elocalcitol, which is a VDR agonist. Can you comment on this?

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It’s not as simple as this agent being a vitamin D agonist; it’s also a Rho-kinase inhibitor. Some early clinical observations have shown it could be used in overactive bladder, and there are good pre-clinical data showing it may be efficacious. Unfortunately, the drug company developing it has closed, and there are no new developments in this area. I do think that Rho-kinase inhibitors in general may offer an interesting possibility for improving patients who have, for example, outflow obstruction.

Next: "There are many possibilities for treating [outlet obstruction] pharmacologically."

 

In general, do you think we’ve hit a barrier in the treatment of outlet obstruction, or do you see potential new advances?

There are many possibilities for treating it pharmacologically. Standard therapy is, of course, alpha-blockers and 5-alpha-reductase inhibitors. There are also combinations, using alpha-blockers and antimuscarinics, in patients with storage symptoms. If a patient has bladder outlet obstruction and has a big prostate, the rational first step is to remove the prostate. However, there are many patients who have storage symptoms after removal of the prostate; up to 30% will still have overactive bladder.

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In such a case, I think we’re talking about two separate disorders. Outflow obstruction can lead to both voiding and storage symptoms, but at the age people experience these symptoms, they also get OAB that may be independent of the outflow obstruction.

 

Looking at all these conditions, I’m hopeful that we may have the greatest chance of a breakthrough in bladder pain syndrome, which has multiple targets-frequency, pain, and urgency. Do you think that they are so interrelated that we can’t see them as individual targets or do you see opportunity here?

I see opportunities. I also recognize that there are two types of patients with bladder pain syndrome: those with Hunner’s lesions and those without Hunner’s lesions. These types could be separate diseases. But I don’t think we’ve completely ruled out that some bladder pain syndrome patients with no morphologic changes in the bladder actually show progression and develop Hunner’s lesions. It may start as a bladder pain syndrome, and a small fraction of patients then show progression.

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Concerning treatment, of course you can’t have sensation of pain from the bladder without activating afferents. That makes bladder afferents a very attractive target. There are many ways of affecting afferents and release of inflammatory mediators. A universally effective drug to treat bladder pain syndrome simply doesn’t exist. That’s why we have to individualize treatment and find some kind of drug combination that could help the patient. I don’t know to what extent distention therapy and instillations are helpful in general. There are some patients who respond to any type of treatment.

Next: In terms of pharmacologic therapy of voiding dysfunction, what are you most excited about at this time?

 

In terms of pharmacologic therapy of voiding dysfunction, what are you most excited about at this time?

I think the central nervous system as it relates to storage symptoms is really the key to new treatments. Any disturbance in bladder function is processed in the brain, and it can also be that the brain itself generates the stimuli that result in bladder contraction.

Theoretically, an ideal drug would modify the central handling of the efferent impulses and do it in a defined way. To say, “a drug is centrally acting and it does something good for the bladder,” that’s not sufficient to recommend it as a therapy. We have a lot of centrally active drugs that do work, but they don’t work well enough and they all have side effects. Duloxetine and tramadol, for example, work in some patients with storage symptoms, but not better than antimuscarinics.

 

Is there anything you would like to add?

I think we must continue to subdivide the patients with lower urinary tract symptoms, who have different pathologies. If we had a biomarker or diagnostic procedure that could subdivide the population, then we could also target therapy. We would then have better efficacy with combination therapies and obtain a reasonable balance between efficacy and adverse effects.

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