EUROPEAN UROLOGY 52 (2007) 1204-:-2:2
`
`available at www.sciencedirect.com
`
`journal homepage: www.europeanurology.com
`
`-$1
`
`European Association of Urology
`
`Incontinence
`
`
`
`Clinical Efficacy, Safety, and Tolerability of Once-Daily
`Fesoterodine in Subjects with Overactive Bladder
`
`Christopher Chapple “**, Philip Van Kerrebroecle 1’, Andrea Tubaro °,
`Cornelia I-Iaag-Moilzenteilerd, Hans-Theo Forstd, Ute Massow d,
`Joseph Wang E, Marina Brodsky”
`
`aThe Royal Hallamshire Hospital, Shejfield, UK
`b University Hospital Maastricht, Maastricht, The Netherlands
`‘Saint Andrea Hospital, La Sapienza University, Rome, Italy
`'3 Schwarz Biosciences GmbH, Monheim, Germany
`EPfizer Inc, New York, NY, USA
`
`Article info
`
`Abstract
`
`Article history;
`Accepted }u1y 5_ 2007
`published online ahead of
`print on July 17’ 2007
`
`gifgljords:
`Micturitions
`,
`_
`Urgency lflcontlnence
`Fesoterodme
`
`Objective: To determine the efficacy, tolerability, and safety of fesoterodine in
`subjects with overactive bladder (OAB).
`_
`i
`‘
`Methods: This was a multicentre, randomised, double-blind, placebo- and active-
`controlled trial with tolterodine extended release (ER) to assess the efficacy and
`safety of fesoterodine. Eligible subjects (218 yr) with increased micturition
`frequency and urgency and/or urgency urinary incontinence (UUI) were random-
`ised to placebo, fesoterodine 4 mg, fesoterodine 8 mg, or tolterodine ER 4- mg for
`12 wk. The primary efficacy variable was a change from baseline to week 12 in
`micturitions per 24 h. Co—primary end points included change from baseline to
`week '12 in UUl episodes per 24 h and Treatment Response ("yes" or “no," based
`on four-point treatment benefit scale). Secondary efficacy variables included
`mean volume voided per micturition, continent days per week, and number of
`urgency episodes.
`Results: At
`the end of treatment, subjects taking fesoterodine 4 and 8 mg
`had significant (p < 0.05) and clinically relevant improvements versus placebo
`in the primary, co-primary, and most secondary efficacy variables. Tolterodine
`ER (active control) also provided significantly greater improvement than placebo
`for most efficacy variables, confirming the sensitivity of the study design. A
`more pronounced effect was observed with fesoterodine 8 mg at most end
`points.
`Conclusions: Both doses of fesoterodine were significantly better than placebo in
`improving the symptoms of OAB and produced a significantly greater Treatment
`Response versus placebo. Efficacy was more pronounced with fesoterodine 8 mg
`compared with the other treatments. Active treatments were well tolerated.
`JP‘: 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`0302-2838/$ - see back matter I‘ 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
`
`doi:10.1016/j.eururo.2007.07.009
`
`* Corresponding author. Sheffield Hallam University, Consultant Urological Surgeon,
`Glossop Road, Sheffield, S10 2 JF, United Kingdom.
`E-mail address: c.r.chapple@shef.ac.ulc (C. Chapple).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0001
`
`

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`EUROPEAN UROLOGY 52 (2007) 12o4—1212
`
`1205
`
`1.
`
`Introduction
`
`study included a tolterodine ER 4mg arm as an
`active control.
`
`Overactive bladder (OAB) syndrome is a collection
`of symptoms, in particular, urinary urgency with
`or without urgency urinary incontinence (UUI),
`usually accompanied by increased micturition fre-
`quency and nocturia [1]. OAB is a chronic condition
`occurring in both men and women, with a pre-
`valence that increases with advancing age [2]. A
`recent population—based study performed in over
`19,000 individuals in four European countries and
`Canada (the EPIC study [3]), using current Interna-
`tional Continence Society definitions, determined
`the overall prevalence of OAB to be 12%, ranging
`from 7% to 10% in individuals <39 yr of age to almost
`20% in those 360 yr of age.
`Because the underlying cause of OAB is multi-
`factorial and often undetermined, treatment mod-
`alities
`focus on symptomatic
`relief. Current
`treatment regimens include nonpharmacological
`(behavioural therapy, coping strategies, protective
`garments, barrier devices, pelvic floor stimulation,
`or sacral nerve stimulation) and pharmacological
`components [4]. The primary pharmacological treat-
`ments considered the mainstay for the relief of OAB
`symptoms are antimuscarinic drugs, which have
`demonstrated efficacy in improving OAB symptoms,
`but are associated with dose—dependent increases in
`antimuscarinic adverse effects, such as dry mouth,
`constipation, and blurred vision.
`Data from phase 2 trials have suggested that
`fesoterodine, a new antimuscarinic drug in devel-
`opment, is an effective and well-tolerated therapy
`for OAB [S]. Fesoterodine acts functionally as a
`prodrug. It is rapidly and extensively hydrolysed
`by nonspecific esterases to 5—hydroxymethy1 tol-
`terodine. The conversion is rapid and virtually
`complete such that, after oral dosing, only the
`metabolite, not
`the parent compound, can be
`detected in patient plasma [6]. This active meta-
`bolite, responsible for the antimuscarinic activity
`of fesoterodine [7], is also the active metabolite of
`tolterodine, 5-hydroxymethyl tolterodine (5-HMT)
`[8—10]. Tolterodine is converted to 5—HMT by the
`cytochrome P450 (CYP) 2D6 enzyme system. Thus,
`the efficacy of conversion of tolterodine to 5-HMT
`is dependent on the activity and expression of
`CYP2D6 in patients. In contrast to tolterodine, the
`conversion of fesoterodine to 5—HMT bypasses
`the CYP system, although CYP3A4 and CYP2D6
`are involved in subsequent inactivation of the
`active metabolite [11].
`The objective of this trial was to investigate the
`efficacy,
`tolerability, and safety of fesoterodine 4
`and 8 mg versus placebo in subjects with OAB. The
`
`2.
`
`Methods
`
`2.1.
`
`Study design
`
`In this randomised, 12-wk treatment, double-blind, double-
`dummy, placebo- and active-controlled, parallel-arm, multi-
`centre study, the efficacy, tolerability, and safety of fesoterodine
`were assessed in men and women with OAB. This phase 3 study
`was conducted at 150 sites in 19 countries (Belgium, Bulgaria,
`Czech Republic, Estonia, France, Germany, Hungary, Italy, the
`Netherlands, Poland, Romania, Russia, Spain, Sweden, Ukraine,
`the United Kingdom, South Africa, Australia, and New Zealand).
`The study was conducted in accordance with the Good Clinical
`Practice Guidelines and the Declaration of Helsinki. The
`
`protocol was approved by respective ethics committees or
`institutional review boards, and all subjects gave written
`informed consent before the start of the study.
`Subjects entered a 2-wk placebo run-in phase during which
`they received one capsule (tolterodine placebo) and one tablet
`(fesoterodine placebo) of placebo medication in the morning
`(Fig. 1). To ensure adequate blinding, placebo had to be given in
`both forms in the run-in phase. Once eligibility was estab-
`lished, subjects were randomised 1:1:1:1 to double-blind
`treatment (once daily in the morning) in one of the treatment
`arms for 12 wk:
`tolterodine ER 4mg, fesoterodine 4 mg,
`fesoterodine 8 mg, or matching placebo. In the double-blind
`phase, placebo was given as a capsule to the fesoterodine
`group and as a tablet to the tolterodine group.
`
`2.2.
`
`Subjects
`
`2.2.1.
`
`Inclusion criteria
`
`Subjects must have had a medical history of OAB symptoms
`with urinary urgency for 26 mo to enrol. Subjects had to be at
`least 18 yr of age with 28 micturitions per 24 h and either 36
`urgency episodes or 23 UUI episodes per 24 h (symptoms were
`recorded in a 3-d diary). In addition, subjects had to indicate on
`a Likert scale that the condition caused them at least moderate
`
`EnrollmentK
`
`4
`Randomization
`
` mi
`1
`2
`3
`4
`5
`5
`
`Visit
`
`Week -2
`
`0
`
`2
`
`4
`
`8
`
`12
`
`Fig. 1 — Study design. ER, extended release.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0002
`
`

`
`1206
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`EUROPEAN UROLOGY 52 (2007) 1204-1212
`
`problems, which is almost identical to the subject perception
`of bladder condition [12]. After the start of the trial, the
`protocol was amended to ensure enrollment of the planned
`80% of subjects with UUI at baseline; the amendment required
`23 UUI episodes per 24h in all remaining subjects. Women
`participating in the trial had to have a negative pregnancy test
`and use adequate contraception throughout the trial.
`
`2.2.2.
`
`Exclusion criteria
`
`Subjects were excluded who had lower urinary tract pathology
`that could, in the investigator’s opinion, be responsible for
`urgency or incontinence (eg, genuine stress incontinence,
`bladder stones, interstitial cystitis, urothelial tumours), pelvic
`prolapse of grade II! or higher, clinically relevant bladder outlet
`obstruction, polyuria (>3 l per 24 h), symptomatic or recurrent
`urinary tract
`infections, or postvoid residual
`(PVR) urine
`volume >100 ml. Subjects who were currently receiving
`treatment, were treated within 2 wk of screening visit with
`antimuscarinic agents, were treated within the past 4 wk with
`
`electrostimulation for bladder training, or had an active
`urinary tract infection or an underlying neurological disease
`responsible for their OAB were not included. Subjects who had
`clinically relevant cardiac arrhythmia and/or unstable angina
`or a QTCB interval >500 ms were not included.
`
`2.3.
`
`Ejficacy analyses
`
`For assessment of efficacy, subjects were asked to complete a
`3-d micturition diary ‘lluring the placebo run-in phase before
`visit 2 and on the days immediately preceding treatment visits
`3,5, and 6. Subjects were also asked to record their micturition
`volumes on one of these 3 cl. In the diaries, subjects recorded
`the time of each micturition and/or urgency episode, urine
`volume with each micturition, any episode of incontinence,
`and the severity of urgency:
`1 = none (normal voiding);
`2 = mild (could have postponed micturition for as long as
`necessary without fear of wetting myself); 3 = moderate (could
`have postponed micturition for a short while without fear of
`
`Table 1 — Definitions of bladder diary variables
`Measurement
`
`Definition
`
`Number of micturitions (frequency) per 24 h
`
`Number of times a subject passed urine (including incontinence episodes).
`
`Treatment Response, yes/no
`
`Number of UUI episodes per 24 h
`(among incontinent subjects)
`
`MW per micturition
`
`Number of micturitions during daytime
`
`Number of micturitions during
`sleeping time (nocturia)
`
`Number of urgency episodes per 24 h
`
`Severity of urinary urgency
`
`Treatment Response was derived from a four-point treatment benefit scale:
`“My condition has been: 1 = greatly improved; 2 = improved; 3 = not changed;
`4 = worsened. during treatment. Treatment Response was set for “yes" if the
`answer was ‘I. or 2; response was set to “no" if the answer was 3 or 4.
`
`Number of times a subject recorded a UUI episode per day within the 3-d
`collection period.
`
`MW (ml) during the 1-d collection period.
`
`Number of times a subject voluntarily passed urine during daytime (including
`incontinence episodes) per day within the 3-d 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 voluntarily passed urine during sleeping time (including
`incontinence episodes) per day within the 3-d collection period. Sleeping time was
`defined as the time between the subject going to bed in the evening and getting up
`in the morning.
`
`The number of times a subject recorded an urgency episode with or without
`incontinence per day within the 3-d collection period.
`
`Each episode was graded using the following four-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: "1 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."
`The number of occurrences of each grade for each valid day during the 3-d collection
`period was counted and expressed as a percentage of the total number of episodes
`recorded on those valid days. The grade for the visit was set equal to the grade with
`the highest percentage of occurrences for that visit. If two or more grades had equal
`percentages, then the grade with the highest severity was used.
`
`Number of continent days per week
`(among incontinent subjects)
`
`Number of times a subject had no incontinence episodes in a day within the 3-d
`collection period, normalized to a 7-d period.
`
`UUI, urgency urinary incontinence; l\.'l'VV, mean volume voided.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0003
`
`

`
`EUROPEAN UROLOGY 52 (2007) 12o4—r212
`
`1207
`
`wetting myself); 4: severe (could not postpone micturition,
`had to rush to the toilet in order not to wet myself).
`Primary efficacy end points were change from baseline to
`week 12 in micturitions per 24 h, change from baseline to week
`12 in UUI episodes per 24 h, and Treatment Response.
`Treatment Response was derived from a four-category treat-
`ment benefit scale, whereby a score of 1 (greatly improved) or 2
`(improved) was considered “yes," and a score of 3 (not changed)
`or 4 (worsened) was considered "no." The definition of
`Treatment Response and all other efficacy end points are listed
`in Table 1.
`
`Secondary efficacy end points included mean volume
`voided per micturition, daytime micturitions per 24 h, noc-
`turnal micturitions per 24 h, urgency episodes per 24 h, and
`continent days per week (calculated based on a 3-d diary).
`
`2.4.
`
`Safety and tolerability
`
`Safety and tolerability were assessed on the basis of the
`observation and assessment of adverse events (AE5). Serious-
`ness, severity, and relatedness to treatment were assessed by
`the investigator. Safety assessments were conducted at each
`visit and after the safety follow-up.
`Safety laboratory parameters included haematology and
`serum chemistry with hepatic and renal parameters. Changes
`deemed of clinical relevance were recorded as AEs. In addition,
`urinalysis parameters, vital signs, centrally read electrocar-
`diogram (ECG), physical examination and urological/urogyne-
`cological examination, residual urinary volume (ml), and
`subject assessment of treatment tolerance using a four-grade
`scale were recorded.
`
`2.5.
`
`Statistical analyses
`
`The primary subject population for statistical analyses of
`efficacy was the full analysis set, which was defined as all
`subjects who were randomised, received any study medica-
`tion, and for whom baseline and double-blind micturition data
`were available. Safety analyses were conducted on the safety
`set, which was defined as all subjects who took at least one
`dose of trial medication after randomisation. Demographic
`characteristics are also presented for this population.
`Parametric analysis for continuous variables (change in
`micturition frequency, UUI episodes, etc) was performed with
`the use of an analysis of covariance model with treatment and
`region as factors and baseline value as a covariate; nonpara-
`metric sensitivity analysis was conducted with the use of
`Wilcoxon rank sum test. Binary data (Treatment Response)
`were analysed with the use of the normal approximation
`method.
`In an exploratory analysis, median percentage
`change from baseline to week 12 was calculated for diary
`end points, and statistical hypothesis testing was conducted
`for secondary end points.
`A sequentially rejective closed-test procedure was applied
`to the primary variables to adequately account for multiplicity.
`A sequentially rejective closed-test procedure is one that
`performs the hypothesis tests in a sequential manner, and
`steps to the next test only if the previous test was significant
`and stops if the previous test was not significant. This kind of
`test procedure is a closed test if the multiple significance level
`
`a can be preserved. According to the requirements suggested
`by the US Food and Drug Administration, the test procedure
`started with micturition frequency per 24 h, performed the
`test of fesoterodine 8 mg compared with placebo for this
`variable, stepped down to test fesoterodine 4 mg versus
`placebo if the first test demonstrated statistical significance,
`and continued with the respective tests for the number of UUI
`episodes per 24 h. According to the requirements of the
`European Agency for the Evaluation of Medicinal Products, the
`test procedure considered micturition frequency per 24- h and
`Treatment Response simultaneously,
`tested fesoterodine
`8 mg versus placebo for both variables first, and, in the case
`of a statistically significant result, continued to test the 4-mg
`dose versus placebo for both variables.
`
`3.
`
`Results
`
`3.1.
`
`Subjects
`
`Subject disposition of the trial is shown in Fig. 2, and
`subject demographics are shown in Table 2. Of the
`1135 subjects who entered the double—b1ind treat-
`ment phase, 1132 received study medication (two
`subjects from the placebo and one subject from the
`fesoterodine 8 mg were not
`treated);
`therefore,
`demographics were captured from the 1132 subjects
`enrolled and treated in the study. The population in
`this trial corresponded to the general clinical OAB
`populations in studies that have been previously
`reported. Subjects were approximately 57 yr of age
`and most were women (80%), with 75-81% of subjects
`reporting UUI in baseline diary. The mean time since
`first diagnosis or onset of OAB was 8-9 yr. Only 5—8%
`of subjects in any group had been diagnosed with
`OAB for less than 1 yr before enrollment; therefore,
`the population in this trial primarily comprised
`subjects with long—term, established OAB.
`
`3.2.
`
`Efficacy
`
`In subjects receiving tolterodine ER, changes from
`baseline in most end points, as well as Treatment
`Response, were statistically significantly greater
`than placebo, which demonstrated the sensitivity
`of the study design. Similarly, changes from baseline
`were statistically significant versus placebo for the
`primary and both co—primary efficacy variables, as
`well as most secondary end points in subjects
`receiving fesoterodine 4 or 8 mg. Efficacy end point
`data are shown in Table 3.
`
`the mean number
`the end of treatment,
`At
`of micturitions per 24h was significantly reduced
`from baseline in subjects receiving tolterodine ER
`(-1.73; p = 0.001 vs. placebo),
`fesoterodine 4 mg
`(-1.76; p < 0.001 vs. placebo), and fesoterodine
`8 mg (-1.88; p < 0.001 vs. placebo).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0004
`
`

`
`Fesoterodine 8 mgiday
`Fesoterodine 4 mgrday
`
`
`
`n=272
`n=288
`
`
`Not treated
`n=1
`
`Not treated
`n=0
`
`Not treated
`n=1
`
`Not treated
`n=1
`
`Discontinued
`n=33
`
`1208
`
`EUROPEAN UROLOGY 52 (2007) 1204-1212
`
`Screened
`N=1463
`
`Enrolled in Placebo Run-In
`
`N=1409
`
`Randomized to Double-Blind Treatment
`
`N=1135
`
`
`n=285
`
`Toltarodine ER 4 mglday
`n=29O
`
`Discontinued
`Discontinued
`n=41
`n=37
`
`
`Discontinued
`n=36
`
`Completed
`n=252
`
`Completed
`n=253
`
`Completed
`n=231
`
`Completed
`n=2 52
`
`Pig. 2 - Subject disposition throughout the trial. ER, extended release.
`
`Treatment with tolterodine ER resulted in signifi-
`cantly greater proportion of subjects who responded
`to treatment compared with placebo (p < 0.001). The
`proportion of subjects reportingapositive Treatment
`Response was significantly greater among subjects
`
`receiving fesoterodine 4 mg (p < 0.001) and fesoter-
`odine 8 mg (p < 0.001) than placebo.
`At the end of treatment, the mean reduction from
`baseline in UUI episodes per 24 h was significantly
`greater for subjects receiving tolterodine ER (-1.74;
`
`Table 2 - Baseline demographics and clinical characteristics'
`
`Parameter
`
`Age, yr (mean i SD)
`Sex, % (M/W)
`
`Race, ‘Yo
`\.Vhite
`Black
`Asian
`Other
`
`BMI, kg/m2 (mean 1 so)
`Duration of OAB symptoms. yr (mean i SD)
`incontinence, %‘
`
`Previous drug treatment for OAB, n (%)
`Oxybutynin
`Tolterodine
`Propiverine
`Trospium
`Flavoxate hydrochloride
`
`PBO
`(I1 = 283)
`
`56.0 :: 13.7
`19/81
`
`98
`<1
`2
`<1
`
`5.2
`27.2
`7.9 i 9.6
`75
`
`112 (40)
`73 (26)
`47 (17)
`12 (4)
`15 (5)
`5 (2)
`
`TOL ER 4 mg
`(I1 = 290)
`
`57.7 i 14.6
`22/73
`
`FESO 4 mg
`(n = 272)
`
`57.1 i 13.2
`19/81
`
`FESO 8 mg
`(n = 287)
`
`55.6 i 14.1
`19/82
`
`98
`0
`2
`<1
`
`27.5 1 5.2
`8.7 1 10.1
`79
`
`135 (47)
`99 (34)
`48 (17)
`17 (6)
`17 (6)
`5 (2)
`
`96
`0
`2
`3
`
`27.5 1 5.5
`9.0 :t 11.2
`75
`
`102 (38)
`74 (27)
`40 (15)
`9 (3)
`8 (3)
`2 (<1)
`
`98
`1
`1
`0
`
`27.1 1 5.2
`7.6 1 8.4
`31
`
`118 (41)
`85 (30)
`37 (13)
`15 (5)
`8(3)
`3 (1)
`
`PBO, placebo; TOL ER, tolterodine extended release; FESO. fesoterodine; BMI. body mass index; OAB. overactive bladder; SD. standard
`deviation.
`
`' Based on safety population. that is, all subjects who took 2 1 dose of medication.
`i Based on PAS population.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0005
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`EUROPEAN UROLOGY 52(2oo7) 1204-1212
`
`1209
`
`Table 3 - Baseline and change from baseline‘ to end of treatment (LOCF) in bladder diary efficacy variables
`
`PBO
`
`TOL ER 4 mg
`
`FESO 4 mg
`
`FESO 8 mg
`
`Treatment group
`
`Primary end point
`MicturiI:ionsi’24 h
`n
`Baseline mean (30)
`1.5 mean (SE) change
`p value
`Median ‘Va change”
`p value"
`
`Co-primary end points
`Treatment Response. %
`H
`Yes
`p value
`ULIU24 h§
`n
`Baseline mean (SD)
`L5 mean (SE) change
`p value
`Median =3 change"
`p value"
`Secondary end points
`MVV, ml
`n‘
`Baseline mean (50)
`1.5 mean (SE) change
`p value
`
`Daytime micturitionsf24 h
`)1
`Baseline mean (SD)
`L5 mean (SE) change
`p value
`Median % change"
`p value"
`Nocturnal micturitions.-'24 h
`n‘
`Baseline mean (SD)
`LS mean (SE) change
`p value
`Median 35 change"
`p value"
`Number of urgency episodes."24h
`ii‘
`Baseline mean (SD)
`1.5 mean (SE) change
`p value
`Median 34 change"
`p value“
`
`Continent days per week§-W
`n
`Baseline mean (SD)
`LS mean (SE) change
`p value
`
`279
`12.0 (3.7)
`-0.95 (0.16)
`
`-11.1
`
`279
`53
`
`211
`3.7 (3.1)
`-1.14 (0.15)
`
`-50.0
`
`278
`150.2 (52.0)
`9.37 (3.33)
`
`279
`10.1 (3.5)
`-0.60 (0.14)
`
`-9.5
`
`279 (254)
`1.8 (1.2)
`-0.32 (0.06)
`
`-26.8
`
`279
`11.4 (4.0)
`-1.07 (0.19)
`
`-11.1
`
`211
`0.8 (1.5)
`2.07 (0.20)
`
`283
`11.5 (2.9)
`-1.73 (0.16)
`0.001
`-13.3
`0.005
`
`283
`72
`<0.001
`
`223
`3.8 (3.1)
`-1.74 (0.16)
`0.003
`-70.0
`0.105
`
`282
`154.3 (52.9)
`23.54 (3.31)
`0.002
`
`283
`9.5 (2.7)
`-1.35 (0.14)
`<0.001
`-13.6
`0.003
`
`283 (266)
`2.0 (1.2)
`-0.40 (0.06)
`0.336
`-25.0
`0.315
`
`253
`11.0 (3.4)
`-2.03 (0.19)
`<0.001
`-15.0
`0.004
`
`223
`0.6 (1.3)
`2.45 (0.20)
`0.139
`
`265
`11.6 (3.2)
`-1.76 (0.17)
`<0.001
`-16.7
`<0.001
`
`265
`75
`<0.001
`
`199
`3.8 (3.4)
`-1.95 (0.17)
`0.001
`-80.0
`0.001
`
`265
`160.0 (59.5)
`27.72 (3.41)
`<0.001
`
`265
`9.6 (2.9)
`-1.37 (0.15)
`<0.001
`-14.3
`0.001
`
`265 (247)
`1.9 (1.3)
`-0.39 (0.06)
`0.394
`-28.6
`0.982
`
`265 (264)
`11.0 (4.2)
`-1.33 (0.20)
`0.003
`-17.5
`0.002
`
`199
`0.3 (1.6)
`2.34 (0.21)
`0.00?
`
`276
`11.9 (3.3)
`-1.88 (0.16)
`<0.001
`-13.6
`<0.001
`
`276
`79
`<0.001
`
`223
`3.7 (3.0)
`-2.22 (0.16)
`<0.00‘1
`-57.5
`<0.001
`
`275
`153.9 (56.9)
`33.52 (3.35)
`<0.00‘l
`
`276
`9.9 (3.2)
`-1.40 (0.14)
`<0.001
`-16.9
`<0.001
`
`275 (255)
`2.0 (1.6)
`-0.39 (0.05)
`0.418
`-23.1
`0.896
`
`276
`11.5 (4.2)
`-2.35 (0.20)
`<0.001
`-19.1
`<0.001
`
`223
`0.5 (1.3)
`3.32 (0.19)
`<0.001
`
`LOCF, last observation carried forward; PBO, placebo; TOL ER, tolterodine extended release; FESO, fesoterodine; SD, standard deviation;
`LS, least squares; SE, standard error; UUI, urinary urgency incontinence; MVV, mean volume voided per micturition.
`Based on FAS population. All median % values and related statistical comparisons are derived from an exploratory analysis.
`. Baseline values are presented as mean :: SD.
`' Change from baseline is presented as LS means i SE.
`1
`r1 = number of subjects from mean change analysis; (r1) = number of subjects from median % change analysis.
`. Exploratory analysis.
`5 Analysis included only subjects with at least one urgency incontinence episode at baseline.
`dd Weekly calculation was based on estimates from 3-d diary data.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0006
`
`

`
`1210
`
`EUROPEAN UROLOGY 52 (2007) 1204-1212
`
`Table 4 - Treatment-emergent adverse events occurring in 2 2% of subjects in any group'
`
`Adverse event, n (96)
`
`PBO (71 = 283)
`
`TOL ER 4 mg (fl = 290)
`
`l"-‘E50 4 mg (11 = 272)
`
`FESO 8 mg (fl = 287)
`
`Any adverse event
`Dry mouth
`Constipation
`Headache
`Dry eye
`Nasopharyngitis
`Fatigue
`Influenza
`Dry throat
`Dizziness
`(Alanine aminotransferase
`Nausea
`
`107 (38)
`20 (7.1)
`4 (1.4)
`14 (4.9)
`0
`7 (2.5)
`1 (<1)
`6 (2.1)
`0
`7 (2.5)
`1 (<1)
`1 (<1)
`
`144 (50)
`49 (15.9)
`B (2.8)
`14 (4.8)
`1 (<1)
`10 (3.4)
`10 (3.4)
`2 (<1)
`3 (1)
`4 (1.4)
`0
`6 (2.1)
`
`PBO, placebo; TOL ER, tolterodine extended release; FESO, fesoterodine.
`. Based on safety population, that is, all subjects who took 2 1 dose of medication.
`
`135 (50)
`59 (21.7)
`9 (3.3)
`12 (4.4)
`6 (2.2)
`8 (2.9)
`1 (<1)
`9 (3.3)
`1 (<1)
`4 (1.5)
`2 (<1)
`1 (<1)
`
`167 (58)
`97 (33.8)
`13 (4.5)
`7 (2.4)
`12 (4.2)
`5 (1.7)
`1 (<1)
`2 (<1)
`3 (2.8)
`3 (1.0)
`6 (2.1)
`4 (1.4)
`
`fesoterodine 4mg (-1.95;
`p = 0.008 vs. placebo),
`p = 0.001 vs. placebo), and fesoterodine 8 mg (—2.22;
`p < 0.001 vs. placebo).
`Active treatment significantly increased mean
`volume voided (MVV)
`from baseline (10 S 0.002)
`compared with placebo. The increases in MVV were
`2.5, 3.0, and 3.6 times greater than placebo in
`subjects
`receiving tolterodine ER,
`fesoterodine
`4 mg, or fesoterodine 8 mg, respectively.
`Statistically significant improvements were also
`observed in active treatment groups versus placebo
`in daytime micturitions and number of urgency
`episodes. Significant improvements in change from
`baseline compared with placebo in number of
`continent days per week were observed in subjects
`receiving fesoterodine 4 mg or 8 mg (Table 3).
`
`3.3.
`
`Safety and tolerability
`
`All treatment—emergent AEs, irrespective of rela-
`tionship to study medication are shown in Table 4.
`The most frequent AE in all treatment groups was
`dry mouth, which was mild or moderate in most
`cases, except for 3% of subjects taking fesoterodine
`8 mg, who reported severe dry mouth. Other than
`dry mouth, no AE occurred in more than 5% of
`subjects. In this trial, no episodes of acute urinary
`retention requiring catheterisation were reported.
`There were no clinically relevant changes in vital
`signs, such as heart rate or blood pressure, labora-
`tory, or ECG parameters. Mean change in heart rate
`was 2.8 bpm in the tolterodine ER group, 3.3 bpm in
`the fesoterodine 4—mg group, and 3.9 bpm in the
`fesoterodine 8—mg group. The change in heart rate in
`the placebo group was 0.8 bpm.
`Overall, 3.2% of subjects (36 of 1132) discontinued
`the study prematurely owing to an AE: placebo, 2%
`(6 of 283); tolterodine ER 4mg, 3% (9 of 290); feso-
`terodine 4 mg, 3% (7 of 272); and fesoterodine 8 mg,
`
`5% (14 of 287) during the treatment phase. No single
`AE resulted in withdrawal of 21% of subjects in any
`treatment group. Among the reasons for disconti-
`nuation was urinary retention, which occurred in
`<1% (1 of 272) and 1% (2 of 287), respectively, in the
`fesoterodine 4 mg and fesoterodine 8 mg groups but
`led to discontinuation in only 1 subject (receiving
`fesoterodine 4 mg). One subject in the tolterodine ER
`4-mg group and 1 subject in the fesoterodine 8—mg
`group withdrew because of dry mouth. Two patients
`in the fesoterodine 8—mg group withdrew because of
`unspecified mucosal dryness.
`
`4.
`
`Discussion
`
`This trial has demonstrated that treatment with
`
`fesoterodine 4 and 8mg resulted in statistically
`significant and clinically relevant improvements in
`bothersome OAB symptoms and end points, includ-
`ing increased micturition frequency, urgency, UUI,
`and MVV, and the treatment was associated with a
`significantly greater Treatment Response rate com-
`pared with placebo. Treatment effects appeared to
`be more pronounced with fesoterodine 8 mg than
`with tolterodine ER 4mg or fesoterodine 4mg,
`especially regarding UUI episodes and volume
`voided per micturition, which may have clinical
`relevance considering the similar tolerability pro-
`files among active treatment groups.
`Pesoterodine 4 and 8mg were generally well
`tolerated, and discontinuations because of an AE
`
`were low in all groups. AEs observed in any of the
`active treatment groups were low and similar to
`placebo, except for dry mouth, which occurred at a
`higher rate with fesoterodine 8 mg. However, only 1
`subject each from the fesoterodine 8 mg and
`tolterodine ER 4 mg groups withdrew from the
`trial because of dry mouth. As expected with
`
`Patent Owner, UCB Pharma GmbH — Exhibit 20?? - 0007
`
`

`
`EUROPEAN UROLOGY 52 (2007) 1204-1212
`
`1211
`
`antimuscarinic therapy, dry mouth and constipa-
`tion [13], respectively, were the first and second
`most common adverse events reported. Dry mouth
`was the most frequently reported class effect in this
`trial, occurring in 7%, 17%, 22%, and 34% of subjects
`treated with placebo, tolterodine ER 4mg, fesoter-
`odine 4-mg, and fesoterodine 8mg, respectively;
`most cases were mild. Because Constipation may
`cause or exacerbate urinary symptoms [14], con-
`sideration of this AB is important in the treatment of
`OAB. In this study, the incidence of constipation was
`low, with 1.4% in subjects receiving placebo, 2.8%
`in subjects receiving tolterodine ER 4mg, 3.3% in
`subjects receiving fesoterodine 4mg, and 4.5% in
`subjects receiving fesoterodine 8mg. With other
`antimuscarinic agents, the incidence of constipa-
`tion in phase 3 trials is reported as 7—13% in subjects
`receiving immediate-release oxybutynin [15], 6%
`treated with tolterodine ER [16], 5—13% in subjects
`treated with solifenacin [17], and 8—21% in subjects
`receiving darifenacin [18]. The higher
`rates of
`constipation in subjects treated with darifenacin
`compared with other antimuscarinic agents is most
`likely attributable to its relative selectivity for the
`M3 receptor [19], which mediates contraction of
`intestinal smooth muscle [18].
`In this trial, an apparent placebo effect was
`observed, whereby treatment with placebo for
`12 wk resulted in marked (albeit not significant)
`improvements from baseline. In contrast, signifi-
`cant effects from baseline to end point were
`observed among active treatment groups for the
`primary and co—primary efficacy variables. A
`marked placebo effect on treatment outcomes is
`generally expected in similarly designed, random-
`ised controlled trials in OAB subjects [20]. These
`effects, although more strongly correlated with
`subjective rather than objective measures, may be
`due at least in part to the use of micturition diaries,
`which draws attention to micturition habits [20].
`Trials with run-in periods, such as the present trial,
`often show less of a placebo effect than those
`without run-in periods, perhaps because the initial
`attention required to fill out the micturition diary is
`attenuated by the time the active treatment begins
`[20].
`Data regarding subjects with OAB of neurogenic
`origin treated with fesoterodine were not collected
`in this study. Studies in a broader subject popula-
`tion, including looking at greater ethnic diversity,
`more men, the very frail elderly (although this study
`did not specify an upper age limit), and the
`paediatric population would be helpful in providing
`greater breadth of knowledge relevant to real—life
`clinical practice. An ongoing, long-term, open-label
`
`extension trial will provide additional information
`regarding long-term continuous use of fesoterodine
`under clinical conditions closer to real life.
`
`5.
`
`Conclusions
`
`Fesoterodine 4 and 8 mg demonstrated statistically
`significant and clinically relevant improvements in
`most OAB symptoms and were associated with a
`significantly higher Treatment Response compared
`with placebo. Efficacy results were generally more
`pronounced with the 8-mg dose. Tolterodine ER
`4 mg was also more effective than placebo on most
`end points, confirming the sensitivity of the study
`design. Both doses of fesoterodine were safe and
`well tolerated, with a low overall incidence of AEs,
`which was similar to that with tolterodine ER. The
`
`incidence of dry mouth was higher in subjects
`receiving fesoterodine 8mg; however, most cases
`were mild to moderate. Discontinuations because of
`
`adverse events were low. These findings are in line
`with expectations based on the pharmacological
`relationship between fesoterodine and tolterodine
`[7]. The availability of two doses of fesoterodine
`presents an additional clinical benefit in that close
`flexibility allows OAB treatment to be tailored to
`individual subject needs.
`
`Conflicts of interest
`
`a consultant/investigator/
`Professor Chapple is
`(Yamanouchi), Pfizer
`Inc,
`speaker
`for Astellas
`Novartis, and Schwarz BioSciences GmbH, and has
`acted as a consultant
`for UCB. Professor Van
`
`Kerrebroeck is an investigator and lecturer for
`Astellas, Eli—Lilly, Ferring, Pfizer Inc, and Novartis.
`Professor Tubaro is a consultant/investigator/lec-
`turer for Pfizer Inc, GlaxoSmithKline, and Novartis.
`
`Drs. Haag—Molkenteller, Forst, and Massow were all
`employees of Schwarz Biosciences GmbH at the
`time the study was perforrned. Drs. Wang and
`Brodsky are employees of Pfizer Inc.
`
`Ackno