Efficacy, Safety and Tolerability of
`Fesoterodine for Overactive Bladder Syndrome
`
`Victor W. Nitti,*,T Roger Dmochowski,:l: Peter K. Sand,§ Hans-Theo Forst,‘ll
`Cornelia Haag-Molkentellerfll Ute Massow,‘ll Joseph Wang,|| Marina Brodsky||
`and Tamara Bavendamll
`From the Department of Urology, New York University School ofMedicine (VWN) and Pfizer, Inc. (JW, MB, TB), New York, New York,
`Department of Urology, Vanderbilt University Medical Center (RD), Nashville, Tennessee, Department of Obstetrics and Gynecology,
`Evanston Northwestern Healthcare, Feinberg School of Medicine, Northwestern University (PKS), Eoanston, Illinois, and Schwarz
`BioSciences GmbH (HTF, CHM, UM), Monheim, Germany
`
`Purpose: We evaluated the efficacy, tolerability and safety of the new antimuscarinic agent fesoterodine relative to placebo
`for overactive bladder syndrome.
`Materials and Methods: This was a randomized, double-blind, placebo controlled, multicenter trial performed in the United
`States. Overall 836 subjects with urinary frequency, urinary urgency or urgency urinary incontinence were randomized to
`placebo (274), 4 mg fesoterodine (283) or 8 mg fesoterodine (279) once daily for 12 weeks. The primary efficacy end point was
`the change in the number of micturitions per 24 hours. Co-primary end points were the change in the number of urgency
`urinary incontinence episodes per 24 hours and the treatment response. Secondary efficacy end points were other bladder
`diary variables, such as the change in mean voided volume per micturition, number of continent days and number of urgency
`episodes per 24 hours. Tolerability and safety were assessed by evaluating adverse events, electrocardiograms, post-void
`residual urine volume, laboratory parameters and treatment withdrawals.
`Results: Treatment with 4 or 8 mg fesoterodine resulted in statistically significant and clinically relevant improvements from
`baseline to end of treatment for the primary and co-primary end points compared with placebo (p <0.05). Results for most
`secondary end points, including mean voided volume per micturition, number of continent days and number of urgency
`episodes per 24 hours, were also significantly improved vs placebo. The adverse events reported more frequently with
`fesoterodine than with placebo were dry mouth, constipation and urinary tract infection.
`Conclusions: The 2 doses of fesoterodine were well tolerated and they statistically significantly improved overactive bladder
`symptoms.
`
`Key Words: bladder; bladder, overactive; rnuscarinic antagonists; urinary incontinence; 5-hydroxyrnethyl tolterodine
`
`O veractive bladder syndrome is defined by the Inter-
`
`national Continence Society as urgency with or with-
`out UUI, usually with frequency and nocturia.1 It is
`a widespread condition affecting men and women, and inci-
`dence rates increase with age.2'3 The prevalence rate in the
`United States and Europe was reported to be 12% to 17%.2"‘
`The mainstay of OAB phannacotherapy consists of anti-
`muscarinic agents,
`such as oxybutyninf’ darifenacin,6
`
`Submitted for publication April 18, 2007.
`Study received approval from the respective institutional review
`boards.
`Supported by Schwarz Biosciences GmbH and Pfizer, Inc.
`* Correspondence: Department of Urology, New York University
`School of Medicine, 150 East 32nd St., New York, New York 10016
`(telephone: 646-825-6343; FAX: 646-825-6397; e-mail: Victor.Nitti@
`nyumc.org).
`interest and/or other relationship with Allergan,
`1‘ Financial
`Astellas, Gynecare, Novartis, Pfizer and Boston Scientific.
`i Financial
`interest and/or other relationship with Allergan,
`Novartis, Astellas and Esprit.
`§ Financial interest and/or other relationship with Pfizer, Ortho,
`Allergen, Watson, Astellas/GlaxoSmith.Kline and Indevus/Esprit.
`‘ll Financial interest and/or other relationship with Schwarz Bio-
`sciences.
`|| Financial interest andfor other relationship with Pfizer.
`For another article on a related topic see page 2683.
`
`trospium chloride,7 solifenacina and tolterodinef’ which have
`shown efiicacy for improving OAB symptoms. However, these
`benefits are offset by dose related increases in AEs, such as dry
`mouth, constipation and blurred vision. There remains a need
`for antimuscarinic agents that may provide further improve-
`ment of the therapeutic index for OAB treatment.
`FESO is a novel antimuscarinic agent that acts function-
`ally as a prodrug. It is rapidly and extensively hydrolyzed by
`nonspecific esterases to 5-HMT, which is an active metabo-
`lite responsible for all antimuscarinic activity of FESO?”
`Also, 5-HMT is the active metabolite of tolterodine, which is
`formed via CYP 2D6 mediated oxidation. The conversion of
`
`FESO to its active metabolite bypasses the hepatic CYP
`pathway, although CYP3A4 and CYP2D6 isozymes are in-
`volved in the further inactivation of 5-HMT.”
`Data from phase II studies demonstrated that FESO
`improves OAB symptoms in dose dependent fashion and it is
`well tolerated.12'13 The primary goal of this 12-week, PBO
`controlled, multicenter study was to evaluate the efficacy,
`safety and tolerability of 4 and 8 mg FESO for OAB.
`
`METHODS
`
`This was a double-blind, randomized, placebo controlled trial
`performed at 83 sites in the United States between October 30,
`
`0022-5347/07/1786-2488/0
`THE JOURNAL or UROLOGY®
`Copyright © 2007 by AMERICAN URo1.oGIcA1. ASSOCIATION
`
`2488
`
`Vol. 178, 2488-2494, December 2007
`Printed in U.S.A.
`
`DOI:10.1016Ij.juro.200'7.0B.D33
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0001
`
`

`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`2489
`
`2003 and February 10, 2005. The study was performed in
`accordance with Good Clinical Practice guidelines and the Dec-
`laration of Helsinki, The protocol was approved by the respec-
`tive institutional review boards and all subjects provided writ-
`ten informed consent before the start of the study.
`
`Subject Selection
`Eligible subjects included men and women 18 years or older
`with OAB syndrome for 6 months or greater, including urinary
`frequency (8 micturitions or greater per 24 hours) and urinary
`urgency (6 episodes or greater during the 3-day diary period) or
`UUI (3 episodes or greater during the 3-day diary period). Slow
`accrual of subjects with UUI led to the introduction of an
`amendment to ensure enrollment of a sufficient number, which
`was prespecified in the protocol to be 80% of each treatment
`group. The amended inclusion criterion required 3 or greater
`UUI episodes to be recorded in the 3-day diary at the end of the
`placebo run-in for all remaining subjects. In addition, subjects
`had to report at least moderate bladder problems on a Likert
`scale that was almost identical to the patient perception of
`bladder condition.” Women participating in the trial had to
`have a negative pregnancy test and use adequate contracep-
`tion throughout the trial.
`Key exclusion criteria were lower urinary tract pathology
`that could in the opinion of the investigator be responsible
`for urgency or incontinence, such as significant stress incon-
`tinence, urolithiasis, interstitial cystitis or urothelial tu-
`mors; pelvic organ prolapse grade III or greater; clinically
`relevant bladder outlet obstruction; PVR volume greater
`than 100 ml; polyuria (greater than 3 1/24 hours); symptom-
`atic or recurrent urinary tract infections; current treatment
`with antimuscarinic agents; a neurogenic cause of OAB;
`
`clinically relevant arrhythmia, unstable angina or a cor-
`rected QT interval (Bazett’s formula) of greater than 500
`milliseconds; or current treatment or treatment within the
`last 4 weeks with electrostimulation or bladder training.
`
`Study Design
`After a 2-week placebo run-in period eligible subjects were
`randomized 1:1:1 to PBO, or 4 or 8 mg FESO per day orally
`once daily for 12 weeks according to a computer generated
`randomization schedule stratified by site (Fig. 1). Treatment
`began the day following randomization. PBO tablets were iden-
`tical in appearance to 4 and 8 mg FESO tablets. Treatment
`compliance was assessed by counting unused trial medication
`and assessing diaries for completion. Subjects completed a
`3-day bladder diary before randomization, and 2, 8 and 12
`weeks afiser initiating treatment, in which the time of each
`micturition, incontinence episode and urgency episode, includ-
`ing severity, was recorded. Voided volumes were recorded on 1
`of the 3 diary days. Treatment response was assessed using a
`self-administered treatment benefit scale.
`
`Clinical Assessments
`
`The primary end point was the change from baseline in the
`number of micturitions per 24 hours. Co-primary end points
`were the change from baseline in the mean number of UUI
`episodes per 24 hours and the treatment response (a yes/no
`variable derived from a 4-point treatment benefit scale).
`Secondary efficacy end points were MVV per micturition,
`and the number of daytime micturitions, nocturnal micturi-
`tions, urgency episodes per 24 hours and continent days per
`week (data normalized from the 3-day bladder diary). Miss-
`ing responses were imputed via last observation carried
`
`Screened
`N=1886
`
`Enrolled in Placebo Run-In
`n=1587
`
`Randomized to Double-Blind Treatment
`n=836
`
`Fesoterodine 4 mg/d
`n=283
`
`Fesoterodine 8 mgid
`n=279
`
`Not Treated
`n=2
`
`Discontinued
`n=58
`
`Not Treated
`
`n=1 Discontinued
`
`n=56
`
`Completed
`n=225
`
`Completed
`n=223
`
`FIG. 1. Study design. 01, day
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0002
`
`Placebo
`n=274
`
`Not Treated
`n=1
`
`Discontinued
`n=41
`
`Completed
`n=233
`
`

`
`2490
`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`PBO
`
`Enrollment
`W 58,
`
`PBO
`
`FESO 4 mg
`
`FESO 8 mg
`
`4
`
`Randomization
`N=83B
`I
`'
`
`2 Weeks
`
`2
`
`0
`
`I
`'
`
`1
`
`Visit
`
`Week
`
`-2
`
`12 Weeks
`
`4
`
`4
`
`2
`
`5
`
`8
`
`FIG. 2. Subject disposition
`
`V
`
`End of Study
`
`I
`'
`
`6
`
`12
`
`RESULTS
`
`Subjects
`A total of 836 subjects were randomized and included in the
`full analysis set population (fig. 2). Table 1 lists subject
`demographic and clinical characteristics. Of the subjects
`76% were women and 82% were white. Mean age was 59
`years (range 21 to 91). Mean time since the first OAB diag-
`nosis was 10 years. Approximately half of the subjects had
`previously received OAB treatment and 81% of randomized
`subjects were incontinent based on a bladder diary com-
`pleted during the placebo run-in. Compliance with study
`medication was noted in 96% or greater of subjects during
`the double-blind phase.
`
`Efficacy
`Treatment with 4 and 8 mg FESO resulted in statistically
`significant and clinically relevant improvements vs PBO from
`baseline to end of treatment in the primary and in the 2
`
`TABLE 1. Baseline demographic and clinical characteristics
`Characteristic
`PBO
`4 mg FESO
`8 mg FESO
`
`forward. The Appendix lists the definitions of all end points.
`At 12 weeks subjects had the option to continue in a long-
`term, open label study or complete a 2-week safety followup
`after the end of treatment.
`
`Statistical Analysis
`Parametric analysis for continuous variables (micturition
`frequency and UUI episodes) was performed in the full anal-
`ysis set population, ie all randomized subjects receiving trial
`medication for whom a baseline and double-blind treatment
`
`measure was obtained, using an ANCOVA model with treat-
`ment and region as factors, and the baseline value as a
`covariate. Nonparametric sensitivity analysis was per-
`formed using the Wilcoxon rank sum test. Treatment re-
`sponse was analyzed using the normal approximation
`method. In exploratory analyses the median percent change
`from baseline to week 12 was calculated for bladder diary
`end points and statistical hypothesis testing was performed
`for secondary end points.
`A sequentially rejective closed test procedure was applied
`to the primary variables to adequately account for multiplic-
`ity. According to requirements of the United States Food and
`Drug Administration the test procedure started with mic-
`turition frequency per 24 hours and performed the test of 8
`mg FESO vs PBO for this variable, stepped down to the 4 mg
`FESO vs PBO test in the event of statistical significance and
`continuing with the respective tests for the number of UUI
`episodes per 24 hours. According to the requirements of the
`European Agency for the Evaluation of Medicinal Products
`the test procedure considered micturition frequency per 24
`hours and treatment response simultaneously, tested 8 mg
`FESO vs PBO for the 2 variables first and in the event of a
`
`statistically significant result continued to test the 4 mg
`dose vs PBO for the 2 variables.
`
`Tolerability and Safety
`Adverse events reported throughout the study duration were
`categorized and the likelihood of a causal relationship to study
`medication was determined. Clinical laboratory parameters,
`vital signs and a centrally read 12 lead electrocardiogram were
`assessed at each visit. PVR volume was measured at each visit
`
`except at week 4 and the safety followup.
`
`No. subjects
`No. women (96)
`Mean age (range)
`No. ethnic origin (96):
`White
`Black
`Asian
`Yrs since OAB diagnosis:
`Mean : SD
`No. Cl—less than 1 (93)
`No. 1—less than 5 (%)
`No. 5—less than 10 (95)
`No. 10-1955 than 15 (93)
`N0. 15 or greater (‘$42)
`No. previous OAB
`treatment (1%):
`Tolterucline
`Oxybutynin
`Trospium chloride
`ND. incontinence (‘$42)
`
`271
`(74)
`200
`59 (24-88)
`218
`(80)
`28
`(10)
`4
`(2)
`
`9.8 : 10.3
`ll
`(4)
`97
`(36)
`65
`(24)
`44
`(16)
`51
`(19)
`145
`(54)
`
`90
`101
`7
`205
`
`(33)
`(37)
`(2.6)
`(77)
`
`282
`(76)
`213
`59 (21-85)
`230
`(82)
`26
`(9)
`3
`(1)
`
`9.1 1 10.3
`16
`(6)
`118
`(42)
`59
`(21)
`39
`(14)
`50
`(18)
`139
`(49)
`
`88
`94
`6
`228
`
`(31)
`(33)
`(2.1)
`(B5)
`
`2'79
`(78)
`218
`59 (23-91)
`233
`(84)
`21
`(8)
`4
`(1)
`
`10.1 i 11.5
`B
`(3)
`111
`(40)
`68
`(24)
`40
`(14)
`52
`(19)
`149
`(53)
`
`95
`97
`3
`218
`
`(34)
`(35)
`(1.1)
`(82)
`
`of 800.
`
`ie all subjects who received 1 or greater
`Based on safety population,
`medication dose, and incontilience based on full analysis set population
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0003
`
`

`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`2491
`
`co-primary end points (p <0.05, table 2 and fig. 3). For most
`diary variables LS mean changes from baseline with 8 mg
`FESO were approximately twice those with PBO. The mean
`change from baseline in the number of micturitions and incon-
`tinence episodes per 24 hours was significantly improved by
`the 2 FESO doses compared with that of PBO. Subject reported
`treatment response rates with the 2 FESO doses were signifi-
`cantly higher than those with PBO at study end (p <0.001, fig.
`4). With respect to secondary end points 4 mg FESO showed
`significant improvement in the mean change from baseline
`compared with PBO for the number of nocturnal micturitions
`(p <0.05), urgency episodes (p <0.001) and continent days per
`week (p <0.001), whereas 8 mg FESO was significantly better
`than PBO for MVV per micturition, number of urgency epi-
`sodes, number of daytime micturitions and continent days per
`week (each p <0.001, table 2).
`
`Tolerability and Safety
`AEs. Treatment emergent AEs occurred in 55% (149 of 271),
`61% (171 of 282) and 69% (193 of 279) of subjects receiving PBO,
`and 4 and 8 mg FESO, respectively. Table 3 lists all treatment
`emergent AEs irrespective of the relationship to study medication
`that were reported by 2% or greater of subjects in any treatment
`group. Dry mouth was the most commonly reported AE. It was
`usually mild to moderate in severity and it occurred in 7% (19 of
`271), 16% (45 of 282) and 36% of subjects (99 of 279) receiving
`PBO, and 4 and 8 mg FESO, respectively.
`Urinary retention was reported in 2 Ways, including PVR
`more than 200 ml in 8 subjects and urinary retention as an
`AE in 11. Three men had a PVR of more than 200 ml and
`
`they reported urinary retention as an AE. One man (less
`than 1%) in the 4 mg FESO group, 5 female and 2 male
`subjects (2%) in the 8 mg FESO group and 0 in the PBO
`
`Micturitions.v'24 hrs:
`No. subjects
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`Median % change
`p Value
`
`UUI episodes1'24 hrs:*
`No. subjects
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`Median % change
`p Value
`
`No. treatment response (% yes)
`p Value
`MVVn’micturition:
`No. subjects
`Baseline mean 1 SD (ml)
`LS mean change 1 SE (ml)
`p Value
`
`Daytime micturitions/24 hrs:
`No. subjects
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`Median % change
`p Value
`Nocturnal micturitions/24 hrs:
`No. subjects LS mean change (median)
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`Median % change
`p Value
`
`Urgency episodes:'24 hrs:
`No. subjects
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`Median % change
`p Value
`
`Continent days/wk:”‘,'t
`No. subjects
`Baseline mean 1 SD
`LS mean change 1 SE
`p Value
`
`TABLE 2. Efficacy results (change from baseline to study end)
`P130
`4 mg FESO
`
`Primary end points
`
`266
`12.2 1
`-1.08 1 0.18
`
`-6.9
`
`205
`3.7 1
`-0.96 1 0.17
`
`-40.0
`
`266
`
`(45)
`
`Secondary and points
`261
`1 69
`159
`8.38 1 4.06
`
`266 (251)
`2.0 1 1.3
`-0.39 1 0.07
`
`-25.0
`
`205
`0.6
`1.31
`
`1.3
`0.20
`
`267
`12.9 1 3.9
`-1.61 1 0.18
`0.032
`-14.9
`<0.001
`
`228
`3.9 1 3.5
`-1.651 0.16
`0.003
`-67.4
`<0.001
`
`267
`<0.00l
`
`(64)
`
`266
`160
`152
`16.5 1 4.00
`0.150
`
`267
`10.7 1 3.4
`-1.04 1 0.16
`0.107
`-11.1
`0.008
`
`(246)
`267
`2.2 1 1.6
`-0.581 0.07
`0.042
`-33.3
`0.013
`
`267
`12.5 1
`-1.91 1
`<0.001
`-16.3
`<0.001
`
`228
`0.7 1 1.5
`2.33 1 0.19
`<0.001
`
`8 mg FESO
`
`267
`12.0 1
`-2.09 1
`<0.001
`-16.0
`<0.001
`
`218
`3.9 1 3.3
`-2.281 0.16
`<0.001
`-81.8
`<0.001
`
`267
`<0.00l
`
`(74)
`
`265
`158
`156
`1 4.04
`33.6
`<0.00l
`
`267
`10.1 1 2.9
`-1.54 1 0.16
`<0.001
`-15.6
`<0.001
`
`(244)
`267
`1.9 1 1.4
`-0.551 0.07
`0.09
`-25.0
`0.267
`
`267
`11.6 1
`-2.30 1
`<D.001
`-18.4
`<0.001
`
`218
`0.7 1
`2.80 1
`<0.D01
`
`Median percent values derived from exploratory analysis and missing end of treatment data imputed using last observation carried forward method.
`* Analysis including only subjects with 1 or greater UUI episode at baseline.
`'1' Normalized from 3-day voiding diary.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0004
`
`

`
`2492
`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`TABLE 3. Treatment emergent AE.<.'
`No. 4 mg
`FESO (9))
`282
`171(61)
`45 (16)
`14 (5)
`10 (4)
`12 (4)
`
`No. PBO (‘Fol
`271
`149 (55)
`19 (7)
`7 (3)
`11 (4)
`7 (3)
`
`No. 8 mg
`FESO (95))
`279
`193 (69)
`99 (35)
`21 (8)
`15 (5)
`9 (3)
`
`
`
`Overall
`Any AE
`Dry mouth
`Constipation
`Urinary tract infection
`Upper respiratory
`tract infection
`2 (less than 1)
`Dry eye
`12 (4)
`(3)
`Headache
`3 (1)
`(2)
`Nausea
`7 (3)
`(3)
`Diarrhea
`3 (1)
`(2)
`Sinusitis
`4 (1)
`1 (less than 1)
`Urinary retention
`6 (2)
`3 (1)
`Cough
`(3)
`1 (less than 1)
`Back pain
`(4)
`7 (3)
`Nasopharyngitis
`(3)
`6 (2)
`Hypertension
`Reported by 2% or greater of subjects in 1 or greater treatment group.
`
`(3)
`(3)
`(3)
`(2)
`(2)
`(2)
`(1)
`(1)
`(1)
`
`Ot\3l\$u'=-O7G>O7-‘l|33QO
`
`707
`
`1
`
`urinary flow was reported in 1 male subject receiving 4 mg
`FESO, and hesitancy was reported in 2 male and 1 female
`subjects on 8 mg FESO, and in 1 female on 4 mg FESO.
`Urinary retention as an AE and/or increased PVR led to
`discontinuation in 1% of the subjects in the 4 mg FESO
`group (2 of 282, including 1 male and 1 female) and in the 8
`mg FESO group (3 of 279, including 2 males and 1 female).
`Only 1 of the 21 subjects with serious AES experienced a
`serious AE (atrial fibrillation) that was deemed possibly
`related to study medication. This subject was found to have
`been on PBO. No deaths occurred during this trial.
`No clinically relevant changes were noted in the mean
`change from baseline to end of study in systolic blood pressure,
`diastolic blood pressure or heart rate. The percent of subjects
`with a QT or corrected QT interval (Fridericia’s formula) of
`greater than 450 milliseconds, or a change from baseline of 30
`milliseconds or greater at the end oftreatment was comparable
`in the active and PBO groups. The mean change in heart rate
`for PBO, and 4 and 8 mg FESO was 1, 3 and 4 bpm, respec-
`tively. There were no clinically relevant changes in laboratory
`parameters in the active and PBO treatment groups.
`
`Discontinuations. Of 836 randomized subjects 681 (81%)
`completed the 12-week study. Overall 19% of subjects (155 of
`836) discontinued the study prematurely. A total of 53 sub-
`jects withdrew because of AEs, including 4% on PBO (11 of
`271), 6% on 4 mg FESO (17 of282) and 9% on 8 mg FESO (25
`of 279) (table 4). Of AEs leading to discontinuation dry
`mouth was given as the reason by 1% of subjects (3 of 282) on
`4 mg FESO and by 1.8% (5 of 279) on 8 mg FESO. Consti-
`pation led to discontinuation in less than 1% of subjects (2 of
`279, both female) on 8 mg FESO.
`
`DISCUSSION
`
`OAB is a widespread and chronic condition that has been
`shown to decrease subject health related quality of life and
`require long—term treatment.”‘” In this study treatment
`with 4 or 8 mg FESO demonstrated statistically significant
`and clinically relevant improvements compared with placebo
`for OAB symptoms and it was also associated with a signifi-
`cantly higher treatment response. Treatment with 8 mg FESO
`resulted in significant decreases in the number of daytime
`micturitions, number of urgency episodes and continent days
`per week, and in significant increases in MVV per micturition.
`
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`+|
`“"3:
`§B$
`53.25
`
`PBO
`
`FES04rng
`
`FESO8rng
`
`~k
`
`D
`
`-
`
`PBO
`
`FES04mg
`
`FESOBmg
`
`‘I:
`
`31-.-.'.
`:>
`E:
`-3
`°
`FIG. 3. LS mean change from baseline to trial end in number of
`micturitions and UUI episodes per 24 hours. Asterisk indicates
`p <0.05 vs PBO.
`
`*
`
`group had a PVR of more than 200 ml. None of these cases
`required catheterization. Of the 11 subjects reporting uri-
`nary retention as an AE 1 was in the PBO group, 4 were in
`the 4 mg FESO group and 6 were in the 8 mg FESO group.
`All patients showed mild to moderate symptoms except the
`1 male subject on PBO. Medication was interrupted, symp-
`toms resolved and he continued in the study. Decreased
`
`01D
`
`Response(‘’/aYes)
`Treatment
`
`25
`
`PBO
`
`FESO 4 mg
`
`FESO 8 mg
`
`FIG. 4. Proportion of subjects at trial end with positive treatment
`response. Asterisk indicates p <0.001 vs PBO.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0005
`
`

`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`2493
`
`The limitations of this study are a lack of gender and
`ethnic diversity in a population that was primarily female
`and white. Efficacy and tolerability in other ethnic groups, a
`larger male population and subjects with neurogenic OAB
`must be confirmed in future studies. Similarly long-term
`efficacy and safety beyond 12 weeks must be determined and
`such trials are currently ongoing. The urgency scale used in the
`current trial allowed 4 choices, including none, mild, moderate
`and severe urgency with mild, moderate and severe counted
`equally as urgency episodes (see Appendix). Thus, an improve-
`ment in urgency from severe, as typically found in OAB, to
`mild, as in the normal desire to void, was not detected on
`analysis. The scale did not include UUI and, thus, the decrease
`in this ultimate expression of urgency was not measured. The
`robust efficacy of FESO for decreasing the number of UUI
`episodes and increasing MVV per micturition suggests that the
`smaller effect on the incidence of urgency was a refiection of
`how urgency was measured in this trial.
`
`CONCLUSIONS
`
`The 2 doses of FESO are safe and well tolerated. Each provides
`statistically significant and clinically relevant improvements
`in OAB symptoms, thus, allowing dose individualization. Fur-
`thermore, the higher 8 mg dose of FESO provides additional
`benefit compared with the lower dose, particularly for decreas-
`ing UUI episodes and increasing MVV per micturition, and it is
`well tolerated. Thus, FESO represents an alternative treat-
`ment modality in subjects with OAB.
`
`ACKNOWLEDGMENTS
`
`Linda Merkel, Complete Healthcare Communications, Inc.,
`assisted with the manuscript.
`
`FESO at doses of 4 and 8 mg increased MVV per micturition by
`8 and 25 ml, respectively, compared with PBO.
`The magnitude of the improvement in symptoms in sub-
`jects treated with 4 mg FESO was generally consistent with
`that reported for tolterodine extended release.9 More pro-
`nounced effects were apparent with the 8 mg dose of FESO,
`which would be expected based on the pharmacological re-
`lationship between tolterodine and FESO.
`Dry mouth was the most commonly reported AE with in-
`creased incidence in the 8 mg FESO group. However, most
`occurrences were mild to moderate in nature and the rate of
`
`related discontinuations was low. The incidence of constipation
`with FESO was relatively low even at the higher FESO dose
`(5% and 8% for 4 and 8 mg, respectively, vs 3% for PBO). For
`example, in phase III trials of other antimuscarinics constipa-
`tion was reported in 7% and 13% of subjects receiving 10 and 5
`to 30 mg oxybutynin,“ in 5% and 13% receiving 5 and 10 mg
`solifenacin (3% for PBO)” and in 15% and 21% receiving 7.5
`and 15 mg darifenacin, respectively (6.2% for PBO).2°
`
`APPENDIX
`
`Diary Definitions
`Measurement
`
`Definition
`
`Number of niicturitions (frequency) per
`24 hours
`
`Number of times a subject passed urine (including incontinence episodes) per day during the 3-day collection
`period.
`
`Number of UUI episodes per 24 hours
`(among incontinent subjects)
`
`Treatment response, yes/no
`
`Number of times a subject recorded a UUI episode per day within the 3-day collection period.
`
`The treatment response was derived from a 4-point Treatment Benefit scale: “My condition has been: 1=greatly
`improved; 2=improved; 3=not changed; 4=worsened, during treatment. The treatment response was set for
`“yes” ifthe answer was 1 or 2; response was set to “no” ifthe answer was 3 or 4.
`
`MVV per micturition
`
`MVV (ml) during the 1-day collection period.
`
`Number of daytime micturitions
`
`Number of nocturnal micturitions
`
`Number of times a subject passed urine during daytime (including incontinence episodes) per day within the
`3-day collection period. Daytime was defined as the time between the subject getting up in the morning and the
`subject going to bed that evening. Any episodes occurring at the time of getting up in the morning or at the
`time of going to bed were attributed to daytime.
`
`Number of times a subject passed urine during sleeping time (including incontinence episodes) per day within
`the 3-day collection period. Sleeping time was defined as the time between the subject going to bed in the
`evening and getting up in the morning.
`
`Number of urgency episodes per 24
`hours
`
`The number of times a subject recorded an urgency episode with or without incontinence per day within the 3-
`day collection period.
`
`Severity of urinary urgency
`
`Each episode was graded using the following 4-point scale:
`1=None: Normal voiding, or “I felt no need to use the bathroom, but did."
`2=Mild: "I could have postponed using the bathroom as long as necessary without fear of wetting myself."
`3=Moderate: “I could have postponed using the bathroom for a short while without fear of wetting myself."
`4-=Severe: I could not postpone using the bathroom and had to rush to the bathroom in order not to wet myself."
`
`Number of continence days per week
`(among incontinent subjects)
`
`Number of times a subject had no incontinence episodes in a day within the 3-day collection period, normalized
`to a 7-day period.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0006
`
`TABLE 4, AEs leading to discontinuation
`No. 4 mg
`FESO 0%)
`282
`3(1)
`2 (1)
`1 (less than 1)
`
`No. PBO (%)
`271
`1 (less than 1)
`0
`1 (less than 1)
`
`AE
`
`Overall
`Dry mouth
`Urinary retention
`Increased 1»-glutamyl
`transferase
`Constipation
`Increased alanine
`aminotransferase
`Headache
`Hypertension
`
`0
`2 (1)
`
`0
`2(1)
`
`In greater than 1 subject in any treatment group.
`
`No. 8 mg
`FESO 0%)
`279
`5 (2)
`3 (1)
`2 (1)
`2(1)
`1(1)
`
`00
`
`2 (1)
`1 (less than 1)
`
`0
`0
`
`

`
`2494
`
`FESOTERODINE FOR OVERACTIVE BLADDER SYNDROME
`
`Abbreviations and Acronyms
`adverse event
`cytochrome P450
`fesoterodine
`5-hydroxyrnethyl tolterodine
`least squares
`mean voided volume
`overactive bladder
`placebo
`post-void residual urine
`
`urgency urinary incontinence
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2078 - 0007