metabolite may also explain the lack of correlation
`between plasma concentration of oxybutynin itself
`and side effects in geriatric patients reported by
`Ouslander et al. [198B]. The plasma half-life of the
`oxybutynin is approximately 2 hours, but with wide
`interindividual variation [Hughes et al., 1992; Dou-
`champs et al. 1988].
`
`Oxybutynin has several pharmacological effects in
`vitro, some of which seem difficult to relate to its
`effectiveness in the treatment of DO. It has both an
`antimuscarinic and a direct muscle relaxant effect,
`and, in addition, local anesthetic actions. The latter
`effect may be of importance when the drug is ad-
`ministered intravesically, but probably plays no role
`when it is given orally. In vitro, oxybutynin was 500
`times weaker as a smooth muscle relaxant than as
`
`an antimuscarinic agent [Kachur et al., 1988]. Most
`probably, when given systemically, oxybutynin acts
`mainly as an antimuscarlnic drug. Oxybutynin has
`a high affinity for muscarinic receptors in human
`bladder tissue and effectively blocks carbachol-
`induced contractions [waldeck et al., 1997; Nilve-
`brant et al., 1988]. The drug was shown to have
`slightly higher affinity for muscarinic M1 and M3
`receptors than for M2 receptors [Nilvebrant et al.,
`1986; Norhona-Blob et al., 1991], but the clinical
`significance of this is unclear.
`
`The immediate release (IR) form of oxybutynin
`(OXY-IR) is recognized for its efficacy and most of
`the newer anti—muscarinic agents have been com-
`pared to it once efficacy over placebo has been
`determined.
`In general,
`the new formulations of
`oxybutynin and other anti-muscarinic agents offer
`patients efficacy roughly equivalent to that of OXY-
`IR, and the advantage of the newer formulations lies
`in improved dosing schedules and side-effect pro-
`file [Appell et al., 2001; Diokno et al., 2003; Dmo—
`chowski et al., 2002]. An extended release oxybu-
`tynin (OXY-ER) once daily oral formulation and an
`oxybutynin transdermal delivery system (OXY—TDS)
`are available. OXY—TDS offers a twice—weekly dos-
`ing regimen and the potential for improved patient
`compliance and tolerability. Some of the available
`formulations of oybutynin were overviewed by Mc-
`Crery and Appell [2006].
`
`Immediate-release oxybutynin (OXY-IR). Several
`controlled studies have have shown that OXY-IR
`
`is effective in controlling DO, including neurogenic
`DO [Yarker et al., 1995; Andersson and Chapple,
`2001]. The recommended oral dose of the IR form
`is 5 mg three times daily or four times daily, even if
`lower doses have been used. Thijroff et al. [1998]
`summarized 15 randomized controlled studies on a
`
`total of 476 patients treated with oxybutynin. The
`mean decrease in incontinence was recorded as
`
`52% and the mean reduction in frequency per 24
`h was 33% (data on placebo not presented). The
`overall "subjective improvement" rate was reported
`as 74 % (range 61% — 100%). The mean percent of
`patients reporting an adverse effect was 70 (range
`
`17% - 93%). Oxybutynin, 7.5 to 15 mgfday, signifi-
`cantly improved quality of life of patients suffering
`from overactive bladder in a large open rnulticenter
`trial.
`In this study. patients’ compliance was 97%
`and side effects, mainly dry mouth, were reported
`by only 8% of the patients [Amarenco et al., 1998].
`In nursing home residents (n=75), Ouslander et
`al. [1995] found that oxybutynin did not add to the
`clinical effectiveness of prompted voiding in a pla-
`cebo—control|ed, double blind, cross—over trial. On
`the other hand, in another controlled trial in elderly
`subjects (n=57), oxybutynin with bladder training
`was found to be superior to bladder training alone
`[Szonyi et al., 1995].
`
`Several open studies in patients with spinal cord in-
`juries have suggested that oxybutynin, given orally
`or intravesically, can be of therapeutic benefit [Szo|-
`lar et al., 1996; Kim et al., 1996].
`
`The therapeutic effect of OXY—lR on D0 is asso-
`ciated with a high incidence of side effects (up to
`80% with oral administration). These are typically
`antimuscarinic in nature (dry mouth, constipation,
`drowsiness, blurred vision) and are often dose—|im—
`iting [Eiaigrie et al., 1988; Jonville et al., 1992]. The
`effects on the electrocardiogram of oxybutynin were
`studied in elderly patients with urinary incontinence
`[Hussain et al., 1998]; no changes were found.
`It
`cannot be excluded that the commonly recommend-
`ed dose 5 mg x 3 is unnecessarily high in some
`patients, and that a starting dose of 2.5 mg x 2 with
`following dose—titration would reduce the number of
`adverse effects [Amarenco et al., 1998].
`
`Extended release oxybutynin (OXY-ER). This for-
`mulation was developed to decrease liver metabo-
`lite formation of desethyloxybutynin (DEO) with the
`presumption that it would result in decreased side
`effects, especially dry mouth, and improve patient
`compliance with remaining on oxybutynin therapy
`[see Arisco et al., 2009]. The formulation utilizes an
`osmotic system to release the drug at a controlled
`rate over 24 hours distally primarily into the large
`intestine where absorption is not subject to first—
`pass metabolism in the liver. This reduction in me-
`tabolism is meant to improve the rate of dry mouth
`complaints when compared to OXY-IR. DEO is still
`formed through the hepatic cytochrome P-450 en-
`zymes, but clinical trials have indeed demonstrated
`improved dry mouth rates compared with OXY-IR
`[AppelI et al., 2003]. Salivary output studies have
`also been interesting. Two hours after administra-
`tion of OXY-IR or TOLT-IR, salivary production
`decreased markedly and then gradually returned
`to normal. With OXY-ER, however, salivary output
`was maintained at predose levels throughout the
`day [Chancellor et al., 2001].
`
`The effects of O)(Y—ER have been well documented
`
`[Siddiqui et al., 2004]. In the OBJECT study [Appell
`et al., 2001], the efficacy and tolerability of 10 mg
`OXY—ER was compared to a twice daily 2 mg dose
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`of TOLT—lR. OXY-ER was statistically more effective
`than the TOLT-IR in weekly urgency incontinence ep-
`isodes (OXY-ER from 25.6 to 6.1%; TOLT-IR 24.1 to
`7.8). total incontinence (OXY-ER from 28.6 to 7.1%:
`TOLT-IR 27.0 to 9.3). and frequency (OXY-ER from
`91.8 to 67.1%; TOLT-IR 91.6 to 71.5) and both medi-
`cations were equally well tolerated. The basic study
`was repeated as the OPERA study [Diokno et al..
`2003] with the difference that this study was a direct
`comparison of the two extended-release forms. OXY-
`ER (10 mg) and TOLT-ER (4 mg) and the results
`were quite different. In this study there was no sig-
`nificant difference in efficacy for the primary endpoint
`of urgency incontinence, however, TOLT-ER had a
`statistically lower incidence of dry mouth. OXY-ER
`was only statistically better at 10 mg than TOLT-ER
`4 mg in the reduction of the rate of urinary frequency.
`These studies made it clearthat in comparative stud-
`ies IR entities of one drug should no longer be com-
`pared with ER entities of the other.
`
`inconti-
`Greater reductions in urgency and total
`nence have been reported in patients treated in
`dose-escalation studies with OXY-ER.
`In two ran-
`
`the efficacy and tolerability of
`domized studies.
`OXY-ER were compared with OXY-IR.
`In the 1999
`study [Anderson et al., 1999], 105 patients with
`urgency or mixed incontinence were randomized
`to receive 5-30 mg OXY-ER once daily or 5 mg of
`OXY—lR 1-4 timesfday. Dose titrations began at 5
`mg and the dose was increased every 4-7 days until
`one of three endpoints was achieved. These were
`1) the patient reported no urgency incontinence dur-
`ing the final two days of the dosing period; 2) the
`maximum tolerable dose was reached; the maxi-
`mum allowable dose (30 mg for OXY-ER or 20 mg
`for OXY-IR) was reached. The mean percentage
`reduction in weekly urgency and total incontinence
`episodes was statistically similar between OXY-ER
`and OXY-IR but dry mouth was reported statistically
`more often with OXY-IR. In the 2000 study [Versi et
`al.. 2000], 226 patients were randomized between
`OXY-ER and OXY-IR with weekly increments of 5
`mg daily up to 20 mg daily. As in the 1999 study,
`OXY-ER again achieved a >80“/a reduction in ur-
`gency and total incontinence episodes and a sig-
`nificant percentage of patients became dry. A nega-
`tive aspect of these studies is that there were no
`naive patients included. as all patients were known
`responders to cxybutynin. Similar efficacy results
`have been achieved, however, with OXY-ER in a
`treatment-na'l've population [Gleason et al.. 1999].
`
`In an RCT comparing different daily doses of oxybu—
`tynin (5. 10 and 15 mg). Corcos et al. [2006] found
`a significant dose-response relationship for both ur-
`gency incontinence episodes and dry mouth. The
`greatest satisfaction was with 15 mg oxybutyninfday.
`
`In a multicentre, prospective. observational, flexi-
`ble—dosing Korean study. Yoo et al. [2012] investi-
`gate the prescription pattern and dose distribution
`
`of OXY-ER in patients the OAB syndrome in actual
`clinical practice. The dosage of for each patient
`was adjusted after discussions of efficacy and toler-
`ability between doctor and patient. over a 12 week
`treatment period. Efficacy was measured by admin-
`istering the Primary OAB Symptom Questionnaire
`(POSQ) before and after treatment. Patients were
`also administered, the patient perception of treat-
`ment benefit (PPTB) questionnaire at the end of the
`study. Of the 809 patients enrolled, 590 (73.2%)
`continued to take study medication for 12 weeks.
`Most patients were prescribed 5-10 mg/day oxybu-
`tynin ER as both starting and maintenance closes,
`with a dose escalation rate of only 14.9%. All OAB
`symptoms evaluated by the POSQ were improved;
`94.1% of patients reported benefits from treatment
`and 89.3% were satisfied.
`
`Transdermal oxybutynin (OXY-TDS). Transder-
`mal delivery also alters oxybutynin metabolism re-
`ducing DEO production to an even greater extent
`than OXY-ER. A study [Davila et al.. 2001] compar-
`ing OXY—TDS with OXY—|R demonstrated a statisti-
`cally equivalent reduction in daily incontinent epi-
`sodes (from ?.3 to 2.3: 66% for OXY-TDS. and 7'.4
`to 2.6: 72% for OXY-IR). but much less dry mouth
`(38% for OXY-TDS and 94% for OXY-IR). In another
`study [Dmochowski et al.. 2002] the 3.9-mg daily
`dose patch significantly (vs placebo) reduced the
`mean number of daily incontinence episodes (from
`4.7 to 1.9: placebo from5.0 to 2.9). while reducing
`average daily urinary frequency confirmed by an in-
`creased average voided volume (from 165 to 198
`ml; placebo from 1?5 to 182 ml). Furthermore, dry
`mouth rate was similar to placebo (7% vs 8.3%). In
`a third study [Dmochowski et al., 2003] OXY-TDS
`was compared not only to placebo but to TOLT-ER.
`Both drugs equivalently and significantly reduced
`daily incontinence episodes and increased the av-
`erage voided volume, but TOLT-ER was associated
`with a significantly higher rate of antimuscarinic ad-
`verse events. The primary adverse event for OXY-
`TDS was application site reaction pruritis in 14%
`and erythema in 8.3% with nearly 9% feeling that
`the reactions were severe enough to withdraw from
`the study. despite the lack of systemic problems.
`
`The pharmacokinetics and adverse effect dynam-
`ics cf OXY-TDS (3.9 mg/day) and OXY-ER (10
`mg/day) were compared in healthy subjects in a
`randomized. 2-way crossover study [Appell et al..
`2003]. Multiple blood and saliva samples were col-
`lected and pharmacokinetic parameters and total
`salivary output were assessed. OXY—TDS adminis-
`tration resulted in greater systemic availability and
`minimal metabolism to DEO compared to OXY-ER
`which resulted in greater salivary output in OXY-
`TDS patients and less dry mouth symptomatology
`than when taking OXY-ER.
`
`Dmcchowski et al. [2005] analyzing the combined
`results of two RCTs concluded that transdermal
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`oxybutynin was shown to be efflcacious and well
`tolerated. The most common sytemic side effect
`was dry mouth (7.0 % vs placebo 5.3%). Applica-
`tion site erythema occurred in 7% and pruritus in
`16.1 %. Also Cartwright and Cardozo [2006]. re-
`viewing published and presented data concluded
`that transdermal oxybutynin has a good balance
`between efficacy and tolerability with a rate of
`systemic antimuscarinic side effects lower that
`with oral antimuscarinics — however,
`this benefit
`was offset by the rate of local skin reaction. The
`reviews of Sahai et al. [2008] and Staskin and Sal-
`vatore [2010] largely confirmed these conclusions,
`which also have been supported by further studies
`[Cartwright et al.. 2011].
`
`Oxybutynin topical’ gel’. Given the efficacy and
`tolerability of the transdermal application,
`limited
`only by skin site reactions, a gel formulation was
`developed. oxybutynin topical gel (OTG) was ap-
`proved by the US FDA in January 2009. OTG is ap-
`plied once daily to the abdomen, thigh, shoulder, or
`upper arm area [Staskin et al., 2009]. The 1 gram
`application dose delivers approximately 4 mg of
`drug to the circulation with stable plasma concen-
`trations and a "favorable" N-desethyloxybutynin
`metabolite: oxybutynin ratio believed to minimizing
`antimuscarinic side effects [Staskin and Robinson.
`2009].
`In a multicenter RCT. 789 patients (89%
`women) with urgency—predominant
`incontinence
`were assigned to OTG or placebo once daily for
`12 weeks [Staskin et al., 2009]. The mean number
`of urgeny episodes, as recorded by 3-day voiding
`diary, was reduced by 3.0 episodes per day ver-
`sus 2.5 in the placebo arm (P <0.0001). Urinary
`frequency decreased by 2.7 episodes per day and
`voided volume increased by 21 mL (versus 2.0
`episodes [P = 0.0017] and 3.8 mL [P = 0.0018].
`respectively. in the placebo group). Dry mouth was
`reported in 6.9% of the treatment group versus
`2.8% of the placebo group. Skin reaction at the
`application site was reported in 5.4% of the treat-
`ment group versus 1.0% in the placebo arm. It was
`felt that improved skin tolerability of the gel over
`the OXY transdermal patch delivery system was
`secondary to lack of adhesive and skin occlusion.
`The gel dries rapidly upon application and leaves
`no residue; person—to—person transference via skin
`contact is largely eliminated if clothing is worn over
`the application site [Dmochowski et al., 2011]. The
`evolution of the transdermal gel allows greater
`patient tolerability and improved compliance. This
`was confirmed by Sand et al. [2012] showing that
`in 704 women with OAB OTG significantly reduced
`the number (mean 1 standard deviation) of daily
`incontinence episodes (OTG, -3.0 1 2.8 episodes;
`placebo, -2.5 i 3.0 episodes), reduced urinary fre-
`quency, increased voided volume, and improved
`select health-related quality-of-life domains vs
`placebo. Dry mouth was the only drug-related ad-
`verse event significantly more common with OTG
`(7.4%) than with placebo (2.8%).
`
`Other administration forms. Rectal administration
`
`[Col|as and Malone-Lee, 1997] was reported to have
`fewer adverse effects than the conventional tablets.
`
`Administered intravesically, oxybutynin has in sev-
`eral studies been demonstrated to increase bladder
`
`capacity and produce clinical improvement with few
`side effects, both in neurogenic and in other types of
`DO, and both in children and adults [Lose and Nor-
`gaard, 2001; Fader et al., 2007; George etal., 2007;
`Guerra et al., 2008], although adverse effects may
`occur [Kasabian et al., 1994; Palmer et al., 1997].
`
`Effects on cognition. Several studies have docu-
`mented the possibility that oxybutynin may have
`negative effects on cognitive functions, particularly
`in the elderly population but also in children [see,
`e.g., Kay et al., 2006; Klausner al Steers, 2007; Kay
`and Ebinger, 2008]. This factor should be taken into
`consideration when prescribing the drug.
`
`Assessment.
`
`Oxybutynin has a well-documented efficacy in the
`treatment of OABIDO (Table 2). Despite the ad-
`verse effect profile,
`it is still an established thera-
`peutic option.
`
`b) Propiverine hydrochloride
`
`Several aspects of the preclinical, pharmacokinetic,
`and clinical effects of propiverine have been reviewed
`by Madersbacher and Murz [2001]. The drug is rapid-
`ly absorbed (tmax 2 h), but has a high first pass me-
`tabolism, and its biological availability is about 50%.
`Propiverine is an inducer of hepatic cytochrome P4 50
`enzymes in rats in doses about 100-times above the
`therapeutic doses in man [Walter et al., 2003]. Sever-
`al active metabolites are formed which quantitatively
`and qualitatively differ from the mother compound
`[Haustein et al., 1988; Muller et al., 1993; Wuest et
`al., 2006; Zhu et al., 2008; Sugiyama et al., 2008].
`Most probable these metabolites contribute to the
`clinical effects of the drug, but their individual contri-
`butions have not been clarified [Michel and Hegde,
`2006]. The half-life of propiverine itself is about 11-14
`n. An extended release preparation was shown to be
`effective [Junemann et al., 2006; May et al., 2008].
`Oral absorption of propiverine is sitedependent and
`influenced by dosage form and circadiantimeu de-
`pendent elimination processes [May et al.. 2008].
`
`Propiverine has combined antimuscarinic and cal-
`cium antagonistic actions [Haruno. 1992; Tokuno et
`al., 1993]. The importance of the calcium antagonis-
`tic component for the drug's clinical effects has not
`been established. Propiverine has no selectivity for
`muscarinic receptor subtypes. The effects of propiv-
`erine on cardiac ion channels and action potentials
`were investigated by Christ et al., [2008]. Propiver-
`ine blocked in a concentration-dependent manner
`HERG channels expressed in HEK293 cells, as well
`as native |(Kr) current in ventricular myocytes of
`guinea pig. However, action potential duration was
`not prolonged in guinea-pig and human ventricular
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`
`tissue, and the investigators concluded that their
`results did not provide evidence for an enhanced
`cardiovascular safety risk with the drug .
`
`Propiverine has been shown to have beneficial ef-
`fects in patients with D0 in several investigations.
`Thiiroff et al [1998] collected 9 randomized studies
`on a total of 230 patients, and found a 17% reduc-
`tion in micturitions per 24 hours, a 64 ml increase
`in bladder capacity, and a 77% (range 33-80%)
`subjective improvement. Side effects were found
`in 14 % (range 8—42%). In patients with neurogenic
`DO. controlled clinical
`trials have demonstrated
`propiverine's superiority over placebo [Stohrer
`et al., 1999]. Propiverine also increased bladder
`capacity and decreased maximum detrusor con-
`tractions. Controlled trials comparing propiverine,
`flavoxate and placebo [Wehnert et al., 1989], and
`propiverine, oxybutynin and placebo [Wehnert et
`al., 1992: Madersbacher et al., 1999], have con-
`firmed the efficacy of propiverine, and suggested
`that the drug may have equal efficacy and fewer
`side effects than oxybutynin. In a comparative RCT
`including 131 patients with neurogenic DO, propiv-
`erine and oxybutynin were compared [Stohrer et al.,
`2007]. The drugs were found to be equally effective
`in increasing bladder capacity and lowering bladder
`pressure. Propiverine caused a significantly lower
`frequency of dry mouth than oxybutynin.
`
`Also in children and adolescents with neurogenic
`DO, propiverine was found to be effective [Schul-
`te—Baukloh et al., 2006: Grigoleit et al., 2006], with
`a low incidence rate of adverse events: <1.5%
`
`[Grigoleit et al., 2006]. A randomized, double-blind,
`placebo-controlled trial with parallel-group design in
`children aged 5-10 yr was performed by Marschall-
`Kehrel et al. [2009]. Of 171 randomized children. 87
`were treated with propiverine and 84 with placebo.
`Decrease in voiding frequency per day was the pri-
`mary efficacy parameter; secondary endpoints in-
`cluded voided volume and incontinence episodes.
`There was a significant decrease in voiding fre-
`quency episodes for propiverine versus placebo.
`Superiority could also be demonstrated for voided
`volume and incontinence episodes per day. Propiv-
`erine was well-tolerated: 23% of side-effects were
`
`reported for propiverine and 20% for placebo.
`
`In a randomised, double—blind, multicentre clini-
`cal trial, patients with idiopathic DO were treated
`with 15 mg propiverine twice daily or 2 mg TOLT-
`IR twice daily over a period of 28 days [Junemann
`et al., 2005]. The maximum cystometric capacity
`was determined at baseline and after 4 weeks of
`
`therapy. The difference of both values was used
`as the primary endpoint. Secondary endpoints
`were voided volume per micturition, evaluation of
`efficacy (by the investigator), tolerability, post void
`residual urine, and quality of life. It was found that
`the mean maximum cystometric capacity increased
`significantly (p < 0.01) in both groups. The volume
`
`at first urgency and the frequencyivolume chart pa-
`rameters also showed relevant improvements dur-
`ing treatment. The most common adverse event,
`dry mouth. occurred in 20 patients in the propiv-
`erine group and in 19 patients in the tolterodine
`group. The scores for the quality of life improved
`comparably in both groups.
`
`Madersbacher et al. [1999] compared the to|erabil-
`ity and efficacy of propiverine (15 mg three times
`daily) oxybutynin (5 mg twice daily) and placebo
`in 366 patients with urgency and urgency inconti-
`nence in a randomized, double-blind placebo—con-
`trolled clinical trial. Urodynamic efficacy of propiv-
`erine was judged similar to that of oxybutynin, but
`the incidence of dry mouth and the severity of dry
`mouth were judged less with propiverine than with
`oxybutynin. Dorschner et al.
`[2000]
`investigated
`in a double-blind, multicentre, placebo-controlled,
`randomized study, the efficacy and cardiac safety
`of propiverine in 98 elderly patients (mean age
`68 years), suffering from urgency, urgency incon-
`tinence or mixed urgency—stress incontinence. Af-
`ter a 2-week placebo run-in period,
`the patients
`received propiverine (15 mg three times daily) or
`placebo (three times daily) for 4 weeks. Propiver-
`ine caused a significant reduction of the micturi—
`tion frequency (from 8.7 to 6.5) and a significant
`decrease in episodes of incontinence (from 0.9 to
`0.3 per day). The incidence of adverse events was
`very low (2% dryness of the mouth under propiv-
`erine — 2 out of 49 patients). Resting and ambu-
`latory electrocardiograms indicated no significant
`changes. The cardiac safety of propiverine was
`further studied by Donath et al. [2011] in two com-
`prehensively designed mono—centric ECG studies
`(including 24 healthy females, followed by a sec-
`ond study on 24 male patients with coronary heart
`disease (CHD) and a pathological Pardee-Q-wave
`in the ECG). Both studies were placebo—control|ed
`and compared the effects of single (30 mg s.i.d.)
`and multiple closing (15 mg t.i.d.) of propiverine
`hydrochloride in a crossover design over 6 and 13
`days, respectively, They were performed to investi-
`gate the influence of propiverine hydrochloride and
`its main metabolite propiverine-N-oxide on cardiac
`function with regard to QTc prolongation, QTc dis-
`persion and T—wave shape. No negative effects on
`cardiac safety could be demonstrated.
`
`Abrams et al. [2006] compared the effects of propiv-
`erine and oxybutynin on ambulatory urodynamic
`monitoring (AUM) parameters, safety, and tolerabi|-
`ity in OAB patients. Patients (n="/7) received two of
`the following treatments during two 2-week periods:
`propiverine 20 mg once daily, propiverine 15 mg
`three times daily, oxybutynin 5 mg three times daily,
`and placebo. They found that oxybutynin 15 mg was
`more effective than propiverine 20 mg in reducing
`symptomatic and asymptomatic involuntary detru—
`sor contractions in ambulatory patients. Oxybutynin
`had a higher rate of dry mouth, and propiverine had
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0224
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`a more pronounced effect on gastrointestinal, car-
`diovascular, and visual function.
`
`Yamaguchi et al. [2008] performed a multicentre,
`12-week, double-blind phase III trial in Japanese
`men and women with OAB (1593 patients were
`randomized and 1584 were treated), compar-
`ing solifenacin 5 or 10 mg, propiverine 20 mg,
`and placebo. Changes at endpoint in number of
`voidsi24 hours, urgency,
`incontinence, urgency
`incontinence and nocturia episodes, volume
`voidedlvoid, restoration of continence and quality
`of life (QoL) were examined. It was found that at
`endpoint, there were greater reductions in mean
`(SD) voidsl24 hours with all drug regimens than
`with placebo. All active treatments improved the
`volume voided and QoL vs placebo; solifenacin
`10 mg reduced nocturia episodes and signifi-
`cantly improved urgency episodes and volume
`voided vs propiverine 20 mg, and solifenacin 5
`mg caused less dry mouth. Solifenacin 10 mg
`caused more dry mouth and constipation than
`propiverine 20 mg. Wada et al. [2011] performed
`a prospective nonrandomized crossover study
`of female OAB patients, assigned alternately to
`treatment with propiverine (20 mg) for 8 weeks
`then so|ifenacin(5 mg) for 8 weeks or solifenacin
`for 8 weeks then propiverine for 8 weeks. At base-
`line, 8th week and 16th week, symptoms were as-
`sessed using overactive bladder symptom score
`(OABSS). Of the 121 patients enrolled 83 were
`analysed. Both drugs were effective. Urgency
`was further improved after switching from propiv-
`erine to solifenacin, but not after switching from
`solifenacin to propiverine. Solifenacin was better
`tolerated than propiverine.
`
`In another multicentre, prospective, parallel, dou-
`bleblind, placebo—controlled trial, Lee et al. [2009]
`studied the effects of 30 mg propiverinelday in 264
`OAB patients (mean age 52.2 years). 221 of whom
`had efficacy data available from baseline and at
`least one on-treatment visit with >75 compliance.
`The study was focused on improving urgency.
`Overall, among patients treated with propiverine,
`39% rated their treatment as providing ‘much ben-
`efit', compared with 15 % in the placebo group.
`Adverse events reported by 32 (22.5%) and 10
`(12.7%) patients in the propiverine and placebo
`group were all tolerable.
`
`Masumori et al. [2011] examined prospectively the
`efficacy and safety of propiverine in patients with
`overactive bladder (OAB) symptoms who poorly
`responded to previous treatment with solifenacin,
`tolterodine or imidafenacin. Of 73 patients enrolled
`(29 males and 44 females, median age 71 years),
`52 completed the protocol treatment. The OABSS
`was significantly improved by propiverine treat-
`ment. The scores of OAB symptoms (nighttime
`frequency, urgency and urge incontinence) except
`daytime frequency also improved significantly. No
`
`increase in PVR was observed. The most frequent
`adverse event was dry mouth (13.7%), followed by
`constipation (6.8%).
`
`In a non—controlled study in patients with wet OAB
`the efficacy of propiverine on symptoms and quality
`of life was confirmed [Komatsu et al. 2009].
`
`Assessment
`
`Propiverine has a documented beneficial effect in
`the treatment of OABIDO (Table 2), and seems to
`have an acceptable side effect profile.
`
`c) Fla voxate hydrochloride
`
`Flavoxate is often discussed as a drug with mixed
`actions, however. its main mechanism of action may
`not be antimuscarinic.Flavoxate is well absorbed,
`and oral bioavailability appeared to be close to
`100% [Guay, 2003]. The drug is extensively me-
`tabolized and plasma half-life was found to be 3.5 h
`[Sheu et al., 2001]. Its main metabolite (3—methylfla—
`vone—8-carboxylic acid, MFCA) has been shown to
`have low pharmacological activity [Cazzulani et al.,
`1988; Caine et al., 1991]. The main mechanism of
`flavoxate's effect on smooth muscle has not been
`
`established. The drug has been found to possess
`a moderate calcium antagonistic activity,
`to have
`the ability to inhibit phosphodiesterase, and to have
`local anesthetic properties; no antimuscarinic ef-
`fect was found [Guarneri et al., 1994]. Uckert et
`al. [2000], on the other hand, found that in strips
`of human bladder, the potency of flavoxate to re-
`verse contraction induced by muscarinic receptor
`stimulation and by electrical field stimulation was
`comparable,
`It has been suggested that pertussis
`toxin-sensitive G-proteins in the brain are involved
`in the flavoxate-induced suppression of the micturi-
`tion reflex, since intracerebroventricularly or intra-
`thecally administered flavoxate abolished isovolu—
`metric rhytmic bladder contractions in anesthetized
`rats [Oka et al., 1996].
`
`The clinical effects of flavoxate in patients with DO
`and frequency, urgency and incontinence have
`been studied in both open and controlled investiga-
`tions. but with varying rates of success [Ruffman,
`1988]. Stanton [1973] compared emepronium bro-
`mide and flavoxate in a double—blind, cross—over
`study of patients with detrusor overactivity and re-
`ported improvement rates of 83% and 66% after fla-
`voxate or emepronium bromide, respectively, both
`administered as 200 mg 3 times daily.
`In another
`doubIe—blind. cross—over study comparing flavoxate
`1200 mglday with that of oxybutynin 15 mg daily
`in 41 women with idiopathic motor or sensory ur-
`gency, and utilising both clinical and urodynamic
`criteria, Milani et al. [1993] found both drugs effec-
`tive. No difference in efficacy was found between
`them, but flavoxate had fewer and milder side ef-
`fects. Other investigators. comparing the effects of
`flavoxate with those of placebo. have not been able
`
`651
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0225
`
`

`
`to show any beneficial effect of flavoxate at dosages
`up to 400 mg three times daily [Briggs et al.. 1980;
`Chapple et al., 1990; Dahm et al., 1995]. In general,
`few side effects have been reported during treat-
`ment with flavoxate. On the other hand its efficacy.
`compared to other therapeutic alternatives,
`is not
`well documented (Table 2).
`
`- Assessment
`
`No RCTs seem to have been performed with flavox—
`ate during the last decade. The scarcity of docu-
`mented clinical eflicacy should be considered be-
`fore using the drug.
`
`3. CL|NfCAL USE OF ANTIMUSCARINICS
`
`The clinical relevance of efficacy of antimuscarin-
`ic drugs relative to placebo has been questioned.
`Herbison et al. [2003] stated in a widely discussed
`article:
`"Anticholinergics produce significant
`im-
`provements in overactive bladder symptoms com-
`pared with placebo. The benefits are, however, of
`limited clinical significance" Large meta—ana|yses
`of studies performed with the currently most widely
`used drugs [Chapple et al.. 2005; 2008; Novara et
`al., 2008], clearly show that antimuscarinics are of
`significant clinical benefit. Novara et al. [2008] re-
`viewed 50 RCTs and 3 pooled analyses. which they
`considered of good methodological quality. They
`concluded that still more clinical studies are needed
`
`to decide which ofthe drugs should be used as first-,
`second-. or third-line treatment. Reviewing informa-
`tion from more than 12,000 references. Chapple et
`al. [2008], based their conclusions ("antimuscarinics
`are efficacious, safe. and well tolerated treatments")
`on 73 RCTs selected for their meta—analysis. It was
`recommended that since the profiles of each drug
`(see below) and dosage differ, these factors should
`be considered in making treatment choices.
`
`The durability of the effects of antimuscarinics is not
`known and the relapse rate of symptoms after dis-
`continuation of treatment has not been systematically
`studied.
`In 173 women with OAB symptoms for >6
`months, Lee et a|.[2011] studied in a prospective, ran-
`domized. open-label, trial what happened 3 months
`after the patients had been successfully treated for 1,
`3, or 6-months. The relapse rate was 62%, and the
`request for treatment was 65 %. indiretly suggesting
`an efficacy of treatment. None of the antimuscarinic
`drugs in common clinical use (darifenacin, fesotero-
`dine,
`imidafenacin, oxybutynin, propiverine,
`solif-
`enacin. tolterodine or trospium) is ideal as a first-line
`treatment for all OABIDO patients. Optimal treatment
`should be individualized,
`implying that the patient's
`co-morbidities and concomitant medications, and the
`pharmacological profiles of the different drugs, should
`be taken into consideration [Chapple et al., 2008].
`
`To compare the effects of different antimuscarinic
`drugs for OAB symptoms, Madhuvrata et al. [2012]
`analyzed 86 trials, 70 with parallel and 16 with cross-
`
`over designs (31,249 adults). They concluded that
`when the prescribing choice is between oral imme-
`diate release oxybutynin or tolterodine, tolterodine
`might be preferred for reduced risk of dry mouth.
`ER preparations of oxybutynin or tolterodine might
`be preferred to immediate release preparations be-
`cause there is less risk of dry mouth. Comparing
`solifenacin and immediate release tolterodine, so-
`lifenacin might be preferred for better efficacy and
`less risk of dry mouth. Fesoterodine might be