Female Urology
`
`Fesoterodine Dose Response in Subjects
`With Overactive Bladder Syndrome
`
`Vik Khullar, Eric S. Rovner, Roger Dmochowski, Victor Nitti, Joseph Wang,
`
`and Zhonghong Guan
`
`OBJECTIVES
`
`METHODS
`
`RESULTS
`
`CONCLUSIONS
`
`To compare the efficacy of fesoterodine 4 mg versus 8 mg in treating subjects with overactive
`bladder (CAB) syndrome.
`This is a pooled analysis of data from 2 randomized placebo (PBO)-controlled phase Ill trials.
`Eligible subjects with frequency and urgency or urgency urinary incontinence (UUI) were
`randomized to PBO or fesoterodine 4 or 8 mg for 12 weeks. Subjects assessed efficacy using 3-day
`bladder diaries recording the time of each void, urgency, and incontinence episode. Endpoints
`included treatment response (based on a 4:point Treatment Benefit scale) and change from
`baseline in micturitions, UUI episodes, mean volume voided. urgency episodes, and continent
`days. We assessed tolerability and safety by evaluating adverse events, residual urine volume,
`laboratory parameters, and treatment withdrawals.
`At the end of treatment, both doses of fesoterodine showed statistically significant improvements
`in all efficacy endpoints versus P130 (P <0.01). These effects were seen 2 weeks after initiation
`of treatment (the earliest evaluation point) and were sustained throughout the treatment period.
`Fesoterodine 8 mg performed significantly better than fesoterodine 4 mg in improving all diary
`variables (P <0.05) except micturition frequency, demonstrating a dose—response relationship.
`Adverse events reported more frequently with fesoterodine than with PBO included dry mouth,
`constipation, and urinary tract infection.
`Both fesoterodine 4 and 8 mg are effective in improving OAB symptoms. The higher 8—mg dose
`provides additional benefit compared with the lower dose in improving most bladder diary
`variables, thus offering the possibility of dose flexibility and titration. UROLOGY 71: 839-843,
`2008. © 2008 Elsevier lnc.
`
`any patients with overactive bladder (DAB)
`syndrome are successfully managed with an-
`timuscarinic agents, but responses are vari-
`able.‘ Further therapeutic benefit might be achieved
`with higher doses; however, dose escalation has not
`become routine in clinical practice.2 This may,
`in
`part, be because previous fixed—dose studies with the
`antimuscarinic agents darifenacinm and solifenacin”
`have failed to demonstrate a clear efficacy dose-
`response in parallel dosing studies. Any new therapeu-
`
`Dr. Vik Khullrir has been a consultant and investigator in elinierii trials sponsored by
`Pfizer hie. Drx. Erie Rmmer and Roger Dmoelmwxlci have served as etinxulrzi:-its and
`investigatrrrs on elinirai
`trials sponsored by Pfizer Inc. Dr. Victor Nitti has been a
`L‘i)7L‘.'uf££i.71I and l.ei.'iurer sponszoretl
`Pfizer lnc. Joseph Wang and Dr. Zhorigliong (Juan
`are employed by Pfizer Inc.
`Scfiwarz Bioscienees GmbH and Pfizer lne.
`Fumling for tfiis study was provided
`Edimriul cissisiuiice was jiruuiaieci hy Linda M1;-rkel, Ph.D., fnmi Cmnpleie Healtlmire
`Communications, lnc., and was funded by Pfizer Inc.
`From St. M.tiry'.\ HtIs[Jiiul, lrnperiul College, Lumlun, United Kingdinn; the Metlieril
`Uniuersitj' of South Carolina. Cfiariestun, South Carolina: the Vanderbilt University
`Mecliezii Center, Nashville, Tennessee; the New York University Medical Center and
`Pfizer inc, New York, New Yr)’rl<
`Reprint requests: Viic Kfiullar, M.D., Department of Urogyneculugy, St. Mary's
`Hcispital, linperiui College, Carnbridge Wing, Freed Street, Lmiduri W2 INY, United
`Kingdom. E—rnriii: uik.lchullar@impe1-ia1.ae.uk
`Suhrniued; Segiicvnher 24, 2007, accepted {with rcvisirnrisir Deceniber 5, 2007
`
`© 2008 Elsevier Inc.
`
`All Rights Reserved
`
`tic agent that can demonstrate significantly improved
`efficacy and greater symptomatic relief at a higher dose
`would be beneficial.
`Fesoterodine is a nonselective oral antimuscarinic
`
`agent that exerts its pharmacologic effects as a com»
`petitive muscarinic receptor antagonist. Fesoterodine
`acts as a prodrug; when administered,
`it
`is rapidly
`hydrolyzed by nonspecific esterases to the active me—
`tabolite, 5-hydroxymethyl tolterodine (5-1-IMT).-" Af-
`ter oral closing, the parent compound is not detectable
`in plasma.7 The main active metabolite of fesoterod«
`ine, 5-HMT,
`is identical to the active metabolite of
`tolterodine; 5-HMT is formed from tolterodine by
`cytochrome P450 ZD6 —mediated oxidation in the liv-
`er.8 In phase I studies it has been demonstrated that
`fesoterodine is associated with a dose—dependent phar-
`macokinetic profileg and low pharmacokinetic vari«
`ability.l0
`The purpose of this pooled analysis was to evaluate
`the 2 doses of fesoterodine used in the phase III clin-
`ical studies (4 and 8 mg) for dose—dependent increases
`in efficacy as well as safety and tolerability in a larger
`population. The goal was to provide evidence to sup-
`
`O0904295/O8/$34.00
`doi:10.1016/j.uro|ogy.2007.12.017
`
`839
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2081 - 0001
`
`

`
`Table 1. Baseline demographic and clinical characteristics*
`
`Characteristic
`
`Gender, % (n) women
`Mean age, yr (range)
`Ethnic origin, % (n)
`White
`Black
`Asian
`Other
`Time since OAB diagnosis, yr (SD)
`Previous treatment for OAB, % (n)
`incontinent, % (n)*
`
`PBO (n = 554)
`
`78 (430)
`57 (19-88)
`
`89 (494)
`5 (29)
`2 (9)
`4 (22)
`9.8 (10.3)
`50 (274)
`76 (416)
`
`Fesoterodine 4 mg
`(n = 554)
`
`Fesoterodine 8 mg
`(n : 566)
`
`78 (434)
`58 (19-86)
`
`88 (490)
`5 (26)
`1 (8)
`5 (so)
`9.1(1o.3)
`48 (264)
`80 (427)
`
`80 (452)
`57 (20-91)
`
`91 (514)
`4 (24)
`1 (7)
`4 (21)
`1o.1(11.5)
`50 (283)
`81 (441)
`
`FAS = full analysis set; OAB = overactive bladder; PBO = placebo; SD = standard deviation.
`* Based on safety population (ie, all subjects who took 21 dose of medication).
`T Based on FAS population.
`
`port the practice of dose individualization in subjects
`with OAB.
`
`MATERIAL AND METHODS
`
`Study Design
`This was a pooled analysis of data from 2 fixed-dose, multi-
`center, double—blind, placebo (PBO)-controlled trials with sim-
`ilar incltision/excltision criteria.“'12 Eligible subjects were ran-
`domized to PBO, fesoterodine 4 mg, or fesoterodine 8 mg, for 12
`weeks. One trial also used tolterodine extended release 4 mg as
`an active comparator; those data are published elsewhere.“
`
`Subjects
`Eligible subjects (18 years of age or older) included men and
`women with OAB syndrome for 6 or more months;
`this in-
`cluded urinary frequency (8 or more micturitions per 24 hours)
`and urinary urgency (6 or more episodes during the 3-day diary
`period) or UUI (3 or more episodes during the 3-day diary
`period). After the start of the trial, a protocol amendment was
`made to require UUI to ensure enrollment of a sufficient num-
`ber of subjects with UUI (prespecified in the protocol to be 80%
`of each treatment group). The amended inclusion criterion
`required 3 or more UUI episodes to be recorded in the 3-day
`diary at the end of the placebo run-in for all remaining sub-
`jects.“'l2 Subjects had to have at least moderate bladder prob-
`lems on a 6-point Likert scale.”
`Key exclusion criteria included the presence of lower urinary
`tract pathology that could,
`in the investigator’s opinion, be
`responsible for urgency or incontinence (for example, significant
`stress incontinence, urolithiasis, interstitial cystitis, urothelial
`tumors); pelvic organ prolapse grade Ill or higher; clinically
`relevant bladder outlet obstruction; postvoid residual urine vol-
`ume greater than 100 mL; polyuria (more than 3 L/24 hours);
`symptomatic or recurrent urinary tract infections; current treat-
`ment with antimuscarinic agents; a neurogenic cause of OAB
`symptoms; clinically relevant arrhythmia, unstable angina, or a
`QTCB interval greater than 500 ms; current
`treatment, or
`treatment within the past 4 weeks, with electrostimulation or
`bladder training during the past 4 weel<s.”'l2
`
`void, volume voided, urgency, and UUl episodes. Voided
`volumes were recorded on 1 day of the 3-day diary.
`The primary endpoint in both trials was the change from
`baseline in the number of micturitions per 24 hours. Co-primary
`endpoints in both trials were change from baseline in the mean
`number of UUI episodes per 24 hours, and treatment response
`(a yes/no variable derived from a 4-point Treatment Benefit
`scale). Secondary efficacy endpoints included changes in mean
`volume voided (MVV) per micturition, mean number of day-
`time micturitions, mean number of nocturnal micturitions, con-
`tinent days per week (data normalized from the 3-day bladder
`diary), and mean number of urgency episodes per 24 hours.
`
`Statistical Analysis
`We performed parametric analysis for continuous variables of
`the pooled data on all randomized subjects for whom baseline
`and double-blind treatment data were obtained (full analysis set
`[FAS]), using an analysis of covariance model with treatment
`and region as factors and baseline value as a covariate. We
`conducted nonparametric sensitivity analysis using the Wil-
`coxon rank sum test. Treatment response was analyzed using
`the asymptotic normal approximation method. ln exploratory
`analyses, we calculated median percentage change from baseline to
`week 2 and week 12 for bladder diary endpoints, and conducted
`statistical hypothesis testing for secondary endpoints.
`We applied a sequentially rejective closed-test procedure to
`the primary variables to adequately account for multiplicity.
`According to requirements of the U.S. Food and Drug Admin-
`istration, the test procedure started with micturition frequency
`per 24 hours, and performed the test of fesoterodine 8 mg versus
`PBO for this variable, stepped down to the fesoterodine 4 mg
`versus PBO test in the event of statistical significance for the
`8-mg dose group, and continued with the respective tests for the
`co-primary endpoint of number of UUIs per 24 hours if results
`for the micturition variable were significant for both doses.
`We conducted safety analyses on all subjects who took at
`least
`1 dose of trial medication after randomization (safety
`population). Demographic characteristics are also presented for
`this population.
`
`Efficacy Analysis
`Efficacy was assessed using a 3-day bladder diary, which was
`completed before randomization and at 2, 8, and 12 weeks
`after initiating treatment. Subjects recorded the time of each
`
`Subjects
`Table 1 presents the baseline demographics. Subjects
`reported a mean (i standard deviation [SD]) age of 57
`
`RESULTS
`
`840
`
`UROLOGY 71 (5), 2008
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2081 - 0002
`
`

`
`Table 2. Primary and secondary efficacy endpoints at 2 weeks and end of treatment (EOT)
`
`Range of
`Mean
`Baseline
`Values
`
`2 wk
`
`FESO
`4 mg
`
`P80
`
`FESO
`8 mg
`
`PBO
`
`EOT
`
`FESO
`4 mg
`
`FESO
`8 mg
`
`Micturition frequency/24 h
`
`12.0-12.2 LS mean change
`Median % change
`n
`
`-0.7 —1.0* —1.3*
`-4.5
`-8.3* -10.7*
`538
`522
`537
`
`-2.0*
`-1.7*
`-1.0
`-10.0 -15.5* -17.1*
`545
`532
`543
`
`UUI episodes/24 h
`
`3.7-3.9
`
`LS mean change
`Median % change
`n
`
`-1.1 —1.9* —2.3**
`-0.6 —1.5* —1.7*
`-23.0 —43.2*
`-58.3“ -42.9 —75.0*
`-83.3“
`410
`422
`437
`416
`427
`441
`
`S mean change
`
`45
`532
`7.2
`529
`
`61*
`514
`18.4*
`518
`
`67“
`532
`33.3“
`532
`
`49
`545
`9.0
`539
`
`69*
`532
`22.2*
`531
`
`77”
`543
`33.6“
`540
`
`% yes
`
`n L
`
`Fl
`
`Treatment response
`
`—
`
`MVV, mL
`
`155-156
`
`Urgency episodes/24 h
`
`11.4-11.8 LS mean change
`Median % change
`['1
`
`-0.7
`-4.1
`538
`
`-1.2*
`-8.8
`522
`
`-1.6“
`-12.1“
`537
`
`-2.3*
`-2.0*
`-0.9
`-7.7 —16.7* —18.6*
`545
`532
`543
`
`Continent days/wki’
`
`0.7-0.8
`
`LS mean change
`['1
`
`0.8
`410
`
`1.5*
`422
`
`2.0“
`437
`
`1.8
`416
`
`2.6*
`427
`
`3.1”
`441
`
`FESO = fesoterodine; LS = least square; MW = mean volume voided: PBO = placebo; UUI = urgency urinary incontinence.
`* P <D.01 versus PBO.
`
`1 P <0.05 versus fesoterodine 4 mg.
`* Extrapolated from 3-day diary data.
`
`(it 13) years, and most were women (79%) and white
`(90%), with 76% to 81% of subjects reporting inconti-
`nence at baseline. The mean time since first diagnosis or
`onset of OAB was 8 to 9 years. Approximately half of the
`subjects had previously received pharmacotherapy for
`their OAB. Only 5% to 8% of subjects in any group had
`been diagnosed with OAB for less than 1 year before
`enrollment;
`therefore,
`the population in this trial was
`primarily composed of subjects with long—term, estab-
`lished OAB.
`
`Efficacy
`By the end of treatment, both fesoterodine—treated groups
`(4 and 8 mg) showed statistically significant
`improve»
`ments in primary and secondary efficacy endpoints from
`baseline, including micturition frequency per 24 hours,
`UUI episodes per 24 hours, treatment response, MVV
`per micturition, urgency episodes per 24 hours, and con»
`tinent days per week versus PBO (P <0.0l) (Table 2).
`These effects were seen at the first clinical evaluation, 2
`weeks after initiation of treatment, and were sustained
`throughout the study (Fig. 1). Fesoterodine 8 mg per-
`formed significantly better than fesoterodine 4 mg in
`improving all diary variables (P <0.05) with the excep-
`tion of micturition frequency, which showed a numerical
`advantage (change from baseline -1.97 and -1.74 for
`fesoterodine 8 and 4 mg, respectively [P = 0184]).
`
`Safety and Tolerability
`The most common treatmenpemergent adverse events
`(2% or greater in any fesoterodine group) are listed in
`
`Table 3 and include dry mouth, constipation, urinary
`tract
`infection, and headache;
`the majority of these
`events were mild to moderate in nature (Table 3).
`Overall, 5.2% of subjects (87 of 1674) discontinued
`the study prematurely owing to an adverse event (AE):
`PBO, 3.4% (19 of554)§fesote1-odine 4 mg, 4.9% (27 of
`554); and fesoterodine 8 mg, 7.2% (41 of 566) during the
`treatment phase. No single AE resulted in withdrawal of
`1% or greater of subjects in any treatment group. Among
`the reasons for discontinuation were urinary retention
`(defined by investigator and not necessarily requiring
`intervention), which occurred in 1% (6 of 554) of sub-
`jects in the fesoterodine 4 mg group and 1% (8 of 566) of
`subjects in the fesoterodine 8 mg group, and led to
`discontinuation in 8 subjects. Similarly, discontinuation
`rates from dry mouth and constipation were low (less
`than 1%), with 9 and 3 subjects (of 1120 subjects receiv—
`ing fesoterodine) withdrawing, respectively.
`
`COMMENT
`
`Fesoterodine significantly improved OAB symptoms as
`early as 2 weeks after initiation of treatment, the earliest
`evaluation point included in the trials, compared with
`P130. Fesoterodine 8 mg was significantly more effica—
`cious than the 4-mg dose in improving UUI episodes,
`urgency episodes, bladder capacity (assessed as MVV per
`micturition), continent days, and treatment response.
`This dose—response relationship is rare in para1le1—group
`studies of antimuscarinics that offer multiple doses. Only
`oxyhutynin has shown statistically significant differences
`
`UROLOGY 71 (5), 2008
`
`841
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2081 - 0003
`
`

`
`Table 3. Treatment~emergent adverse events at end of
`study (22% of subjects receiving fesoterodine)
`
`PBO
`(N = 554)
`% (n)
`
`Fesoterodine Fesoterodine
`4 mg
`8 mg
`(N = 554)
`(N = 566)
`% (n)
`% (n)
`
`7 (39)
`5 (27)
`2 (11)
`<1 (1)
`2 (11)
`1 (8)
`<1 (1)
`<1 (2)
`3 (17)
`
`2 (12)
`1 (5)
`0
`4 (23)
`3 (19)
`<1 (3)
`<1 (1)
`0
`<1 (3)
`<1 (2)
`2 (12)
`
`19 (104)
`15 (84)
`3 (16)
`<1 (4)
`4 (23)
`2 (14)
`1 (8)
`<1 (1)
`3 (18)
`
`2 (11)
`1 (7)
`0
`4 (24)
`3 (15)
`1 (6)
`<1 (3)
`1(8)
`2 (9)
`1 (5)
`2 (14)
`
`35 (196)
`22 (126)
`9 (53)
`3 (17)
`6 (34)
`3 (18)
`2 (14)
`<1 (2)
`4 (24)
`
`3 (15)
`1 (8)
`<1 (1)
`3 (15)
`2 (9)
`1(5)
`<1 (1)
`4 (21)
`2 (13)
`2 (13)
`2 (10)
`
`Adverse Event
`
`Dry mouth
`Mild
`Moderate
`Severe
`Constipation
`Mild
`Moderate
`Severe
`Urinary tract
`infection
`Mild
`Moderate
`Severe
`Headache
`Mild
`Moderate
`Severe
`Lacrimal disorder
`Dyspepsia
`Dry throat
`Upper respiratory
`tract
`infection
`
`Nasopharyngitis
`
`2 (14)
`
`3 (18)
`
`1 (7)
`
`P80 = placebo.
`
`among the 15—mg dose and the 2 lower doses (5 and 10
`mg) for reduction of UUI episodes and MVV per micv
`turition. 14 Dose separation has not been demonstrated for
`efficacy outcomes with darifenacin,1"l5 solifenacin,5 or
`tolterodine.16'18 The reason for the Fesoterodine dose
`
`response may lie in its pharmacokinetic and pharmaco-
`logic profile. Unlike tolterodine, darifenacin, or solifena—
`cin, which are metabolized in the liver to produce active
`metabolites,” hepatic enzymes are not involved in the
`conversion of fesoterodine to its active metabolite. In-
`
`stead, this conversion is mediated by nonspecific ester«
`ases, which are not known to exhibit
`interindividual
`variability, nor to be involved in drug interactions. In
`addition, given the ubiquitous localization of nonspecific
`esterases, intersubject variability in the formation of the
`active metabolite was demonstrated to be very low.]°
`Similar to other antimuscarinic agents, such as 0xybu«
`tynin. solifenacin, and darifenacin, adverse events with
`fesoterodine, such as dry mouth,
`increased in a dose—
`dependent fashion. Although adverse events were ex-
`pected based on the antimuscarinic mechanism of action,
`the relative contribution of typical antimuscarinic ad-
`verse events for any antimuscarinic agent most
`likely
`results from its unique balance of activity at different
`muscarinic receptor subtypesl For example,
`the inci-
`dence of dry mouth increased from 19% (fesoterodine 4
`mg) to 35% (fesoterodine 8 mg; PBO, 7%) with most
`cases being mild to moderate in nature. This incidence
`rate is somewhat higher than that reported for solifena-
`
`—I:|— Placebo
`
`—A— FESO 4 mg
`—o— FESO 8 mg
`
`NumberofMicturitions
`
`1>
`
`
`
`8wk
`
`12 wk
`EOT
`
`—I:I— Placebo
`
`—.n— FESO 4 mg
`—'I— FESO 8 mg
`
` NumberofUUI
`Episodesper24hr
`
`1
`
`BL
`
`2 wk
`
`8 wk
`
`12 wk
`EOT
`
`—v— FESO 8 mg
`
`-3- FESO 4 mg
`—I:|— Placebo
`
`*
`
`4:
`
`*T
`*
`
`"T
`
`,.
`
`B
`
`3200
`5190
`
`CO
`
`93 180
`5
`jg 170
`160
`
`E5
`
`OJ
`:3.
`
`g 150
`5 14o
`
`(3
`
`BL
`
`2 wk
`
`8 wk
`
`12 wk
`
`EOT
`
`Figure 1. (A) Time course of micturition frequency with PBO
`or fesoterodine 4 or 8 mg. Data shown are mean : SEM at
`baseline, at 2 and 8 weeks, and at end of treatment (12
`weeks, EOT). *P <0.05 versus PBO; *P <0.05 versus fe-
`soterodine 4 mg. (B) Time course of number of UUI episodes
`with PBO or fesoterodine 4 or 8 mg. Data shown are mean :
`SEM at baseline, at 2 and 8 weeks, and at end of treatment
`(12 weeks, EOT). *P <0.05 versus PBO; *P <0.05 versus
`fesoterodine 4 mg. (C) Time course of MW per micturition
`with PBO or fesoterodine 4 or 8 mg. Data shown are mean :
`SEM at baseline, at 2 and 8 weeks, and at end of treatment
`(12 weeks, EOT). *P <0.05 versus PBO; TP <0.05 versus
`fesoterodine 4 mg. BL = baseline; PBO = placebo.
`
`842
`
`UROLOGY 71 (5), 2008
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2081 - 0004
`
`

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`Yamanouchi Pharma America, Inc., and ClaxoSmithKline, Nor-
`man. OK, 2004.
`Gomez A, Martos F, Bellido 1, et al: Muscarinic receptor subtypes in
`human and rat colon smooth muscle. Biochem Pharmacol 43:
`2413-2419, 1992.
`Matsui M, Motomura D, Fujilcawa T, at al: Mice lacking M2 and
`M3 muscarinic acetylcholine receptors are devoid of cholinergic
`smooth muscle contractions but still viable. ] Neurosci 22: 10627-
`10632, 2002.
`Napier C, and Gupta P: Darifenacin is selective for the human
`recombinant M3 receptor subtype. Presented at the 32nd annual
`meeting of the International Continence Society, August 27 to 29,
`2002, Heidelberg, Germany.
`Nelson CP, Gupta P, Napier CM, er 01: Functional selectivity of
`muscarinic receptor antagonists for
`inhibition of m3-mediated
`phosphoinositide responses in guinea pig urinary bladder and sub-
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`2004.
`
`10.
`
`ll.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
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`21.
`
`22.
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`23.
`
`cinm (5 mg, 11%; 10 mg, 28%; PBO, 4%) and is lower
`than that reported for oxybutynin” (5 mg, 56%; 10 mg,
`68%; 15 mg, 70%) and darifenacinlfi (7.5 mg, 23%; 15
`mg, 40%; PBO, 8%).
`lnterestingly, compared with other antimuscarinic
`agents, the incidence of constipation with fesoterodine
`was relatively low, increasing from 4% with the 4-mg
`dose to 6% with the 8-mg dose. In comparison, consti-
`pation was 4% to 5% with oxybutynin (for 5, 10, or 15
`mg),l4 5% and 13% with solifenacin (5 and 10 mg,
`respectively),2O and 16% and 25% with darifenacin (7.5
`and 15 mg, respectively)” In the gastrointestinal tract,
`as in the bladder, M2 receptors outnumber M3 receptors
`approximately 4 to 1:”; the M3 subtype mediates cholin-
`ergic stimulation of gastrointestinal motility.” The low
`incidence of constipation with fesoterodine may be at-
`tributed to its nonselective receptor binding profile,
`which is in contrast to the M3 selectivity of darifena-
`cin.2l”24
`
`Pooled data from these two phase 111 trials have thus
`demonstrated that fesoterodine has the ability to signif-
`icantly reduce OAB symptoms,
`including urgency and
`UUI, in a dose—dependent fashion. The 8-mg dose pro-
`vides significant additional benefit
`in improving most
`bladder diary variables compared with the lower dose and
`allows for dose titration and individualization in subjects
`with OAB. This allows subjects to achieve a more opti-
`mal balance between treatment efficacy and tolerability.
`
`References
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`l. Chapple C, Khullar V, Gabriel Z, at al: The effects of antimusca-
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`5. Cardozo L, Lisec M, Millard R, et al: Randomized, double-blind
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`atic overactive bladder. BJU Int 93: 303-310, 2004.
`
`24.
`
`UROLOGY 71 (5), 2008
`
`843
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2081 - 0005