BU BJU INTERNATIONAI
`
`Comparison of fesoterodine and tolterodine in
`patients with overactive bladder
`
`Christopher R. Chapple, Philip E. Van l(errebroeck*, Klaus—Peter Jiinemann+.
`Joseph T. Wang* and Marina Brodsky*
`The Royal Hollomshlre Hospital, Sheffield, UK, ‘University Hospital Mdostricht, ll/loostrlchr, the Netherlands,
`“Christion-Albreehts-Universitdt Kiel, Kiel, Germany, and *Pfizer inc, New York, NY, USA
`Accepted for publication 28 March 2008
`
`primary endpoints [UUI episodesl24h and
`treatment response], several secondary
`endpoints (severe urgency plus UUI per 24 h,
`mean W IMV\/llvoid, and continent days!
`week}, HRC1oL, using the King's Health
`Questionnaire [KHO] and the International
`Consultation on Incontinence
`Questionnaire-Short Form IICIO-SF], and
`self-reported bladder-related problems. A
`subanalysis also assessed all endpoints for
`patients who were incontinent at baseline.
`Tolerability and safety were assessed by
`evaluating adverse events, residual urine
`volume, laboratory variables and treatment
`withdrawals.
`
`group, with positive changes in most
`domains of the KHO and an improvement in
`ICIO-SF score. The fesoterodine El-mg group
`had statistically significant improvements
`over placebo in eight of nine KHC1 domains.
`A major improvement in the severity of
`bladder-related problems was reported by
`39% of the fesoterodine 8 mg and 34% of
`the tolterodine ER groups vs 25% of those
`on placebo [PS 0.01}. Results for the
`subgroup of incontinent patients at baseline
`were similar to the overall results. Adverse
`
`events reported most commonly with active
`treatment included dry mouth, constipation,
`dry eye. dry throat, and nausea.
`
`RESULTS
`
`CONCLUSIONS
`
`By week 12, patients with OAB in both
`active-treatment groups showed significant
`improvements in most bladder diary
`variables and treatment response rates
`compared with placebo. Fesoterodine 8 mg
`was statistically significantly better than
`tolterodine ER 4 mg for improving UUI
`episodes, severe urgency plus UUI, mean W,
`and number of continent dayslweek. In
`addition, the fesoterodine and tolterodine ER
`groups showed significantly greater
`improvements in HRQoL than the placebo
`
`Both fesoterodine and tolterodine ER
`
`significantly improved DAB symptoms and
`HROoL, with statistically significant
`advantages for fesoterodine 8 mg compared
`with tolterodine ER on several important
`endpoints.
`
`KEYWORDS
`
`overactive bladder, incontinence, quality of
`life, antimuscarinic
`
`
`Study Type — Therapil IRCTI
`Level of Evidence
`1b
`
`OBJECTIVE
`
`
`
`To compare, in a post hoc analysis of a phase
`III trial, the maximum recommended doses
`of fesoterodine [8 mg] and tolterodine
`[4 mg] for improving overactive bladder
`[DAB] symptoms and health-related quality
`of life [HROoL), as fesoterodine effectively
`reduces OAB symptoms vs placebo.
`
`PATIENTS AND METHODS
`
`Eligible patients with frequency [2eight
`voidsl24 h] and either urgency lzsix
`episodes over 3 days] or urgency urinary
`incontinence [UU|; Ethree episodes over
`3 days] were randomized to placebo,
`fesoterodine 4 or 8 mg, or tolterodine
`extended-release [ER] 4 mg for 12 weeks;
`fesoterodine 4 mg data were published
`elsewhere. Patients completed a 3-day
`bladder diary in which they recorded the
`time of each void, voided volume [\/V],
`and the severity of urgency. A post hoc
`inferential analysis was conducted on the
`primary endpoint [voidsi'24 h], the two co-
`
`
`
`INTRODUCTION
`
`Fesoterodine is a new antimuscarinic agent
`for treating overactive bladder (OI-‘-.B]; it acts
`functionally as a pro—drug and is rapidly
`and extensively converted by nonspecific
`esterases to its primary active metabolite,
`5-hydroxymethyl tolterodine {5-HMT} [1].
`Fesoterodine is not detectable in plasma after
`oral dosing [2]. 5-HMT is also the major active
`metabolite of tolterodine, but it is formed
`from tolterodine via cytochrome P450 [CYP}
`
`1123
`
`2D8-mediated oxidation in the liver. Because
`
`both tolterodine and 5-HMT are potent
`muscarinic receptor antagonists, the overall
`effect of tolterodine is the combined result of
`both moieties. The ratio of tolterodine to 5-
`
`HIVIT is affected by a patient's CYP2D6
`genotype and relevant drug interactions,
`which can result in pharmacokinetic
`variability [3]. A subset of individuals [up to
`10% of whites and up to 19% of blacks) [4]
`lack CYPZDB enzyme activity and are referred
`to as ‘poor metabolizers’; the remainder of the
`
`population is referred to as ‘extensive
`metabolizersi In the former, 5-HMT plasma
`levels are virtually undetectable after
`tolterodine administration [3]. Because
`fesoterodine does not require CYP2D6
`metabolism for activation, it has the potential
`for less pharmacokinetic variability than
`tolterodine extended-release [ER].
`
`The efficacy of fesoterodine 4 mg and 8 mg
`and its effect on health-related quality of life
`[HROoL] have previously been assessed in
`
`© 2008 BJU INTERNATIONAL I 102, 1123-1132 I doi:10.1111i'j.14E4-410X.2flDB.D79D7.x
`NO CLAIM TO ORIGINAL US GOVERNMENT WORKS
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2089 - 0001
`
`

`
`COMPARISON OF FESOTERODINE AND TOLTERODINE IN PATIENTS WITH OM;
`
`patients with OAB in a phase III study that
`also included tolterodine ER 4 mg as an active
`control [5]. The purpose of the present post
`hoc analysis was to compare the effects
`of the maximum recommended doses of
`
`fesoterodine (8 mg] and tolterodine ER [4 mg]
`on OAB symptoms and HROoL in patients
`with OAB, both in all patients and only in
`those who were incontinent at baseline.
`
`PATIENTS AND METHODS
`
`This is a post hoe analysis of data from a
`multicentre, double-blind, double-dummy,
`placebo-controlled trial; details of the study
`design were published previously [6]. Eligible
`patients [218 years old} with frequency and
`urgency or urgency urinary incontinence
`[UUI] were randomized to placebo.
`fesoterodine 4 or 8 mg, or tolterodine ER
`4 mg for 12 weeks. Because the purpose of
`this analysis was to compare the efficacy
`of the highest recommended doses of
`fesoterodine [8 mg] and tolterodine ER
`(4 mg], only data from these two groups and
`the placebo group are reported here.
`
`Patients were randomized and the process
`administered by Schwarz BioSciences
`[Monheim, Germany] according to a
`computer-generated schedule anticipating a
`balancing of treatments [equal proportions
`for placebo, fesoterodine 4 and 8 mg, and
`tolterodine ER 4 mg] across countries and
`sites. After successfully completing visit 2,
`patients were consecutively randomized to
`one of four treatment arms and assigned
`sequential randomization numbers. which
`served as a basis for packaging the trial
`medication. Placebo tablets were identical in
`
`appearance to fesoterodine 4 and 8 mg
`tablets; placebo capsules were identical to
`tolterodine ER 4 mg capsules.
`
`Men and women aged 218 years with OAB
`syndrome for 26 months were eligible to
`participate in this study. This included urinary
`frequency (zeight voids,l24 h). and urinary
`urgency (zsix episodes during the 3-day diary
`period] or UUI [zthree episodes during the 3-
`day diary period). To ensure enrolment of a
`sufficient number of patients with UUI [pre-
`specified in the protocol to be 80% of each
`treatment group], the protocol was amended
`shortly after the start of the trial to require
`Zthree UUI episodes to be recorded in the 3-
`day diary at the end of the placebo run-in for
`all remaining patients [6]. Also, patients had
`
`to report at least moderate bladder problems
`on a six-point Likert scale.
`
`Exclusion criteria included the presence of
`lower urinary tract pathology that could, in
`the investigator's opinion, be responsible for
`urgency or Ul (e.g. significant stress Ul.
`urolithiasis, interstitial cystitis, urothelial
`tumours]; pelvic organ prolapse grade 2|||;
`clinically relevant BOO; a postvoid residual
`urine volume of>1OO mL; polyuria (>3 Lf
`24 h]; symptomatic or recurrent UT|s; current
`treatment with antimuscarinic agents; a
`neurogenic cause for OAB; clinically relevant
`arrhythmia, unstable angina, or a OTcB
`interval of >500 ms; and current treatment,
`or treatment within the past 4 weeks, with
`electrostimulation or bladder training [6].
`
`Efficacy was assessed from the 3-day bladder
`diaries, which were completed before
`randomization and at 2,8 and 12 weeks after
`initiating treatment. The primary efficacy
`endpoint was voiding frequeneyf24 h. Co-
`primary endpoints included UUI episodes]
`24 h (assessed only in patients who were
`incontinent at baseline] and treatment
`response (a yeslno variable derived from a
`four-point Treatment Benefit Scale] [7].
`Secondary efficacy endpoints included mean
`voided volume [MVV] per void, urgency
`episodes,l'24 h, continent daysfweek (data
`normalized from the 3-day bladder diary;
`assessed only in patients who were
`incontinent at baseline], severity of urgency,
`and severe urgency plus UUI [assessed only in
`patients who were incontinent at baseline].
`Patients recorded the time of each urgency
`episode and void, W, and the severity of
`urgency, as 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
`
`wetting myself‘); and 4 (severe; ‘could not
`postpone micturition, had to rush to the toilet
`in order not to wet myself‘).
`
`HFlOoL was assessed using the King's Health
`Questionnaire [KHO] [8], the International
`Consultation on Incontinence Questionnaire-
`
`Short Form [ICIO-SF} [9]. and a six-point Likert
`scale assessing the severity of bladder-related
`problems. The KHD comprises nine domains;
`scores range from El (best outcome] to 100
`(worst outcome]. A negative change from
`baseline indicates improved HROoL. Changes
`in KHO domain scores of 25 points (minimally
`important difference] are considered to be
`
`(3 2003 BJU INTERNATIONAL
`NO CLAIM TO ORIGINAL US GOVERNMENT WORKS
`
`meaningful for the patient [10]. The ICIO-SF
`assesses urinary frequency, urine leakage, and
`the effects these symptoms have on daily life;
`scores range from 0 [low bother) to 21
`[maximum bother]. The patients‘ bladder
`condition was assessed by responding on the
`following six—point Likert scale: ‘My bladder
`causes me no [0], very minor [1], minor [2],
`moderate [3], severe [4], or very severe [5]
`problems.‘ A decrease of 22 points on this
`scale was considered a major improvement.
`
`A post hoc inferential analysis was performed
`for the full-analysis set population [i.e.
`all randomized patients receiving trial
`medication for whom a baseline and double-
`blind treatment measure was obtained
`
`for primary, co-primary, and secondary
`endpoints]. Parametric assessment was by
`analysis of covariance with treatment and
`region as factors and baseline value as a
`covariate; nonparametric analysis was
`conducted using the Wileoxon rank—sum test.
`Patients completed the KHO, the ICIO-SF, and
`the bladder condition six-point Likert scale at
`baseline and end of the study. All efficacy and
`patient-reported outcomes were also assessed
`in a subgroup of patients who were
`incontinent at base|ine.Additiona||y, the least-
`squares [LS] mean changes from baseline to 2,
`8 and 12 weeks were determined for voiding
`frequency and UUI episodes.
`
`RESU LTS
`
`Of 1135 patients enrolled in the parent study.
`1132 took study medication (placebo, 283;
`fesoterodine 4 mg, 272; fesoterodine 8 mg,
`287; tolterodine ER 4 mg, 290). Most patients
`were women [80010] and white [>950/n], with a
`mean [SD] age of 57 [14] years. The mean time
`since first diagnosis or onset of OAB was
`8-9 years, and 80% of patients were
`incontinent at baseline.
`
`There were treatment-related improvements
`in the diary variables designated as primary
`and co-primary endpoints as early as 2 weeks
`after the start of the study, the first clinical
`evaluation, that were sustained at 8 weeks
`and through to the end of the study (Fig. 1).
`Both the fesoterodine and tolterodine ER
`
`groups had significant LS mean changes from
`baseline for voiding frequency and the
`number of UUI episodes,l24 h vs placebo at all
`time points.
`
`At the end of the study, treatment with
`fesoterodine 8 mg resulted in statistically
`
`1129
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2089 - 0002
`
`

`
`FIG. 2. Median percentage change in: the number of
`{Al voids and {B} UUI episodes {assessed only in
`those who were incontinent at baseline} per 24 h
`from baseline to the end of treatment," and {C}
`treatment response at the end of treatment for
`placebo, tolterodine ER 4 mg, and fesoterodine 8 mg
`for all patients and those who were incontinent at
`baseline. ‘P < 0.001 vs placebo; +P < 0.05 vs placebo,‘
`FESO, fesoterodine; TOL ER, tolterodine ER.
`
`A
`
`Placebo
`
`TOL ER 4 mg
`
`FESO 8 mg
`
`ChangeinNumberofMicturitionsper24h
`MedianPercentage
`
`
`1 All Subjects 1 lncontinent Subjects
`
`Placebo
`
`TOL ER 4 mg
`
`FESO 8 mg
`
`B M
`
`0
`
`3'‘:
`g E
`% ‘g_ -25
`S 33
`
`§ § -50
`E E
`E 5 -75
`“E? i’
`E " -100
`
`En-IAPPLE ET AL.
`
`FIG. 1. L5 mean change from baseline in voiding
`frequency among {A} all patients and {5} patients
`who were incontinent at baseline,’ and (C) in UUl
`episodes among those lncontinent at baseline.
`‘P <0.05 vs placebo.
`
`A
`
`All Subjects
`
`—-— Placebo
`2
`-9-TOL ER 4 mg
`.9
`_._ FESO 8 mg
`"g 9 12 *\
`.3 E
`u.
`I
`ia “
`r“\§
`E
`“ 5
`3.
`it
`*
`‘E E 10
`*\.*:~_./’%
`
`To
`*
`5
`BL
`2 wk
`3 wk
`EOT
`
`13
`
`9
`
`
`
`B
`
`13
`
`12
`
`,,
`E
`'2
`g g
`5 S 11
`
`lncontinent Subjects
`—-— Placebo
`—o—roL ER 4 mg
`E
`'\ —-— FESO 8 mg
`+
`I
`
`3 3 10
`3
`E
`Z
`9
`
`l
`BL
`
`5\;‘
`*
`0
`5
`I
`lfil
`$-
`2 wk
`8 wk
`EOT
`
`C
`
`5
`
`FlG. 3. L5 mean change in: (A) MW/void, (8) number
`of continent days/week {assessed only in patients
`who were incontinent at baseline; data extrapolated
`from 3-day diary}; and the median percentage
`change in {C} the number of urgency episodes, and
`{D} severe urgencyplus UUI {assessed onlyin patients
`who were incontinent at baseline} from baseline to
`the end of treatment for placebo, tolterodine ER
`4 mg, and fesaterodine 8 mg for all pa tients and
`those who werelncontlnentotbaseline. ‘P < 0.001 vs
`placebo; +P <0. 05 vs placebo.
`
`A
`
`‘All Subjects 1 lncontinent Subjects
`
`P< 0.05
`
`P<0.05
`
`..
`
`
`
`Placebo
`
`TOL ER 4 mg FESO a mg
`
`1|nconti'nent Subjects
`
`P < 0.05
`
`'
`
`40
`E‘
`E5 30
`.5
`35'.
`20
`
`‘IO
`0
`
`56 5
`
`U E
`
`fl
`B
`
`E g 4
`E %
`‘E 83" 9U
`
`Eli 2
`
`P< 0.001
`
`,
`
`P< 0.05
`
`100
`80
`
`_
`Ec:
`EL
`at
`E}
`3'5 ¥ 50
`‘ §
`E
`4o
`E¢
`
`20
`
`Placebo
`
`TOL ER 4 mg FESO 8 mg
`
`[Fig. 2B], MWlvoid [Fig. 3A], continent days!
`week (Fig. 3B}, and severe urgency plus UUI
`[Fig. 3C].
`
`Scores from the KHC1 and |C|O—SF showed a
`
`significant improvement in HROoL for the
`groups treated with fesoterodine 8 mg and
`tolterodine ER vs placebo [Table 1). The
`fesoterodine B-mg dose produced statistically
`significant improvements over placebo on
`
`lncontinent Subjects
`—-— Placebo
`—o—TOL ER 4 mg
`—-— FESO 3 mg
`
`=3
`
`I +
`
`BL
`
`2 wk
`
`1
`J.-i—
`go4.
`I-
`8 wk
`
`EOT
`
`4
`
`LU
`
`
`
`NumberofUUIepisodesper24hours
`
`significant median percentage
`improvements of OAB symptoms compared
`with placebo, including voiding frequency]
`24 h (Fig. 2A). UUI episodes] 24 h (Fig. 2B],
`treatment response [Fig. 2C], MWlvoid
`[Fig. 3A], continent dayslweek (Fig. 3B},
`urgency episodesl24 h (Fig. 3C], and severe
`urgency plus UUI [Fig. 3D). Treatment with
`tolterodine ER also produced significantly
`greater improvements than with placebo
`for most efficacy variables, confirming the
`sensitivity of the study design [Figs 2,3}.
`
`By the end of treatment, fesoterodine 8 mg
`was significantly better than tolterodine
`ER 4 mg in improving several important
`endpoints, including UUI episodes,'24 h
`
`1130
`
`Placebo
`
`TOL ER 4 mg
`
`FESO 8 mg
`
`65
`
`‘.3 1
`§ 5
`9 “5 O
`
`C
`
`1 lncontinent Subjects
`
`C
`
`I All Subjects 1 lncontinent Subjects
`
`3 -5
`.5 ‘E
`
`0
`
`Placebo TOL ER 4 mg FESO 8 mg
`
`g E -10
`u ‘E5‘ |.|.I
`g 5-15
`15 5
`= u.
`an: DE‘ -20
`.2 ° -25
`
`J‘
`
`o
`
`.
`
`1A|| Subjects 1|ncontinent Subjects
`
`E
`
`U
`
`Placebo TOL ER 4 mg FESO 8 mg
`
`+
`
`P < o.os ’
`
`
`
`inSevereUrgencyEpisodesper24h LO
` MedianPercentageChange
`
`
`
`C
`
`é -
`
`50
`
`1|ncorrtinerrt Subjects
`
`© 2003 BJU INTERNATIONAL
`N0 CLAIM T0 UR|GlNAL US GOVERNMENT WORKS
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2089 - 0003
`
`

`
`COMPARISON OF FESOTERODINE AND TOLTERODINE IN PATIENTS WITH Ol-‘(Ia
`
`TABLE I A summaryofHROol.,' the mean changes from baseline for the KHO and lClO-SFfor all patients
`and for incontinent patients only
`
`lnstrumentidomain
`No. of patients
`KHO
`
`Severity [coping]
`Emotions
`Role limitations
`
`Physical limitations
`Social limitations
`
`Sleeplenergy
`Personal relationship
`Incontinence Impact
`General health
`ICICI-SF
`
`Patients
`All
`
`Placebo
`279
`
`-9.0
`-10.1
`-11.8
`
`-11.4
`-8.?
`
`-9.5
`-8.2
`-16.1
`-3.8
`-2.55
`
`TOL ER
`283
`
`-12.6“
`-16.3‘
`-22.1“
`
`-19.7“
`-14.1’
`
`-11.7
`-10.4
`-23.3’
`-4.3
`-3.95’
`
`FESO
`275
`
`-14.0“
`-114*
`-21.7‘
`-21.7’
`—1s.4*
`-13.5’
`-11.9“
`—24.e*
`-4.0
`-4.41*
`
`incontinent at baseline
`Placebo
`TOL ER
`203
`213
`
`FESO
`217
`
`-10.3
`-11.3
`-12.4
`-11.1
`-9.5
`-10.4
`-5.3
`-17.7
`-5.5
`-3.12
`
`-14.9’
`-113*
`-23.2‘
`-20.5’
`-151*
`-12.5
`-12.7*
`-23.a*
`-4.5
`—4.56*
`
`-15.3’
`-135*
`-23.7‘
`-23.3’
`—16.2*
`-15.3‘
`-12.3
`—2B.5*
`-4.3
`—5.29*
`
`FESO, fesoterodine; TOL ER, tolterodine ER. ‘P <0.05 vs placebo.
`
`TABLE 2 Treatment-related‘ adverse events occurring in 22% ofpa tients and more frequently than with
`placebo, as n (912)
`
`Adverse event
`
`No. of patients
`Dry mouth
`Constipation
`Dry eye
`Nasopharyngitis
`Fatigue
`Dry throat
`Increased alanine aminotransferase
`Nausea
`
`Placebo
`
`283
`20 [7.1)
`4 (1.4)
`0
`7 (2.5)
`1 [<1)
`0
`1 (<1)
`1 (<1)
`
`Tolterodine ER 4 mg
`290
`
`Fesoterodine 3 mg
`237
`
`49 (16.9)
`s (2.3)
`1 (<1}
`10 13.4]
`1013.4)
`3 (1)
`0
`6 [2.1)
`
`97 [33.Bl
`13 (4.5)
`12 (4.21
`5 (1.7]
`1 (<1)
`13 (2.3)
`6 (2.1)
`4 (1.4)
`
`eight of the nine domains assessed, including
`SleeplEnergy and Personal Relationships.
`By comparison, tolterodine ER-treated
`patients reported statistically significant
`improvements over placebo in six of nine KHO
`domains. Both fesoterodine 8 mg and
`tolterodine ER treatment resulted in a 25-
`
`point improvement from baseline, which
`constitutes a meaningful change for the
`patient [10], for all domains except General
`Health. A major improvement in the severity
`of bladder-related problems from baseline to
`the end of treatment was reported by 39% of
`fesoterodine 8 mg and 340/0 of tolterodine ER
`patients [P= 0.01 for both groups vs placebo),
`compared with 25% on placebo. The results
`were similar in patients who were incontinent
`at baseline (Table 1).
`
`Adverse events reported in 22% of patients in
`the active-treatment groups and occurring
`
`more frequently than placebo included dry
`mouth, constipation, dry eye, dry throat, and
`elevated levels of alanine aminotransferase
`
`(Table 2]. More patients treated with
`fesoterodine 8 mg had dry mouth than those
`receiving tolterodine ER or placebo. Most
`cases of dry mouth were mild or moderate;
`3% of patients on fesoterodine 8 mg reported
`severe dry mouth. Similarly, more patients on
`fesoterodine 8 mg reported constipation than
`those receiving tolterodine ER or placebo;
`most cases were mild to moderate.
`
`Overall, 3.20/0 of patients discontinued the
`study prematurely because of an adverse
`event: placebo, 2%; tolterodine ER 4 mg, 3%;
`fesoterodinelil mg, 5°/o.Among the reasons for
`discontinuation was urinary retention, which
`occurred in 1% of patients in the fesoterodine
`B—mg group, and required catheterization in
`one patient; no patients receiving tolterodine
`
`(3 2003 BJU INTERNATIONAL
`NO CLAIM TO ORIGINAL US GOVERNMENT WORKS
`
`ER or placebo discontinued due to urinary
`retention, and none required catheterization.
`Although the incidence of dry mouth in the
`fesoterodine 8 mg group was higher than that
`in the tolterodine ER group, only one patient
`[<10/n) in either group withdrew because ofdry
`mouth. One patient [0.3%] in the fesoterodine
`8-mg group discontinued because of
`constipation; no patients in the tolterodine ER
`or placebo groups discontinued because of
`constipation.
`
`DISCUSSION
`
`This post hoc analysis of bladder diary
`variables from a phase III trial [6] shows that
`the maximum recommended dose of
`
`fesoterodine [8 mg] is significantly more
`effective than the maximum recommended
`
`dose of tolterodine ER [4 mg) in improving
`several important OAB outcomes, including
`incontinence, MW/void, number of continent
`dayslweek, and severe urgency plus UUI.
`Urgency, incontinence, and MW are three of
`five bladder variables that have been shown
`
`to be central to OAB [11]. Numerical
`differences in favour of fesoterodine 8 mg on
`the other endpoints [voiding frequency,
`number of urgency episodes;'24 h, and rate of
`treatment response) were not statistically
`significant. It is possible that the total number
`of urgency episodes was not statistically
`significant because the urgency measurement
`scale used in this trial did not include UUI, the
`ultimate expression of urgency.
`
`In the present study, treatment with
`tolterodine ER provided significantly greater
`improvements than placebo for most
`efficacy variables, confirming the sensitivity
`of the study design. The magnitude of the
`improvement in OAB symptoms with
`tolterodine ER was generally consistent
`with that reported in previous trials
`[12—14].
`
`Because HROOL is thought to be worse in
`patients with UUI than in those who have
`urgency only, it might be expected that HROoL
`improvements with treatment would be
`greater in patients who were incontinent at
`baseline. However, a subanalysis of patients
`incontinent at baseline revealed no apparent
`differences on HRQOL or bladder diary
`variables between this group and the overall
`study population. These findings suggest that
`all OAB symptoms, not just incontinence, can
`be bothersome and can diminish the HRQOL
`
`of those affected [15-17].
`
`1131
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2089 - 0004
`
`

`
`[cl-IAPPLE ET AL.
`
`Although the incidence of dry mouth with
`fesoterodine 8 mg (34%) was higher than that
`with tolterodine ER 4 mg 117%], the related
`discontinuation rate was low and similar. Only
`one patient in each ofthe fesoterodine 8 mg
`and tolterodine ER groups discontinued the
`trial because of dry mouth. This suggests that
`most cases of dry mouth did not bother
`patients enough to discontinue (indeed, most
`cases were categorized as mild or moderate).
`The incidence of constipation in the
`fesoterodine 8-mg group 14.5%] was higher
`than in the tolterodine ER 4 mg group [2.8%].
`
`Limitations of the present study include that
`this was a post hoc analysis of a study which
`was not powered for a comparison between
`active treatments or for HRCloL; prospective
`studies are currently underway. Another
`shortcoming of the study is the urgency
`classification; there is no consensus on
`whether to measure urgency by episodes or
`with a graduated scale, and whether UUI
`should be a part ofthe urgency continuum or
`a discrete event. The scale used in this study
`allowed for four choices, i.e. none, mild,
`moderate, or severe urgency. Ratings of mild,
`moderate and severe were equally counted as
`urgency episodes, which was suboptimal. A
`separate assessment of category 4 urgency
`combined with UUI episodes (Fig. 20] clearly
`shows that not only was this urgency
`(characteristic of OAB] significantly reduced
`by active therapy, but that fesoterodine 8 mg
`was more effective than tolterodine ER on
`
`this endpoint. The use of different methods to
`document urgency makes it difficult to
`compare the present results to previously
`published tolterodine ER studies.
`
`In conclusion, both fesoterodine 8 mg and
`tolterodine ER are safe and well tolerated.
`and they provide statistically significant
`improvements in OAB symptoms and
`HROoL. The maximum recommended dose
`
`of fesoterodine (8 mg} provides additional
`benefit compared with the maximum
`recommended dose of tolterodine ER [4 mg)
`on several important endpoints, including
`reduction in UUI episodes and increase in
`MW,r'void, thus offering an alternative
`treatment option for patients with OAB.
`
`ACKNOWLEDGEMENTS
`
`Funding for this study was provided by
`Schwarz BioSciences GmbH and Pfizer Inc.
`
`Editorial assistance was provided by Linda
`Merkel, PhD, from Complete Healthcare
`
`1132
`
`Communications, Inc., and was funded by
`Pfizer Inc.
`
`CONFLICT OF INTEREST
`
`Philip E. Van Kerrebroeck and Christopher R.
`Chapple are Study Investigators funded by the
`Sponsor, and Joseph T. Wang and Marina
`Brodsky are Employees of the Sponsor.
`
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`Correspondence: Christopher Chapple,
`Honorary Professor of Urology, Sheffield
`Hallam University, Glossop Road, Sheffield
`S10 2 JF, UK.
`e-mail: c.r.chapp|e@shef.ac.uk
`
`Abbreviations: OAB. overactive bladder;
`5-HMT, 5-hydroxymethyl tolterodine; CYP,
`cytochrome P; ER, extended-release; HRQOL,
`health-related quality of life; [U)U|, [urgency]
`urinary incontinence; LS, least squares; MW,
`mean voided volume; |C|0—SF, International
`Consultation on Incontinence Questionnaire-
`
`Short Form; KHC1, King’s Health Questionnaire.
`
`© 2005 BJU INTERNATIONAL
`NO CLAIM TD ORIGINAL US GOVERNMENT WORKS
`
`Patent Owner, UCB
`
`Pharma GmbH — Exhibit 2089 - 0005