REVIEW URRENT C OPINION
New strategies in treating male lower urinary tract symptoms Claudius Fu¨llhase a, Roberto Soler b, and Christian Gratzke a
Purpose of review Improved understanding of the pathogenesis of lower urinary tract symptoms (LUTS) has led to the development of new drugs to treat male LUTS. The review aims to give an overview to the new drugs and to compounds in the pipeline. Recent findings Tadalafil, a phosphodiesterase type 5 inhibitor, is a drug newly approved for the treatment of male LUTS and a true new challenger for the current standard treatment with alpha1 blockers, particularly in men with concomitant erectile dysfunction. Botulinum toxin and mirabegron, a beta3 agonist, might be of value in treating persistent storage LUTS. Intraprostatic injections with botulinum toxin, NX-1207, and PRX302, need further evaluation but might be treatment alternatives in the future. Similarly, vitamin D3 receptor analogues (e.g., elocalcitol), gonadotropin-releasing hormone antagonists (e.g., cetorelix), and modulators of the cannabinoid system (e.g., fatty acid amide hydrolase inhibitors) need further evaluation in clinical studies. Other compounds, such as transient receptor potential vanilloid antagonists, Rho kinase inhibitors, purinergic receptor blockers, and endothelin targeting drugs, are still at experimental stages. Summary Novel drugs for the treatment of male LUTS have been introduced recently. Clinical practice along with further trials will have to prove their value, along with other compounds that are still in their early phase of development. Keywords drug therapy, lower urinary tract symptoms, prostatic hyperplasia, urinary bladder
INTRODUCTION
Botulinum toxin
Alpha1 adrenergic antagonists, 5-alpha reductase inhibitors, and muscarinic receptor antagonists are the established medical therapy for male lower urinary tract symptoms (LUTS); the latter one as add-on to persistent storage LUTS. However, new insights into the pathophysiological origins of LUTS, particularly our understanding of how the bladder seems to be involved in LUTS, have led and are leading to new pharmacological treatment options, which are reviewed here in detail. The manuscripts will first (section I) present new drugs, which just have been recently approved, then (section II) present drugs, which are currently tested in first clinical trials, and last (section III) present some new compounds, which seem to have a promising profile targeting LUTS.
Botulinum toxin (BoNT) hinders the attachment and fusion of synaptic vesicles to the cell membrane in terminal nerve endings of the neuromuscular junction. Thus, BoNT prevents exocytosis of the neurotransmitter acetylcholine (Ach) into the synaptic cleft, and inhibits consecutive muscle contraction. The action is not permanent because BoNT does not induce cell death, and eventually the toxin is inactivated and removed. From seven known BoNT subtypes subtype A (BoNTA) is clinically the most relevant. Onabotulinum toxin A (onabotA),
NEWLY APPROVED DRUGS This section summarizes the mechanisms of action and current clinical results of just recently introduced new drugs for the treatment of LUTS.
a
Department of Urology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany and bDivision of Urology, Federal University of Sa˜o Paulo (RS), Sa˜o Paulo, Brazil Correspondence to Christian Gratzke, MD, Department of Urology, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. Tel: +49 89 7095 5960; e-mail: [email protected] Curr Opin Urol 2014, 24:29–35 DOI:10.1097/MOU.0000000000000003
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KEY POINTS Tadalafil, a PDE5 inhibitor, was just recently approved for the treatment of male LUTS and is a true challenger to alpha1 blockers; particularly in men with concomitant erectile dysfunction. BoNT (intravesical) and mirabegron, an orally active beta3 agonist, might be alternatives to antimuscarinics as add-on therapeutics in men with persistent storage LUTS. The principle of intraprostatic injections is re-emerging, several proteins with apoptotic properties are tested, but need further verification. Other drugs and compounds are underway, but still need further evaluation in clinical studies.
abobotulinum toxin A (abobotA), and incobotulinum toxin A (incobotA) are available BoNTAs [1,2]. There is only one randomized controlled clinical trial (RCT) assessing intravesical onabotA injection (200 U) in idiopathic detrusor overactivity, including male patients. Terminologically, symptomatic detrusor overactivity can be regarded as storage LUTS, and therefore the drug is discussed here as potential male LUTS therapy. Compared with the placebo group, patients in the onabotA group showed significant improvements in maximum cystometric capacity, urinary frequency, and incontinence episodes at 4 and 12 weeks. The postvoid residual urine (PVR) increased at first (4 weeks) but turned insignificant at 12 weeks. Quality of life (QoL) was significantly improved in the onabotA group. The mean duration of onabotA efficacy was around 10 months. However, 37.5% of the patients needed temporary clean intermittent catheterization [3]. In another, mostly females including, dose ranging trial, 288 females and 25 males with idiopathic detrusor overactivity were randomized to receive different doses of onabotA (50–300 U). As doses above 150 U showed minimal clinical additional benefit, but did also increase PVR, the authors recommended 100 U to be the safest dose with an adequate clinical outcome [4]. In experimental studies, intraprostatic injections of BoNTA resulted in prostatic atrophy and prostate volume reduction [5–7]. In a following multicenter, double-blind, randomized phase II clinical trial, Crawford et al. [8] reported 30% improvement from baseline to 3 months in American Urologic Association (AUA) symptom score and maximum urinary flow rate with intraprostatic injections of 100 or 300 U of onabotA in LUTS associated with benign prostatic hyperplasia 30
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(BPH). One hundred units dosage showed comparable efficacy to 300 U, but reduced costs and showed less adverse events. However, despite symptomatic improvement, the trial, in contrast to previous reports, did not observe any reduction of prostate volumes. In a prospective single-armed cohort study intraprostatic injections of BoNTA into the transition zone of men with BPH/LUTS resulted in significant improvements in International Prostate Symptom Score (IPSS), Qmax, and PVR. Fifty-six percent of the patients reported subjective LUTS improvement, and 67% reported treatment satisfaction. However, a lack of a placebo group, short study period (3 months), and concurrent medical LUTS therapy weakened the validity of this study [9 ]. Recently, intraprostatic onabotA 100–300 U was tested versus placebo in a phase 2 dose-ranging study. Various significant outcome improvements (IPSS, Qmax, prostate volume) were reported in all groups, indicating a strong placebo effect in injection therapy. Still, in a post-hoc analysis 200 U onabotA showed significant benefits in patients after unsuccessful alpha1 adrenergic antagonist (a1-blocker) therapy, which is currently further assessed [10 ]. Right now, BoNTA has no official approval for the treatment of male LUTS suggestive of BPH, but has approval for the treatment of idiopathic detrusor overactivity (which can be considered as storage LUTS). However, in analogy to muscarinic antagonists (antimuscarinics), which are nowadays officially recommended by many guidelines as add-on therapy for BPH patients with (mainly) storage LUTS, which are insufficiently treated with an a1-blocker alone (and have a PVR < 200 ml), intravesical injection of 100 U BoNTA might be an off-label therapeutic attempt in those patients (storage LUTS), which are other ways treated insufficiently. Furthermore, studies should better evaluate the role of BoNTA as add-on to a1-blocker therapy. Intraprostatic injections of BoNTA need further exploration before they can be recommended. &
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Beta3 adrenergic agonists The relaxing effects of beta3 adrenergic agonists on isolated bladder strips in organ bath experiments led to the development of such compounds for human use, of which GW427353 (solabegron) and YM178 (mirabegron) were the only ones tested in humans so far. Mirabegron was just recently approved officially for the treatment of the overactive bladder syndrome (OAB). In a phase III North-American RCT 1328 patients (25% males) received either placebo or Volume 24 Number 1 January 2014
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Treatment of male lower urinary tract symptoms Fu¨llhase et al.
mirabegron (50–100 mg) for 1 year. Both doses of mirabegron resulted in a significant improvement in incontinence periods, frequency, urgency, nocturia, and voided volume per micturition. First improvements were reported after 4 weeks of treatment. Treatment-emergent adverse events were similar among the three groups [11]. The European counterpart of the mirabegron approval RCT (1978 patients, 27% males) included next to the placebo and mirabegron groups (50 or 100 mg) a tolterodine (4 mg) group over a 12-week study period. Similarly to the American results mirabegron at both doses significantly improved key parameters of OAB compared with placebo. In a post-hoc analysis mirabegron as well as tolterodine were both effective in antimuscarinic-naı¨ve patients. In patients, who had stopped a prior antimuscarinic medication, mirabegron was able to improve OAB symptoms regardless of what was the reason for drug discontinuation. However, tolterodine was only able to improve OAB symptoms in patients who had stopped prior antimuscarinic therapy for side-effects (poor tolerability) but not in those who had stopped it because of an insufficient treatment perception. The incidence of adverse events was similar in all groups (placebo, mirabegron, tolterodine) [12 ]. The safety of mirabegron was particularly evaluated in men with bladder outlet obstruction (BOO). In 200 men with BOO/LUTS mirabegron (50 or 100 mg) or placebo was administered for 12 weeks, and outcomes surveyed urodynamically. Mirabegron was noninferior to placebo in maximum flow, detrusor pressure at maximum flow, and bladder contractility index. PVR was statistically only different than placebo in the 100 mg group [13 ]. Mirabegron is a new treatment alternative to antimuscarinics in the treatment of OAB (storage LUTS). Antimuscarinics are nowadays recommended as add-on therapy for men suffering from BPH/LUTS, which have a focus on storage LUTS, a PVR below 200 ml, and who are insufficiently treated with an a1-blocker alone. In the same scenario, mirabegron might present an alternative treatment attempt, even though it has not been approved for this indication ‘expressis verbis’ yet. As for BoNT, further studies should address the role of mirabegron as an add-on to a1-blocker therapy. &
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Phosphodiesterase type 5 inhibitors Initially, it was a coincidental finding that men taking phosphodiesterase type 5 inhibitors (PDE5-I) on demand for their erectile dysfunction reported an improvement of their LUTS. Those ‘beneficial sideeffects’ led consequently to the design of several clinical trials, which at the end led to the approval
of tadalafil for the treatment of male LUTS [14]. PDE5-I inhibits the degradation of cyclic nucleotides in smooth muscle cells, and consequently led to relaxation of those cells. Even though the mechanism of action of PDE5-I has been well established for erectile dysfunction, the exact mechanism of action in LUTS still remains to be elucidated. As thoroughly discussed by Andersson et al. [15] PDE5-I might exert relevant effects on various anatomical structures (prostate, detrusor, urethra, as well as bladder blood vessels and bladder autonomous nerves) and via various biochemical pathways (upregulating NO/cGMP activity, down-regulating Rho-kinase activity, or acting anti-inflammatory). The beneficial effects of PDE5-I on BPH/LUTS have been clearly demonstrated by various investigators in clinical studies for sildenafil, vardenafil, tadalafil, and UK-369003. PDE5-I or PDE5-I/ a1-blocker combinations were compared with placebo or to a-blocker alone, respectively. Compared with placebo the use of PDE5-I alone was associated with a significant improvement of IPSS. The combination of PDE5-I with an a1-blocker significantly improved IPSS and maximum flow rate compared with a-blockers alone [14,16 ]. Tadalafil is now officially approved in Europe and the USA for the treatment of male LUTS. Particularly, because of the known association between LUTS and erectile dysfunction PDE5-I seems to be a promising new treatment alternative in the treatment of LUTS. Tadalafil is a truly new challenger for a1-blockers, the current standard medical treatment for male LUTS. Particularly, men suffering from LUTS and erectile dysfunction might benefit from PDE5-I therapy. It seems reasonable to stratify male LUTS patients better, for example, men suffering mainly from obstructive LUTS without any erectile dysfunction might be prescribed a classical a1-blocker, whereas men with LUTS and concomitant erectile dysfunction or men after failure of a1-blocker monotherapy might be candidates for a PDE5-I monotherapy. &&
DRUGS IN CLINICAL TRIALS (PROOF OF CONCEPT) Some compounds showed promising results in experimental studies, and are now progressing into clinical trials. However, clinical data are scarce, RCTs as well as long-term results and approval are outstanding.
Vitamin D3 receptor analogues Vitamin D3 receptors (VDRs) are expressed in the human urethra, prostate and bladder [17].
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Elocalcitol, a VDR agonist, decreases cell proliferation and induces apoptosis in the prostate [18]. In the bladder, elocalcitol was shown to counteract growth factor and androgen-induced cell proliferation [19]. In urethral cells, elocalcitol-inhibited Rho effectors (‘molecular switches’ of cell proliferation and apoptosis) and reduced inflammatory responses [17]. Inhibition of Rho signaling by elocalcitol was also shown in human bladder muscle [20]. Anti-inflammatory effects of elocalcitol in the prostate are mediated via cyclooxygenase type 2 (COX2) inhibition and inhibition of nuclear translocation of the transcription factor NF-kB [21]. In in-vivo models of BOO treatment with elocalcitol for 14 days significantly reduced the occurrence of spontaneous bladder contractions [22]. Treatment with elocalcitol also enhanced the effects of tolterodine on bladder compliance in rats [23 ]. In human BPH patients, elocalcitol was not able to significantly increase Qmax, but was able to arrest prostate growth [24]. In consequence, further development of this drug did not seem promising [25]. However, in women with OAB elocalcitol significantly reduced incontinence episodes [26 ]. Preliminary results on elocalcitol have to be confirmed in larger trials. &
incontinence episodes with D9-tetrahydrocannabinol [32]. Nabiximol (Sativex), an endocannabinoid modulator, failed to reduce incontinence episodes (primary endpoint), even though it significantly reduced the number of daytime voids (secondary endpoint) [33]. In rats with partial urethral obstruction-induced detrusor overactivity daily treatment with cannabinor, a CB2 agonist, significantly reduced nonvoiding contractions [34]. To date, no clinical studies with cannabinoids on male LUTS are available. However, based on the results on neurogenic LUTS and experimental data, cannabinoids seem to be a promising treatment perspective, which needs further evaluation by clinical studies. Taming the endocannabinoids by inhibiting their degradation (through the inhibition of the fatty acid amide hydrolases) seems a very promising approach to harness the cannabinoid system without inducing central-nervous side-effects (as they are known from cannabinoid receptor agonists). However, this pharmacological approach is still in an experimental stage [35 ]. &
&
Gonadotropin-releasing hormone antagonists Antiandrogens or GnRH agonists, as used in prostate cancer treatment, can not be used in LUTS treatment because of the unacceptable side-effects of medical castration (‘complete’ testosterone suppression). However, in contrast to GnRH agonists, GnRH antagonists might be used to induce ‘intermediate’ testosterone suppression only, and as such achieve therapeutic benefits in the prostate without inducing systemic side-effects [27]. Cetorelix, a luteinizing-hormone releasing hormone antagonist, showed a significant 4-point IPSS reduction compared with placebo, following 4 weeks after intramuscular injection (60 mg). Testosterone suppression was only moderate, and symptom improvement was maintained for 6 months [28]. Regrettably, those results could not be confirmed by phase III RCTs in Europe and the USA [29,30].
Cannabinoids The beneficial effects of cannabinoids on neurogenic LUTS are known from studies in multiple sclerosis (MS) patients. In those patients, whole plant extracts reduced urgency and frequency [31]. The Cannabinoids in Multiple Sclerosis study (CAMS) showed significant reduction of 32
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NX-1207 NX-1207 is under investigation in a phase III RCT for the treatment of BPH/LUTS. NX-1207 is a protein of proprietary composition with supposedly selective proapoptotic properties. In rats and dogs, intraprostatic injection of NX-1207 led to a 40–47% reduction in prostate volume over a 12-month period. NX-1207 was reported to induce focal cell loss through apoptosis and consecutive prostate shrinkage. In a phase II RCT, 2.5–10 mg NX-1207 was tested in 175 men. 2.5 mg induced a mean reduction of 11 AUA symptom score points. Compared with finasteride, a 5alpha reductase inhibitor, NX-1207 reduced AUA symptom scores by 9.7 points vs. 4.1 points over a 90-day period (P < 0.001). No clinical study on NX-1207 reported any safety issue or sexual side-effects [36]. Even though promising current data have to be confirmed by the ongoing phase III RCT, and by other investigators.
PRX302 PRX302 is an inactive precursor of a bacterial cytolytic pore-forming protein (protoxin), which is activated via proteolytic processing by prostate specific antigen (PSA), a glycoprotein enzyme. In non-PSA producing dog prostates PRX302 was inactive, whereas in monkey PSA producing glands it was activated [37]. In phase I and II RCTs, PRX302 was injected in prostates of BPH patients (n ¼ 32) to assess safety and efficacy [38]. A 30% decrease of Volume 24 Number 1 January 2014
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IPSS was observed in 67–73% of PRX302 treated patients after 3 months and in 64–67% after 1 year. In analogy, significant improvements in QoL and prostate size (20% reduction in prostate volume at 1 year) were reported. Side-effects were reported to be only mild-to-modest, and transient, and sex life seemed not to be affected [38]. As for NX-1207, further studies need to confirm the efficacy and safety of PRX302. In addition, as both compounds are proteins, particularly, antibody formation upon repeated administration has to be assessed.
COMPOUNDS WITH INTERESTING THERAPEUTIC APPROACHES Based on pathophysiological hypotheses some potential drug candidates have been tested in experimental settings. Clinical data for these compounds are outstanding.
Transient receptor potential vanilloid channel blockers In various animal models of chemically induced cystitis, the orally active TRPV1 antagonist GRC 6211 counteracted bladder hyperactivity. Given at the same doses GRC 6211 had no urodynamic effects in sham animals [39]. Similarly HC067047, a TRPV4 antagonist, decreased frequency in cyclophosphamide-induced cystitis [40]. Coadministration of TRPV1 and TRPV4 antagonists showed synergistic effects in reducing lipopolysaccharide-induced bladder hyperactivity, whereas the doses applied of each drug were so small that they had no effect when given alone. The latter fact might be relevant when it comes to reduce TRPV1 or TRPV4 specific side-effects [41].
Rho-kinase inhibitors In male spontaneous hypertensive rats (SHR), which are rats with genuine occurring bladder hyperactivity, hydroxyfasudil, a nonselective Rho-kinase inhibitor, significantly ameliorated bladder dysfunction. Treated animals showed a similar bladder blood flow and growth factor levels than healthy controls. The authors speculated that hydroxyfasudil might improve ischemia-induced bladder damage in SHR [42]. In rats with cyclophosphamide-induced cystitis, hydroxyfasudil significantly increased voiding volume and decreased elevated detrusor pressures. In vitro, the carbachol concentration response curve (CRC) was significantly lower in the hydroxyfasudil group compared with controls [43]. Y-27632, another Rho-kinase inhibitor,
similarly attenuated carbachol CRCs, whereas those effects were more pronounced in the bladder tissues from obstructed rats than in controls [44].
Purinergic receptor blockers AF-353, a P2X3/P2X2/3 antagonist, reduced the frequency of nonvoiding contractions in a rat model of neurogenic bladder dysfunction [45]. Even though, not having been tested in animal models of obstruction-induced bladder hyperactivity yet, this approach nonetheless seems interesting to be looked at in other scenarios of bladder hyperactivity, such as BOO.
Endothelin converting enzyme inhibitors The endothelin converting enzyme (ECE) generates endothelin 1 (ET-1), which is a potent vasoconstrictor. ET-1 was shown to contract human detrusor, and was reported to be overexpressed in detrusor muscle of obstructed rabbits. WO-03028719, an oral ECE inhibitor, inhibited nonvoiding contractions in rats with BOO-induced bladder hyperactivity [46].
CONCLUSION PDE5 inhibitors, namely tadalafil, which is officially approved for the treatment of BPH/LUTS, are true treatment alternatives to alpha1 blockers, the current medical standard treatment. A better stratification of patients seems desirable. Particularly, men with LUTS and concomitant erectile dysfunction might benefit from PDE5 inhibitors. OAB can be considered as storage LUTS. As such, drugs with official approval to treat OAB might be used to treat male patients with LUTS either first-line if their symptoms are mainly storage (irritative) and not obstructive or second-line, as ‘add-on’, if storage LUTS persist after the initiation of an alpha1 blocker therapy. For the latter scenario antimuscarinics, the gold standard in the treatment of OAB, are officially recommended in symptomatic men with a PVR below 200 ml. As a consequence, even though they do not have official approval to treat male LUTS, mirabegron, a beta3 agonist, and intravesical BoNT (100 U), both of which have official approval for OAB, seem to be treatment alternatives to antimuscarinics. Regular surveillance of PVR should be recommended. The principle of intraprostatic drug injection, either with BoNT or with various proteins of supposedly specific apoptotic properties (such as NX-1207 and PRX302), experiences a resurgence, and is currently tested in several clinical trials. However, despite first encouraging results, further studies are needed to confirm current data. Several
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other compounds might be interesting candidates in the treatment of male LUTS but need further evaluation through clinical studies. Among those, vitamin D3 receptor analogues (elocalcitol), GnRH antagonists (cetorelix), and cannabinoid derivates are already tested in humans. Acknowledgements None. Conflicts of interest R. Soler is consultant for Astellas. C. Gratzke is on advisory boards for AMS, Astellas, Bayer, GSK, Lilly, MSD, Neotract, Recordati, Rottapharm Madaus and Steba. C. Fullhase has nothing to declare.
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Treatment of male lower urinary tract symptoms Fu¨llhase et al. 39. Charrua A, Cruz CD, Narayanan S, et al. GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models. J Urol 2009; 181:379–386. 40. Everaerts W, Zhen X, Ghosh D, et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A 2010; 107:19084–19089. 41. Charrua A, Cruz CD, Cruz F. TRPV1 and TRPV4 antagonists have synergistic effect for treating bladder overactivity in rats. Eur Urol Suppl 2012; 11: e365. 42. Inoue S, Saito M, Takenaka A. Hydroxyfasudil ameliorates bladder dysfunction in male spontaneously hypertensive rats. Urology 2012; 79:1186; e9 e14. Epub 2012/03/01.
43. Masago T, Watanabe T, Saito M, et al. Effect of the rho-kinase inhibitor hydroxyfasudil on bladder overactivity: an experimental rat model. Int J Urol 2009; 16:842–847; Epub 2009/09/09. 44. Takahashi N, Shiomi H, Kushida N, et al. Obstruction alters muscarinic receptor-coupled RhoA/Rho-kinase pathway in the urinary bladder of the rat. Neurourol Urodyn 2009; 28:257–262; Epub 2009/02/21. 45. Munoz A, Somogyi GT, Boone TB, et al. Modulation of bladder afferent signals in normal and spinal cord-injured rats by purinergic P2X3 and P2X2/3 receptors. BJU Int 2012; Epub 2012/05/01. 46. Schroder A, Tajimi M, Matsumoto H, et al. Protective effect of an oral endothelin converting enzyme inhibitor on rat detrusor function after outlet obstruction. J Urol 2004; 172:1171–1174; Epub 2004/08/18.
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New strategies in treating male lower urinary tract symptoms Claudius Fu¨llhase a, Roberto Soler b, and Christian Gratzke a
Purpose of review Improved understanding of the pathogenesis of lower urinary tract symptoms (LUTS) has led to the development of new drugs to treat male LUTS. The review aims to give an overview to the new drugs and to compounds in the pipeline. Recent findings Tadalafil, a phosphodiesterase type 5 inhibitor, is a drug newly approved for the treatment of male LUTS and a true new challenger for the current standard treatment with alpha1 blockers, particularly in men with concomitant erectile dysfunction. Botulinum toxin and mirabegron, a beta3 agonist, might be of value in treating persistent storage LUTS. Intraprostatic injections with botulinum toxin, NX-1207, and PRX302, need further evaluation but might be treatment alternatives in the future. Similarly, vitamin D3 receptor analogues (e.g., elocalcitol), gonadotropin-releasing hormone antagonists (e.g., cetorelix), and modulators of the cannabinoid system (e.g., fatty acid amide hydrolase inhibitors) need further evaluation in clinical studies. Other compounds, such as transient receptor potential vanilloid antagonists, Rho kinase inhibitors, purinergic receptor blockers, and endothelin targeting drugs, are still at experimental stages. Summary Novel drugs for the treatment of male LUTS have been introduced recently. Clinical practice along with further trials will have to prove their value, along with other compounds that are still in their early phase of development. Keywords drug therapy, lower urinary tract symptoms, prostatic hyperplasia, urinary bladder
INTRODUCTION
Botulinum toxin
Alpha1 adrenergic antagonists, 5-alpha reductase inhibitors, and muscarinic receptor antagonists are the established medical therapy for male lower urinary tract symptoms (LUTS); the latter one as add-on to persistent storage LUTS. However, new insights into the pathophysiological origins of LUTS, particularly our understanding of how the bladder seems to be involved in LUTS, have led and are leading to new pharmacological treatment options, which are reviewed here in detail. The manuscripts will first (section I) present new drugs, which just have been recently approved, then (section II) present drugs, which are currently tested in first clinical trials, and last (section III) present some new compounds, which seem to have a promising profile targeting LUTS.
Botulinum toxin (BoNT) hinders the attachment and fusion of synaptic vesicles to the cell membrane in terminal nerve endings of the neuromuscular junction. Thus, BoNT prevents exocytosis of the neurotransmitter acetylcholine (Ach) into the synaptic cleft, and inhibits consecutive muscle contraction. The action is not permanent because BoNT does not induce cell death, and eventually the toxin is inactivated and removed. From seven known BoNT subtypes subtype A (BoNTA) is clinically the most relevant. Onabotulinum toxin A (onabotA),
NEWLY APPROVED DRUGS This section summarizes the mechanisms of action and current clinical results of just recently introduced new drugs for the treatment of LUTS.
a
Department of Urology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany and bDivision of Urology, Federal University of Sa˜o Paulo (RS), Sa˜o Paulo, Brazil Correspondence to Christian Gratzke, MD, Department of Urology, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. Tel: +49 89 7095 5960; e-mail: [email protected] Curr Opin Urol 2014, 24:29–35 DOI:10.1097/MOU.0000000000000003
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KEY POINTS Tadalafil, a PDE5 inhibitor, was just recently approved for the treatment of male LUTS and is a true challenger to alpha1 blockers; particularly in men with concomitant erectile dysfunction. BoNT (intravesical) and mirabegron, an orally active beta3 agonist, might be alternatives to antimuscarinics as add-on therapeutics in men with persistent storage LUTS. The principle of intraprostatic injections is re-emerging, several proteins with apoptotic properties are tested, but need further verification. Other drugs and compounds are underway, but still need further evaluation in clinical studies.
abobotulinum toxin A (abobotA), and incobotulinum toxin A (incobotA) are available BoNTAs [1,2]. There is only one randomized controlled clinical trial (RCT) assessing intravesical onabotA injection (200 U) in idiopathic detrusor overactivity, including male patients. Terminologically, symptomatic detrusor overactivity can be regarded as storage LUTS, and therefore the drug is discussed here as potential male LUTS therapy. Compared with the placebo group, patients in the onabotA group showed significant improvements in maximum cystometric capacity, urinary frequency, and incontinence episodes at 4 and 12 weeks. The postvoid residual urine (PVR) increased at first (4 weeks) but turned insignificant at 12 weeks. Quality of life (QoL) was significantly improved in the onabotA group. The mean duration of onabotA efficacy was around 10 months. However, 37.5% of the patients needed temporary clean intermittent catheterization [3]. In another, mostly females including, dose ranging trial, 288 females and 25 males with idiopathic detrusor overactivity were randomized to receive different doses of onabotA (50–300 U). As doses above 150 U showed minimal clinical additional benefit, but did also increase PVR, the authors recommended 100 U to be the safest dose with an adequate clinical outcome [4]. In experimental studies, intraprostatic injections of BoNTA resulted in prostatic atrophy and prostate volume reduction [5–7]. In a following multicenter, double-blind, randomized phase II clinical trial, Crawford et al. [8] reported 30% improvement from baseline to 3 months in American Urologic Association (AUA) symptom score and maximum urinary flow rate with intraprostatic injections of 100 or 300 U of onabotA in LUTS associated with benign prostatic hyperplasia 30
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(BPH). One hundred units dosage showed comparable efficacy to 300 U, but reduced costs and showed less adverse events. However, despite symptomatic improvement, the trial, in contrast to previous reports, did not observe any reduction of prostate volumes. In a prospective single-armed cohort study intraprostatic injections of BoNTA into the transition zone of men with BPH/LUTS resulted in significant improvements in International Prostate Symptom Score (IPSS), Qmax, and PVR. Fifty-six percent of the patients reported subjective LUTS improvement, and 67% reported treatment satisfaction. However, a lack of a placebo group, short study period (3 months), and concurrent medical LUTS therapy weakened the validity of this study [9 ]. Recently, intraprostatic onabotA 100–300 U was tested versus placebo in a phase 2 dose-ranging study. Various significant outcome improvements (IPSS, Qmax, prostate volume) were reported in all groups, indicating a strong placebo effect in injection therapy. Still, in a post-hoc analysis 200 U onabotA showed significant benefits in patients after unsuccessful alpha1 adrenergic antagonist (a1-blocker) therapy, which is currently further assessed [10 ]. Right now, BoNTA has no official approval for the treatment of male LUTS suggestive of BPH, but has approval for the treatment of idiopathic detrusor overactivity (which can be considered as storage LUTS). However, in analogy to muscarinic antagonists (antimuscarinics), which are nowadays officially recommended by many guidelines as add-on therapy for BPH patients with (mainly) storage LUTS, which are insufficiently treated with an a1-blocker alone (and have a PVR < 200 ml), intravesical injection of 100 U BoNTA might be an off-label therapeutic attempt in those patients (storage LUTS), which are other ways treated insufficiently. Furthermore, studies should better evaluate the role of BoNTA as add-on to a1-blocker therapy. Intraprostatic injections of BoNTA need further exploration before they can be recommended. &
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Beta3 adrenergic agonists The relaxing effects of beta3 adrenergic agonists on isolated bladder strips in organ bath experiments led to the development of such compounds for human use, of which GW427353 (solabegron) and YM178 (mirabegron) were the only ones tested in humans so far. Mirabegron was just recently approved officially for the treatment of the overactive bladder syndrome (OAB). In a phase III North-American RCT 1328 patients (25% males) received either placebo or Volume 24 Number 1 January 2014
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Treatment of male lower urinary tract symptoms Fu¨llhase et al.
mirabegron (50–100 mg) for 1 year. Both doses of mirabegron resulted in a significant improvement in incontinence periods, frequency, urgency, nocturia, and voided volume per micturition. First improvements were reported after 4 weeks of treatment. Treatment-emergent adverse events were similar among the three groups [11]. The European counterpart of the mirabegron approval RCT (1978 patients, 27% males) included next to the placebo and mirabegron groups (50 or 100 mg) a tolterodine (4 mg) group over a 12-week study period. Similarly to the American results mirabegron at both doses significantly improved key parameters of OAB compared with placebo. In a post-hoc analysis mirabegron as well as tolterodine were both effective in antimuscarinic-naı¨ve patients. In patients, who had stopped a prior antimuscarinic medication, mirabegron was able to improve OAB symptoms regardless of what was the reason for drug discontinuation. However, tolterodine was only able to improve OAB symptoms in patients who had stopped prior antimuscarinic therapy for side-effects (poor tolerability) but not in those who had stopped it because of an insufficient treatment perception. The incidence of adverse events was similar in all groups (placebo, mirabegron, tolterodine) [12 ]. The safety of mirabegron was particularly evaluated in men with bladder outlet obstruction (BOO). In 200 men with BOO/LUTS mirabegron (50 or 100 mg) or placebo was administered for 12 weeks, and outcomes surveyed urodynamically. Mirabegron was noninferior to placebo in maximum flow, detrusor pressure at maximum flow, and bladder contractility index. PVR was statistically only different than placebo in the 100 mg group [13 ]. Mirabegron is a new treatment alternative to antimuscarinics in the treatment of OAB (storage LUTS). Antimuscarinics are nowadays recommended as add-on therapy for men suffering from BPH/LUTS, which have a focus on storage LUTS, a PVR below 200 ml, and who are insufficiently treated with an a1-blocker alone. In the same scenario, mirabegron might present an alternative treatment attempt, even though it has not been approved for this indication ‘expressis verbis’ yet. As for BoNT, further studies should address the role of mirabegron as an add-on to a1-blocker therapy. &
&&
Phosphodiesterase type 5 inhibitors Initially, it was a coincidental finding that men taking phosphodiesterase type 5 inhibitors (PDE5-I) on demand for their erectile dysfunction reported an improvement of their LUTS. Those ‘beneficial sideeffects’ led consequently to the design of several clinical trials, which at the end led to the approval
of tadalafil for the treatment of male LUTS [14]. PDE5-I inhibits the degradation of cyclic nucleotides in smooth muscle cells, and consequently led to relaxation of those cells. Even though the mechanism of action of PDE5-I has been well established for erectile dysfunction, the exact mechanism of action in LUTS still remains to be elucidated. As thoroughly discussed by Andersson et al. [15] PDE5-I might exert relevant effects on various anatomical structures (prostate, detrusor, urethra, as well as bladder blood vessels and bladder autonomous nerves) and via various biochemical pathways (upregulating NO/cGMP activity, down-regulating Rho-kinase activity, or acting anti-inflammatory). The beneficial effects of PDE5-I on BPH/LUTS have been clearly demonstrated by various investigators in clinical studies for sildenafil, vardenafil, tadalafil, and UK-369003. PDE5-I or PDE5-I/ a1-blocker combinations were compared with placebo or to a-blocker alone, respectively. Compared with placebo the use of PDE5-I alone was associated with a significant improvement of IPSS. The combination of PDE5-I with an a1-blocker significantly improved IPSS and maximum flow rate compared with a-blockers alone [14,16 ]. Tadalafil is now officially approved in Europe and the USA for the treatment of male LUTS. Particularly, because of the known association between LUTS and erectile dysfunction PDE5-I seems to be a promising new treatment alternative in the treatment of LUTS. Tadalafil is a truly new challenger for a1-blockers, the current standard medical treatment for male LUTS. Particularly, men suffering from LUTS and erectile dysfunction might benefit from PDE5-I therapy. It seems reasonable to stratify male LUTS patients better, for example, men suffering mainly from obstructive LUTS without any erectile dysfunction might be prescribed a classical a1-blocker, whereas men with LUTS and concomitant erectile dysfunction or men after failure of a1-blocker monotherapy might be candidates for a PDE5-I monotherapy. &&
DRUGS IN CLINICAL TRIALS (PROOF OF CONCEPT) Some compounds showed promising results in experimental studies, and are now progressing into clinical trials. However, clinical data are scarce, RCTs as well as long-term results and approval are outstanding.
Vitamin D3 receptor analogues Vitamin D3 receptors (VDRs) are expressed in the human urethra, prostate and bladder [17].
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Elocalcitol, a VDR agonist, decreases cell proliferation and induces apoptosis in the prostate [18]. In the bladder, elocalcitol was shown to counteract growth factor and androgen-induced cell proliferation [19]. In urethral cells, elocalcitol-inhibited Rho effectors (‘molecular switches’ of cell proliferation and apoptosis) and reduced inflammatory responses [17]. Inhibition of Rho signaling by elocalcitol was also shown in human bladder muscle [20]. Anti-inflammatory effects of elocalcitol in the prostate are mediated via cyclooxygenase type 2 (COX2) inhibition and inhibition of nuclear translocation of the transcription factor NF-kB [21]. In in-vivo models of BOO treatment with elocalcitol for 14 days significantly reduced the occurrence of spontaneous bladder contractions [22]. Treatment with elocalcitol also enhanced the effects of tolterodine on bladder compliance in rats [23 ]. In human BPH patients, elocalcitol was not able to significantly increase Qmax, but was able to arrest prostate growth [24]. In consequence, further development of this drug did not seem promising [25]. However, in women with OAB elocalcitol significantly reduced incontinence episodes [26 ]. Preliminary results on elocalcitol have to be confirmed in larger trials. &
incontinence episodes with D9-tetrahydrocannabinol [32]. Nabiximol (Sativex), an endocannabinoid modulator, failed to reduce incontinence episodes (primary endpoint), even though it significantly reduced the number of daytime voids (secondary endpoint) [33]. In rats with partial urethral obstruction-induced detrusor overactivity daily treatment with cannabinor, a CB2 agonist, significantly reduced nonvoiding contractions [34]. To date, no clinical studies with cannabinoids on male LUTS are available. However, based on the results on neurogenic LUTS and experimental data, cannabinoids seem to be a promising treatment perspective, which needs further evaluation by clinical studies. Taming the endocannabinoids by inhibiting their degradation (through the inhibition of the fatty acid amide hydrolases) seems a very promising approach to harness the cannabinoid system without inducing central-nervous side-effects (as they are known from cannabinoid receptor agonists). However, this pharmacological approach is still in an experimental stage [35 ]. &
&
Gonadotropin-releasing hormone antagonists Antiandrogens or GnRH agonists, as used in prostate cancer treatment, can not be used in LUTS treatment because of the unacceptable side-effects of medical castration (‘complete’ testosterone suppression). However, in contrast to GnRH agonists, GnRH antagonists might be used to induce ‘intermediate’ testosterone suppression only, and as such achieve therapeutic benefits in the prostate without inducing systemic side-effects [27]. Cetorelix, a luteinizing-hormone releasing hormone antagonist, showed a significant 4-point IPSS reduction compared with placebo, following 4 weeks after intramuscular injection (60 mg). Testosterone suppression was only moderate, and symptom improvement was maintained for 6 months [28]. Regrettably, those results could not be confirmed by phase III RCTs in Europe and the USA [29,30].
Cannabinoids The beneficial effects of cannabinoids on neurogenic LUTS are known from studies in multiple sclerosis (MS) patients. In those patients, whole plant extracts reduced urgency and frequency [31]. The Cannabinoids in Multiple Sclerosis study (CAMS) showed significant reduction of 32
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NX-1207 NX-1207 is under investigation in a phase III RCT for the treatment of BPH/LUTS. NX-1207 is a protein of proprietary composition with supposedly selective proapoptotic properties. In rats and dogs, intraprostatic injection of NX-1207 led to a 40–47% reduction in prostate volume over a 12-month period. NX-1207 was reported to induce focal cell loss through apoptosis and consecutive prostate shrinkage. In a phase II RCT, 2.5–10 mg NX-1207 was tested in 175 men. 2.5 mg induced a mean reduction of 11 AUA symptom score points. Compared with finasteride, a 5alpha reductase inhibitor, NX-1207 reduced AUA symptom scores by 9.7 points vs. 4.1 points over a 90-day period (P < 0.001). No clinical study on NX-1207 reported any safety issue or sexual side-effects [36]. Even though promising current data have to be confirmed by the ongoing phase III RCT, and by other investigators.
PRX302 PRX302 is an inactive precursor of a bacterial cytolytic pore-forming protein (protoxin), which is activated via proteolytic processing by prostate specific antigen (PSA), a glycoprotein enzyme. In non-PSA producing dog prostates PRX302 was inactive, whereas in monkey PSA producing glands it was activated [37]. In phase I and II RCTs, PRX302 was injected in prostates of BPH patients (n ¼ 32) to assess safety and efficacy [38]. A 30% decrease of Volume 24 Number 1 January 2014
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IPSS was observed in 67–73% of PRX302 treated patients after 3 months and in 64–67% after 1 year. In analogy, significant improvements in QoL and prostate size (20% reduction in prostate volume at 1 year) were reported. Side-effects were reported to be only mild-to-modest, and transient, and sex life seemed not to be affected [38]. As for NX-1207, further studies need to confirm the efficacy and safety of PRX302. In addition, as both compounds are proteins, particularly, antibody formation upon repeated administration has to be assessed.
COMPOUNDS WITH INTERESTING THERAPEUTIC APPROACHES Based on pathophysiological hypotheses some potential drug candidates have been tested in experimental settings. Clinical data for these compounds are outstanding.
Transient receptor potential vanilloid channel blockers In various animal models of chemically induced cystitis, the orally active TRPV1 antagonist GRC 6211 counteracted bladder hyperactivity. Given at the same doses GRC 6211 had no urodynamic effects in sham animals [39]. Similarly HC067047, a TRPV4 antagonist, decreased frequency in cyclophosphamide-induced cystitis [40]. Coadministration of TRPV1 and TRPV4 antagonists showed synergistic effects in reducing lipopolysaccharide-induced bladder hyperactivity, whereas the doses applied of each drug were so small that they had no effect when given alone. The latter fact might be relevant when it comes to reduce TRPV1 or TRPV4 specific side-effects [41].
Rho-kinase inhibitors In male spontaneous hypertensive rats (SHR), which are rats with genuine occurring bladder hyperactivity, hydroxyfasudil, a nonselective Rho-kinase inhibitor, significantly ameliorated bladder dysfunction. Treated animals showed a similar bladder blood flow and growth factor levels than healthy controls. The authors speculated that hydroxyfasudil might improve ischemia-induced bladder damage in SHR [42]. In rats with cyclophosphamide-induced cystitis, hydroxyfasudil significantly increased voiding volume and decreased elevated detrusor pressures. In vitro, the carbachol concentration response curve (CRC) was significantly lower in the hydroxyfasudil group compared with controls [43]. Y-27632, another Rho-kinase inhibitor,
similarly attenuated carbachol CRCs, whereas those effects were more pronounced in the bladder tissues from obstructed rats than in controls [44].
Purinergic receptor blockers AF-353, a P2X3/P2X2/3 antagonist, reduced the frequency of nonvoiding contractions in a rat model of neurogenic bladder dysfunction [45]. Even though, not having been tested in animal models of obstruction-induced bladder hyperactivity yet, this approach nonetheless seems interesting to be looked at in other scenarios of bladder hyperactivity, such as BOO.
Endothelin converting enzyme inhibitors The endothelin converting enzyme (ECE) generates endothelin 1 (ET-1), which is a potent vasoconstrictor. ET-1 was shown to contract human detrusor, and was reported to be overexpressed in detrusor muscle of obstructed rabbits. WO-03028719, an oral ECE inhibitor, inhibited nonvoiding contractions in rats with BOO-induced bladder hyperactivity [46].
CONCLUSION PDE5 inhibitors, namely tadalafil, which is officially approved for the treatment of BPH/LUTS, are true treatment alternatives to alpha1 blockers, the current medical standard treatment. A better stratification of patients seems desirable. Particularly, men with LUTS and concomitant erectile dysfunction might benefit from PDE5 inhibitors. OAB can be considered as storage LUTS. As such, drugs with official approval to treat OAB might be used to treat male patients with LUTS either first-line if their symptoms are mainly storage (irritative) and not obstructive or second-line, as ‘add-on’, if storage LUTS persist after the initiation of an alpha1 blocker therapy. For the latter scenario antimuscarinics, the gold standard in the treatment of OAB, are officially recommended in symptomatic men with a PVR below 200 ml. As a consequence, even though they do not have official approval to treat male LUTS, mirabegron, a beta3 agonist, and intravesical BoNT (100 U), both of which have official approval for OAB, seem to be treatment alternatives to antimuscarinics. Regular surveillance of PVR should be recommended. The principle of intraprostatic drug injection, either with BoNT or with various proteins of supposedly specific apoptotic properties (such as NX-1207 and PRX302), experiences a resurgence, and is currently tested in several clinical trials. However, despite first encouraging results, further studies are needed to confirm current data. Several
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other compounds might be interesting candidates in the treatment of male LUTS but need further evaluation through clinical studies. Among those, vitamin D3 receptor analogues (elocalcitol), GnRH antagonists (cetorelix), and cannabinoid derivates are already tested in humans. Acknowledgements None. Conflicts of interest R. Soler is consultant for Astellas. C. Gratzke is on advisory boards for AMS, Astellas, Bayer, GSK, Lilly, MSD, Neotract, Recordati, Rottapharm Madaus and Steba. C. Fullhase has nothing to declare.
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Treatment of male lower urinary tract symptoms Fu¨llhase et al. 39. Charrua A, Cruz CD, Narayanan S, et al. GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models. J Urol 2009; 181:379–386. 40. Everaerts W, Zhen X, Ghosh D, et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A 2010; 107:19084–19089. 41. Charrua A, Cruz CD, Cruz F. TRPV1 and TRPV4 antagonists have synergistic effect for treating bladder overactivity in rats. Eur Urol Suppl 2012; 11: e365. 42. Inoue S, Saito M, Takenaka A. Hydroxyfasudil ameliorates bladder dysfunction in male spontaneously hypertensive rats. Urology 2012; 79:1186; e9 e14. Epub 2012/03/01.
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